Category Archives: Medicine

Neuroprotection with Taurine in a Parkinson’s Model System

“There is no medicine like hope, no incentive so great, and no tonic so powerful as expectation of something tomorrow.” Orison Swett Marden

“Hope sees the invisible, feels the intangible, and achieves the impossible.” Helen Keller

Introduction: Many of us take levodopa/carbidopa for substantial symptomatic relief; however, this dopamine replacement treatment only relieves symptoms without offering either neuroprotection or neuro-restoration. We are still anxiously waiting for the study to be released that announces “We describe a new Parkinson’s compound and we’ve nicknamed it hopeful, helpful, and protective“.   Today’s post will review an interesting paper from Yuning Che and associates in Dalian, China recently published in Cell Death and Disease (open access, click here to download paper).  The ‘hopeful’ neuroprotective compound is the amino sulfonic compound taurine.  Before we get lost in all of the possibilities, let’s discuss the science and see what they describe, ok? First, we begin with some background.

Screenshot 2018-04-02 09.55.23

“I truly believe in positive synergy, that your positive mindset gives you a more hopeful outlook, and belief that you can do something great means you will do something great.” Russell Wilson

Neuroinflammation and Oxidative Stress are Pathological Processes that  Promote the Development of Parkinson’s:   Parkinson’s is a neurodegenerative disorder where we lose dopamine-producing neurons in the mid-brain substantia nigra.   There are several pathological patterns known to contribute to the development of Parkinson’s as highlighted below.  Related to this post is the negative-effect contributed by long-term neuroinflammation and oxidative stress.

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“It’s hope as a decision that makes change possible.” Jim Willis

Macrophages in the Brain are Called Microglia Cells:  In many instances, the body initiates and uses the pro-inflammatory machinery as a host-defense response; in other words, we use it to protect ourselves.  When it gets highjacked and becomes detrimental to be host, we realize the sheer firepower of our inflammatory system.  The good-and-the-bad of inflammation is mediated primarily by the cells named neutrophils (along with the eosinophils and basophils), monocytes and macrophages.  The monocyte leaves the bloodstream and migrates to various organs/tissues where it can ‘mature’ into a macrophage, which is a ‘field commander’ type-of-cell.  Think of a macrophage as a General in the bunker of a battlefield, not only giving detailed marching orders but they are also leading the charging brigade of soldiers.  Macrophages in the brain are named microglia cells .  First, macrophages (microglia cells) are ‘phagocytic’ cells that are capable of engulfing foreign-damaged-invading substances/cells (phagocyte comes from the Greek phagein, “to eat” or “devour”, and “-cyte”, the suffix in biology denoting “cell”).  Second, macrophages (microglia cells) direct the inflammatory response by releasing all kinds of substances that give other inflammatory/immune cells their instructions.  Sometimes these cells and their instructions become bad to the neighboring tissue/organs; in our case, the dopamine-produing neurons in the midbrain.

activated_microgliaMicroglia-mediated neuroinflammation(Figure credit): Various substances initiate contact with resting unstimulated microglia cells.  This ‘activates’ the microglia cell into an cell of considerable fire-power by producing and releasing many substances [nitric oxide (NO), reactive oxygen species (ROS),  and several inflammatory cytokines (e.g., IL-1, IL-6, and  TNF-alpha)]. This collection of pro-inflammatory substances secreted by the activated microglia cells creates a hostile microenvironment that promotes neuronal cell dysfunction and potential death to the cell.

Depending on the need and response of the ‘environmental challenge’, macrophages (microglia cells) can be activated to become either ‘M1’ (focused on becoming a pro-inflammatory) microglia cell or ‘M2’ (transforms into an anti-inflammatory) microglia cell [see Figure below, credit].  In the setting of an invasion or infiltration by microbes, you would want the microglia cell to be activated to a M1 state’ they could attack, engulf and kill the invading microorganism. In this setting, the M1 microglia cell would be protective of you. By contrast, the role of M2 microglia cells would be to turn-off the resultant pro-inflammatory response.  This implies that long-term inflammatory events that promote inappropriate M1 microglia cell activation could lead to dysfunction and even cell/tissue death. This description of appropriate/inapproriate microglia cell activation illustrates the complex nature of these inflammatory cells. What this says is in Parkinson’s, chronic activation to M1 microglia cells could generate a detrimental neuroinflammatory environment able to attack host cells/tissues.

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“It is difficult to say what is impossible, for the dream of yesterday is the hope of today and the reality of tomorrow.” Robert H. Goddard

Taurine: Taurine is an amino sulfonic compound (many erronously use the term amino acid) and it is considered to be a conditionally essential nutritient.  We do not use taurine in the assembly of proteins from genes; however, it participates in several physiological systems.  Taurine is apparently a popular additive/supplement in many different energy drinks.  Both WebMD (click here) and the Mayo Clinic (click here) have posted overviews of taurine and consider it mostly safe.  The structure of taurine is shown below (credit). Taurine is found in the brain, heart, muscle and in many other organs.  Good sources of dietary taurine are animal and fish proteins. An interesting overview for using taurine to stay healthy and to promote longevity has recently been posted (click here). Taurine has many proposed physiological functions that range from neurotransmitter to cell anti-oxidant, from anti-inflammatory to enhancing sports performance.  The ‘problem’ with having a multi-talented substance like taurine is actually studying these diverse functions individually and trying to test them in rigorous scientific studies, which leads us (finally!) to the paper introduced at the beginning.

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“Hope is the mainspring of life.” Henry L. Stimson

Taurine protects dopaminergic neurons in a mouse Parkinson’s disease model through inhibition of microglial M1 polarization: Here are some key aspects to this  study:

  • It is becoming more evident that neuroinflammation and oxidative stress are likely key participants to the development of Parkinson’s.
  • Surrounding the substantia nigra are a lot of unactivated microglia cells, which when activated to become M1 microglia cells they secrete several cytotoxic compounds that can easily harm or kill dopaminergic-producing neurons.
  • In particular, these neurons are susceptible to ‘injury’ due to their low antioxidant potential, low levels of calcium, increased amounts of iron, and the oxidation-susceptible dopamine.
  • Taurine has been shown in several reports to be a neuromodulating substance, boosting intracellular levels of calcium, anti-oxidant, and anti-inflammatory.
  • A recent report linked motor severity in Parkinson’s to low levels of taurine in blood plasma.
  • The authors tested a hypothesis that the supplementation with exogenous taurine might be neuroprotective in a Parkinson’s model sy\stem.
  • Previous studies have revealed a neuroprotective role for taurine in both glutamate-induced and hypoxic-ischemic brain models.
  • They used a mouse model of Parkinson’s caused by injection with paraquat and maneb [(P + M) a two-pesticide model of Parkinson’s], which showed progressive dopaminergic neurodegenera-
  • tion, gait abnormality and α-synuclein aggregation.
  • Taurine treatment protected the mouse from the detrimental effect of  P + Mu.
  • Their results revealed three effects of taurine in the P + M model of Parkinson’s (i) inhibition of microglia cell activation; (ii) reduced M1 microglia cell polarization; and (iii) reduced activation of cellular NOX2 and nuclear factor-kappa B (NF-κB).

“Losing the possibility of something is the exact same thing as losing hope and without hope nothing can survive.” Mark Z. Danielewski

Overview of Some of Their Results: Figure 1 presents the effect of P + M to promote a pathological state that resembles Parkinson’s.  Panels 1A and 1B show the loss of dopaminergic neurons by the staining of the brain with an antibody to tyrosine hydroxylase (a major dopaminergic neuron protein) following P + M injection.  Panels !C and 1D show that P + M treatment lead to expression of the toxic olgiometic α-synuclein.  Not shown here, but P + M treatment resulted in displayed abnormal gaits (Figure 2 in the paper). Screenshot 2018-04-05 11.18.39

Taurine protected against P + M-mediated neurotoxicity.  Using the same tests as done in Figure 1 above, taurine preserved neurons even with P + M present (Figure 3 panels A and B) and taurine reduced expression of oligomeric α-synuclein in the presence of P + M (Figure 3 panels C and D).  Not included here, the protective effects of taurine during P + M treatment was partly due to the inhibition of migroglia cell-mediated chronic inflammation.  Furthermore, the ability of microglia cells to become  ‘polarized’ or activated to either M1 (pro-inflammatory) or M2 (anti-inflammatory) was also studied in the presence of taurine plus P + M-treatment.  Both M1 and M2 microglia cells are present in the mid-brain of the mice treated with P + M; interestingly, taurine treatment reduced expression levels of damaging M1 microglia cell products (results not included here).  Finally, two key M1-linked gene products were studied, NOX2 and NF-kB.  They found that taurine was able to reduce expression of both NOX2 and NF-kB, which indicates that taurine blocked these key products important for neuroinflammation (NOX2) and polarization of the M1 microglia cell-type (NF-kB)

Screenshot 2018-04-05 11.37.57

“The present is the ever moving shadow that divides yesterday from tomorrow. In that lies hope.” Frank Lloyd Wright

What do these results show? (1) In an interesting model of Parkinson’s, taurine showed  a potent benefit to the mice; (2) taurine reduced loss of dopamine-producing neurons in P + M mice; (3) taurine reduced oligomeric α-synuclein in P + M mice; (4) taurine treatment reduced neuroinflammation by suppressing M1 microglia cells to suggest a neuroprotectice effect; and finally, (5) taurine reduced expression of both NOX2 and NF-kB,  important genes for microglia cell activation. A similar neuroprotective effect was also found for taurine in an experimental model of Alzheimer’s disease, which resulted in improved coognitive ability. The Parkinson’s model clearly suggests that disease progression by P + M treatment is promoted by chronic neuroinflammation and M1-type microglia cells.  Under the test conditions used, taurine was shown to convincingly reduce dopamine-producing neuronal cell degeneration in the presence of the pesticides P + M.

What do these results suggest? There is still much to learn about taurine. There is much potential to taurine being neuroprotective.  However, there have been other seriously–convincing-positive mouse model results with other compounds that failed miserably in human clinical trials.  The data shown here uses an interesting mouse model of Parkinson’s with a simple yet elegant and solid set of data (that does not appear to be overly interpreted).  Taurine has been shown to be safe in treating other human maladies (diabetes and cardiovascular disease).  The results here are hopeful that taurine could provide neuroprotection in human Parkinson’s. Hopefully, clinical trials will be started somewhere soon to determine the ability of taurine to provide neuroprotection in human Parkinson’s disease.

“Every one of us is called upon, perhaps many times, to start a new life. A frightening diagnosis, a marriage, a move, loss of a job…And onward full-tilt we go, pitched and wrecked and absurdly resolute, driven in spite of everything to make good on a new shore. To be hopeful, to embrace one possibility after another–that is surely the basic instinct…Crying out: High tide! Time to move out into the glorious debris. Time to take this life for what it is.” Barbara Kingsolver

Cover photo credit: wallpaper/nature/1024×768/Dawn_skies_over_Gulf_of_St._Lawrence_Prince_Edward_Island_Canada_1024x768.jpg

Dopamine Agonist Withdrawal Syndrome (DAWS) in Parkinson’s

“Some remedies are worse than the disease.” Publilius Syrus

“Each patient carries his own doctor inside him.” Norman Cousins

Summary: Dopamine agonists are widely used in the treatment of Parkinson’s, especially as a first-line therapy. Some patients on a dopamine agonist experience side-effects that require either tapering or discontinuation of the drug.  First described in 2010, dopamine agonist withdrawal syndrome (DAWS) is a complication of ~20% of Parkinson’s patients who are either lowering or stopping the dopamine agonist.  DAWS presents as a cluster of physical and behavioral symptoms [e.g., agitation, depression, drug craving, and panic attacks (to give a few possible symptoms)]. There is no known standard-of-care in dealing with DAWS in Parkinson’s. Presented here is a brief overview of DAWS in Parkinson’s including dopamine agonists, clinical description, risk factors and prevalence, mechanism of action, treatment/management, and key publications.

“To heal illness, begin by restoring balance.” Caroline Myss

Dopamine agonists (DA): Dopamine agonists are ‘mimics’ of dopamine that pass through the blood brain barrier to interact with target dopamine receptors. Symptomatic treatment of Parkinson’s remains dopamine replacement, including the DA’s.  Dopamine agonists are frequently the first line of choice for therapy for the just diagnosed Parkinson’s patient. Dopamine agonists do help control motor symptoms in Parkinson’s although there can be significant side-effects (see Table below). Also below is a Table describing DA’s. The DA side effects can become intolerable for some people-with-Parkinson’s, and the decision to taper or withdraw the DA is made. Or maybe you’re a candidate for deep-brain stimulation (DBS) surgery and to calibrate the device you’ll be asked to stop your Parkinson’s medication for a short period of time.

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18.01.03.DA+DAWS

“I enjoy convalescence. It is the part that makes the illness worth while.” George Bernard Shaw

First report of dopamine agonist withdrawal syndrome (DAWS): Dopamine agonist withdrawal syndrome (DAWS) was first described in 2010 by Rabinak and Nirenberg on five of their patients with non-motor impulse control behavioral disorders (ICD) caused by the DA; thus, they were tapered. Two patients were further described in this publication. The first patient was a 67-year-old woman with a six year history of Parkinson’s, and she had been taking various drugs including a DA. She had developed a difficult ICD, and they elected to taper the DA; unexpectedly, she then had severe anxiety and dysphoria. They tried an increase in carbidopa/levodopa and they used other therapy for cognitive behavior control; to no benefit to the patient. They changed her back to the original DA dose and she had a rapid and dramatic improvement in all of her symptoms. This patient continues to use the DA and remains with the difficult ICD.

Patient #2 was a 61-year-old woman with a six-year history of Parkinson’s and likewise an ICD prompted by the DA; she began a DA tapering with increased carbidopa/levodopa medication.  During the DA taper, she developed depression and severe anxiety and became agitated; she also had fatigue and insomnia.  As with Patient #1, adding back the DA improved all of her non-motor symptoms. It took several years for her to successfully reduce her DA doseage. The figure below visually highlights some of the key symptoms of DAWS.

18.01.04.DAWS_faces

What both cases shared were prominent psychiatric symptoms, poor response to both additional carbidopa/levodopa (to take the place of the DA) and psychiatric medication; however, both had rapid improvement in their ‘new symptoms’ when placed back on the DA. The majority of DAWS symptoms are presented in the the Table below.Document5“The secret of learning to be sick is this: Illness doesn’t make you less of what you were. You are still you.” Tony Snow

Risk-factors and prevalence of DAWS: Since the original study in 2010, there have been several follow-up studies on DAWS. Some of the studies speculated that a large DA dose in the presence of pre-existing ICD are the most important risk factors for DAWS. The ‘number’ talked about frequently is something called the ‘levodopa equivalent daily dose’ (LEDD) of the dopamine agonist, where it has been suggested that >150 mg was linked to an increased risk of DAWS. Use this on-line program to calculate your LEDD (click here).  Here is an LEDD example: someone taking 14 mg ropinirole/day (with the online algorithm), the LEDD would be 280 mg daily.  What? OK, so what did you say?  This means if you wanted to replace the 14 mg/day ropinirole with carbidopa/levodopa you would need about 300 mg per day of levodopa based on this calculation.  I refer you to do the papers cited at the end of the blog post for more details about LEDD. What is interesting is several of the studies have compared the taper versus total withdrawal of the DA; it does not seem to alter the risk of DAWS.  Good news is if you’re not having any detrimental side effects from the DA, just continue on and you’re good to go. The bad news is if you are having some side effects and you want to try and eliminate them by tapering down need to carefully consult with your neurologist and work up a feasible plan.  Please remember I’m a biochemist, not a physician, and I just am interpreting data from publications.

The prevalence of DAWS has been reported to be between 15 and 19% in patients with Parkinson’s; it seems to be consistently about one-in-five.  As mentioned previously, there appears to be no difference in relative risk of DAWS comparing patients that discontinue DA completely or those that reduce the DA by taper. Based on the percentage mentioned above, this says ~4 out of 5 people-with-Parkinson’s can DA taper without any problems.

“It is in moments of illness that we are compelled to recognize that we live not alone but chained to a creature of a different kingdom, whole worlds apart, who has no knowledge of us and by whom it is impossible to make ourselves understood: our body.” Marcel Proust

DA mechanism of action to cause DAWS:  To recap, DAWS occurs in a subset of patients with Parkinson’s that have had difficulties managing the side effects of a DA, and the decision has been made to remove that DA from the patient’s regimen.  The simplest notion is that you would then replace the DA with an increased dose of carbidopa/levodopa (using the LEDD); however, this is Parkinson’s and this is the brain and it’s just not going to be that easy. The diagram below summarizes a very simplistic view of dopamine and DA’s in their interactions with motor and reward pathways.  There is no doubt that in treating Parkinson’s, the replacement of dopamine is crucial for many different physiological functions in the human body. Dopamine agonists and dopamine share similar binding properties to dopamine receptors. They are very important in improving motor symptoms (through the nigrostriatal pathway) but there is also some potential detrimental crossover to the reward center (through the mesocorticolimbic pathway).  It is this minor pathway that is linked to the increased risk of ICD in some patients being treated with a DA. It is not clear, however from the data published so far that there is a difference in this 20% of the patient population in their mesocorticolimbic circuitry system with the DA in comparison to the other 80% of the population.  In summary, what causes DAWS during DA tapering is not well understood.18.01.07.Dopamine_Motor_Reward“Medicine is intention. Those who are proficient at using intention are good doctors.” Sun Simiao

Treatment/management of DAWS during DA taper:  DAWS is a relatively recent phenomena related to DA withdrawal.  Patients with (i) a predisposition to ICD and (ii) a larger dose of DA are apparently at increased risk of developing DAWS. There is no well-delineated treatment plan that the neurologist can follow; best recommendation (from the papers cited below) is the patient should be tapered at a very slow dose reduction over a long period of time, and see what happens. Clearly, it is crucial that the patient and the neurologist carefully evaluate signs of ICD and DAWS at every visit, especially for patients at high risk.

“The treatments themselves do not ‘cure’ the condition, they simply restore the body’s self-healing ability.” Leon Chaitow

 Summary: As someone with Parkinson’s, I’ve done a lot of reading about treatment strategies (what’s good and what’s not so good). For someone my age there would almost always be a recommendation to begin the DA (the so-called sparing one of levodopa until it’s absolutely needed) and then as symptoms progressed, you would switch over and combine the DA with carbodipa/levodopa.  Had I read the opinions of Dr. Ahlskog in the beginning, I might have opted to start with carbidopa/levodopa without the DA (Ahlskog JE. Cheaper, Simpler, and Better: Tips for Treating Seniors With Parkinson Disease. Mayo Clinic Proceedings. 2011;86(12):1211-6. doi: https://doi.org/10.4065/mcp.2011.0443). Biochemically, DAWS is an interesting problem but there needs to be additional studies to delineate the mechanism of action. Finally  DAWS clinically is worrisome and definitely not well-understood; and likely, the scope of DAWS is under-recognized.

Key References:

  1. Rabinak CA, Nirenberg MJ. Dopamine agonist withdrawal syndrome in Parkinson disease. Arch Neurol. 2010;67(1):58-63. doi: 10.1001/archneurol.2009.294. PubMed PMID: 20065130.
  2. Nirenberg MJ. Dopamine agonist withdrawal syndrome and non-motor symptoms after Parkinson’s disease surgery. Brain. 2010;133(11):e155; author reply e6. doi: 10.1093/brain/awq165. PubMed PMID: 20659959.
  3. Cunnington AL, White L, Hood K. Identification of possible risk factors for the development of dopamine agonist withdrawal syndrome in Parkinson’s disease. Parkinsonism Relat Disord. 2012;18(9):1051-2. doi: 10.1016/j.parkreldis.2012.05.012. PubMed PMID: 22677468.
  4. Pondal M, Marras C, Miyasaki J, Moro E, Armstrong MJ, Strafella AP, Shah BB, Fox S, Prashanth LK, Phielipp N, Lang AE. Clinical features of dopamine agonist withdrawal syndrome in a movement disorders clinic. J Neurol Neurosurg Psychiatry. 2013;84(2):130-5. doi: 10.1136/jnnp-2012-302684. PubMed PMID: 22933817.
  5. Edwards MJ. Dopamine agonist withdrawal syndrome (DAWS): perils of flicking the dopamine ‘switch’. J Neurol Neurosurg Psychiatry. 2013;84(2):120. doi: 10.1136/jnnp-2012-303570. PubMed PMID: 22993451.
  6. Nirenberg MJ. Dopamine agonist withdrawal syndrome: implications for patient care. Drugs Aging. 2013;30(8):587-92. doi: 10.1007/s40266-013-0090-z. PubMed PMID: 23686524.1.
  7. Nirenberg MJ. Dopamine agonist withdrawal syndrome: implications for patient care. Drugs Aging. 2013;30(8):587-92. doi: 10.1007/s40266-013-0090-z. PubMed PMID: 23686524.
  8. Solla P, Fasano A, Cannas A, Mulas CS, Marrosu MG, Lang AE, Marrosu F. Dopamine agonist withdrawal syndrome (DAWS) symptoms in Parkinson’s disease patients treated with levodopa-carbidopa intestinal gel infusion. Parkinsonism Relat Disord. 2015;21(8):968-71. doi: 10.1016/j.parkreldis.2015.05.018. PubMed PMID: 26071817.
  9. Huynh NT, Sid-Otmane L, Panisset M, Huot P. A Man With Persistent Dopamine Agonist Withdrawal Syndrome After 7 Years Being Off Dopamine Agonists. Can J Neurol Sci. 2016;43(6):859-60. doi: 10.1017/cjn.2015.389. PubMed PMID: 26842385.
  10. Patel S, Garcia X, Mohammad ME, Yu XX, Vlastaris K, O’Donnell K, Sutton K, Fernandez HH. Dopamine agonist withdrawal syndrome (DAWS) in a tertiary Parkinson disease treatment center. J Neurol Sci. 2017;379:308-11. doi: 10.1016/j.jns.2017.06.022. PubMed PMID: 28716269.
  11. Yu XX, Fernandez HH. Dopamine agonist withdrawal syndrome: A comprehensive review. J Neurol Sci. 2017;374:53-5. doi: 10.1016/j.jns.2016.12.070. PubMed PMID: 28104232.
  12. Solla P, Fasano A, Cannas A, Marrosu F. Dopamine agonist withdrawal syndrome in Parkinson’s disease. J Neurol Sci. 2017;382:47-8. doi: 10.1016/j.jns.2017.08.3263. PubMed PMID: 29111017.

“Life always gives us exactly the teacher we need at every moment. This includes every mosquito, every misfortune, every red light, every traffic jam, every obnoxious supervisor (or employee), every illness, every loss, every moment of joy or depression, every addiction, every piece of garbage, every breath. Every moment is the guru.” Joko Beck

Cover photo credit: f.fwallpapers.com/images/sun-peeking-through-snow-covered-trees.jpg

Agitation- img.aws.livestrongcdn.com/ls-article-image-400/cme/cme_public_images/www_livestrong_com/photos.demandstudios.com/49/85/fotolia_4199215_XS.jpg
Depression- http://www.scientificamerican.com/sciam/cache/file/FCD288AE-5C2E-49F2-85858FA255A8034B_source.jpg
Fatigued- www.belmarrahealth.com/wp-content/uploads/2017/03/fatigue-in-the-elderly-300×200.jpg
Panic attack- lifetimewoman.com/wp-content/uploads/2016/09/panica-1.jpg

Complementary and Alternative Medicine (CAM) and Over-the-Counter Therapies in Parkinson’s

With Parkinson’s, exercise is better than taking a bottle of pills. If you don’t do anything you’ll just stagnate.” Brian Lambert

“With Parkinson’s you have two choices: You can let it control you, or you can control it. And I’ve chosen to control it.” US Senator Isakson

Introduction: Having one of the numerous neurodegenerative disorders can be disheartening, difficult and life-threatening/ending; however, Parkinson’s remains in the forefront of treatment schemes and therapeutic options.  We may have a slowly evolving disorder, yet I remain firmly entrenched both in striking back to try-to-slow its progression and in remaining hopeful that new advances are on the horizon to throttle-back its progression.  Recently, several people have asked for an update on my strategy for treating Parkinson’s.  My plan consists of (i) traditional Parkinson’s medication,  (ii) supplemented by a complementary and alternative medicine (CAM) approach, and (iii) fueled by exercise. My philosophy is simple because I truly believe there are steps I can follow to remain as healthy as possible, which include having a positive mindset to support this effort, and to accept the axiom of the harder I try the better I’ll be.

“Life is to be lived even if we are not healthy.” David Blatt

Complementary and Alternative Medicine (CAM):The National Institutes of Health defines CAM as follows: “Complementary and alternative medicine (CAM) is the term for medical products and practices that are not part of standard medical care. ‘Complementary medicine’ refers to treatments that are used with standard treatment. ‘Alternative medicine’ refers to treatments that are used instead of standard treatment.”  Here is a nice overview of CAM (click here). The National Center for CAM (click here for NCCAM) gives five categories to broadly describe CAM (see below, and followed by some representative components for each of the 5 categories):

17.12.31.CAM_Summary

(1) Alternative medical systems include treatment by traditional Chinese medicine, Ayurveda and naturopathic medicine;
(2) Mind-body interventions like mindfulness meditation;
(3) Biologically-based therapies include over-the-counter natural products and herbal therapies;
(4) Manipulative and body-based methods describe chiropractic and massage therapies;
(5) Energy therapies include techniques such as Reiki and therapeutic touch.

“My way of dealing with Parkinson’s is to keep myself busy and ensure my mind is always occupied.” David Riley

CAM and Parkinson’s: Published CAM clinical trial studies have yielded only a sliver of positive response to slowing the progression of Parkinson’s, several were halted due to no change compared to the placebo-control group. Regardless of these ‘failed’ studies, many have embraced a CAM-based approach to managing their disorder, including me. Please remember that I’m not a clinician, and I’m not trying to convince you to adopt my strategy.  I am a biochemist trained in Hematology but I do read and ponder a lot, especially about Parkinson’s.  We know a lot about Parkinson’s and we’re learning a lot about the molecular details to how it promotes the disease.  There is not a cure although we have a growing array of drugs for therapeutic intervention.  Without a  cure, we look at the causes of Parkinson’s (see schematic below), we consider various CAM options, and we go from there (see schematic below). If you venture into adding to your portfolio of therapy, it is imperative you consult with your Neurologist/family medicine physician beforehand.  Your combined new knowledge with their experience can team-up to make an informed decision about your herb, over-the-counter compound use and its potential benefit/risk ratio.

17.12.31.PD_Cause.CAM“I discovered that I was part of a Parkinson’s community with similar experiences and similar questions that I’d been dealing with alone.”Michael J. Fox

A strategy for treating Parkinson’s: The treatment plan I follow uses traditional medical therapy, CAM (several mind-body/manual practices and numerous natural products) and the glue that ties it all together is exercise.  Presented here is an overview of my medical therapy and CAM natural products. I only list the exercises I am using, not describe or defend them.  Due to my own personal preference for the length of a blog post, I will return to them later this year and include an update of the mind-body/manual practices that I’m currently using. Please note that these views and opinions expressed here are my own. Content presented here is not meant as medical advice. Definitely consult with your physician before taking any type of supplements.   The schematic below gives a ‘big-picture’ view of my treatment strategy.

18.01.01.Daily_Take. brain.druge.CAM.Exercise

To some, my treatment plan may seem relatively conservative. It has been developed through conversations with my Neurologist and Internist.  This was followed by studying the medical literature on what has worked in Parkinson’s treatment, the list of compounds to consider was defined/refined (actually, my choice of OTC compounds has been trimmed from several years ago).  My CAM drug/vitamin/natural products strategy for treating Parkinson’s goes as follows: a) compounds (reportedly) able to penetrate the blood brain barrier; b) compounds (possibly) able to slow progression of the disorder; c) compounds that either are anti-oxidative or are anti-inflammatory; d) compounds that don’t adversely alter existing dopamine synthesis/activity; e) compounds that support overall body well-being; and f) compounds that support specific brain/nervous system health/nutrition. [Please consult with your physician before taking any type of supplements.] The Table below presents a detailed overview of my strategy for treating Parkinson’s.

18.01.01.DailyTherapy4Note of caution: Most herbs and supplements have not been rigorously studied as safe and effective treatments for PD. The U.S. Food and Drug Administration (FDA) does not strictly regulate herbs and supplements; therefore, there is no guarantee of safety, strength or purity of supplements.

REPLACING DOPAMINE:
On a daily basis, I use a combination of Carbidopa/Levodopa (25 mg/100 mg tablet x 4 daily, every 5 h on an empty stomach if possible, typically 6AM, 11AM, 4PM, 9PM) and a dopamine agonist Requip XL [Ropinirole 6 mg total (3 x 2 mg tablets) x 3 daily, every 6 h, typically 6AM, noon, 6PM).  This treatment strategy and amount combining Carbidopa/Levodopa and Ropinirole has been in place for the past 18 months (NOTE: I stopped using the additional dopamine agonist Neupro transdermal patch Rotigotine). For an overview on Carbidopa/Levodopa, I highly recommend the following 2 papers:
[1.] Ahlskog JE. Cheaper, Simpler, and Better: Tips for Treating Seniors With Parkinson Disease. Mayo Clinic Proceedings. 2011;86(12):1211-6. doi: https://doi.org/10.4065/mcp.2011.0443.
[2.] 1. Espay AJ, Lang AE. Common Myths in the Use of Levodopa in Parkinson Disease: When Clinical Trials Misinform Clinical Practice. JAMA Neurol. 2017. doi: 10.1001/jamaneurol.2017.0348. PubMed PMID: 28459962.

ISRADIPINE:
An FDA-approved calcium-channel blocker (CCB) named Isradipine penetrates the blood brain barrier to block calcium channels and potentially preserve dopamine-making cells. Isradipine may slow the progression of Parkinson’s. The primary use of Isradipine is in hypertension; thus, to treat my pre-hypertension I switched from the diuretic Hydrochlorothiazide to the CCB Isradipine.  A CCB is a more potent drug than a diuretic; importantly, my blood pressure is quite normal now and maybe I’m slowing the progression of my Parkinson’s. Please see this blog post for a review of Isradipine (click here). [Please consult with your physician before taking any type of new medication.

ANTIOXIDANTS/VITAMINS/GENERAL HEALTH:
N-Acetyl-Cysteine (NAC; 600 mg x 3 daily) is a precursor to glutathione, a powerful anti-oxidant. In several studies, NAC has been shown to be neuroprotective in Parkinson’s (click here).  I have recently posted an overview of NAC (click here). Furthermore, the ‘Science of Parkinson’s disease’ has presented their usual outstanding quality in a blog post on NAC in PD (click here);
trans-Resveratrol (200 mg daily) is an antioxidant that crosses the blood-brain barrier, which could reduce both free-radical damage and inflammation in Parkinson’s. If you decide to purchase this compound, the biologically-active form is trans-Resveratrol. The ‘Science of Parkinson’s disease’ has an excellent blog post on Resveratrol in PD (click here);
Grape Seed (100 mg polyphenols, daily) is an antioxidant that crosses the blood-brain barrier, which could reduce both free-radical damage and inflammation in Parkinson’s;
Milk Thistle (Silybum Marianum, 300 mg daily) and its active substance Silymarin protects the liver.  Dr. Jay Lombard in his book, The Brain Wellness Plan, recommends people with PD who take anti-Parkinson’s drugs (metabolized through the liver) to add 300 mg of Silymarin (standardized milk thistle extract) to their daily medication regime.
Melatonin (3 mg 1 hr before sleep) Melatonin is a hormone that promotes sustained sleep. Melatonin is also thought to be neuroprotective (click here);
Probiotic Complex with Acidophilus is a source of ‘friendly’ bacteria to contribute to a healthy GI tract.
Vitamin (daily multiple)
A high-potency multivitamin with minerals to meet requirements of essential nutrients, see label for content [I only take 1 serving instead  of the suggested 2 gummies due to my concern about taking a large amount of Vitamin B6 as described in a recent blog (click here)]:
IMG_2059 copyVitamin D3 (5000 IU 3 times/week) is important for building strong bones. Now we also know that vitamin D3 is almost like ‘brain candy’ because it stimulates hundreds of brain genes, some of which are anti-inflammatory and some support nerve health (click here). Supplementation with vitamin D3 (1200 IU/day) for a year slowed the progression of a certain type of Parkinson’s (click here). Furthermore, augmentation with vitamin D3 was recently shown to slow cognitive issues in Parkinson’s (click here).

NO LONGER TAKE Coenzyme Q10 (CoQ10), Creatine and Vitamin E because they did not delay the progression of Parkinson’s or they were harmful.
NO LONGER TAKE a high potency Vitamin B Complex (see label below) due to my concern that a large excess vitamin B6 could be detrimental to Carbidopa/Levodopa (click here for blog post):
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List of several recent PubMed peer-reviewed CAM reviews (includes a more comprehensive overview of all areas of CAM in treating Parkinson’s):
Bega D, Zadikoff C. Complementary & alternative management of Parkinson’s disease: an evidence-based review of eastern influenced practices. J Mov Disord. 2014;7(2):57-66. doi: 10.14802/jmd.14009. PubMed PMID: 25360229; PMCID: PMC4213533.

Bega D, Gonzalez-Latapi P, Zadikoff C, Simuni T. A Review of the Clinical Evidence for Complementary and Alternative Therapies in Parkinson’s Disease. Current Treatment Options in Neurology. 2014;16(10):314. doi: 10.1007/s11940-014-0314-5.

Ghaffari BD, Kluger B. Mechanisms for alternative treatments in Parkinson’s disease: acupuncture, tai chi, and other treatments. Curr Neurol Neurosci Rep. 2014;14(6):451. doi: 10.1007/s11910-014-0451-y. PubMed PMID: 24760476.

Kim HJ, Jeon B, Chung SJ. Professional ethics in complementary and alternative medicines in management of Parkinson’s disease. J Parkinsons Dis. 2016;6(4):675-83. doi: 10.3233/JPD-160890. PubMed PMID: 27589539; PMCID: PMC5088405.

Kim TH, Cho KH, Jung WS, Lee MS. Herbal medicines for Parkinson’s disease: a systematic review of randomized controlled trials. PLoS One. 2012;7(5):e35695. doi: 10.1371/journal.pone.0035695. PubMed PMID: 22615738; PMCID: PMC3352906.

Wang Y, Xie CL, Wang WW, Lu L, Fu DL, Wang XT, Zheng GQ. Epidemiology of complementary and alternative medicine use in patients with Parkinson’s disease. J Clin Neurosci. 2013;20(8):1062-7. doi: 10.1016/j.jocn.2012.10.022. PubMed PMID: 23815871. 

Today we take control over our Parkinson’s:
Please stay focused on dealing with your disorder.
Please learn as much as you can about Parkinson’s.
Please work with your neurologist to devise your own treatment strategy.
Please stretch and exercise on a daily basis, it will make a difference.
Please be involved in your own disorder; it matters that you are proactive for you.
Please stay positive and focused as you deal with this slowly evolving disease.
Please stay hopeful you can mount a challenge to slow the progression.
Please remain persistent; every morning your battle renews and you must be prepared.

 

In the midst of winter, I found there was, within me, an invincible summer.  And that makes me happy. For it says that no matter how hard the world pushes against me, within me, there’s something stronger – something better, pushing right back.” Albert Camus

Cover photo credit: news.nowmedia.co.za/medialibrary/Article/109153/Wine-grape-crop-6-7-down-in-2016-800×400.jpg

 

B Vitamins (Folate, B6, B12) Reduce Homocysteine Levels Produced by Carbidopa/Levodopa Therapy

“The excitement of vitamins, nutrition and metabolism permeated the environment.” Paul D. Boyer

“A substance that makes you ill if you don’t eat it.” Albert Szent-Gyorgy

Introduction: Claire McLean, an amazing-PT who is vital to my life managing my Parkinson’s, posted a very interesting article about the generation of homocysteine from the metabolism of levodopa to dopamine in the brain. Here is the article:

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This was all a very new concept to me. And as an ‘old-time’ biochemist by training, it led me down a trail of wonderful biochemical pathways and definitely a story worth retelling  for anyone taking carbidopa/levodopa.  Excessive generation of homocysteine leads to something called hyper-homocysteinuria, which is very detrimental to the cardiovascular system and even the neurological system.  Over time this could lead to a depletion of several B vitamins, which themselves would have biochemical consequences. This post is about the supplementation with a complex of B vitamins (including a cautionary note) during long-term therapy with carbidopa/levodopa.

“There are living systems; there is no ‘living matter’.” Jacques Monod

A reminder about Parkinson’s, dopamine and carbidopa/levodopa:  Someone with Parkinson’s  has reduced  synthesis of dopamine, an essential neurotransmitter produced by the substantia nigra of the midbrain region. A common medical treatment for Parkinson’s is the replacement of dopamine with its immediate precursor levodopa. Here are some of the key aspects regarding use of carbidopa/levodopa for treating Parkinson’s:

  1. Dopamine does not make it through the blood brain barrier to get to the brain;
  2. Levodopa (also known as L-3,4,-dihydroxyphenylalanine) is an amino acid that can cross the blood brain barrier and then be converted to dopamine;
  3. In the G.I. tract and the bloodstream, levodopa can be converted to dopamine by an enzyme named aromatic-L-amino-acid decarboxylase (DOPA decarboxylase or DDC),  which reduces the amount of levodopa that reaches the brain;
  4.  Carbidopa is a small molecule that prevents DOPA decarboxylase from converting levodopa to dopamine;
  5.  Carbidopa cannot pass through the blood brain barrier;
  6.  The “gold standard” treatment for Parkinson’s is a combination of carbidopa/levodopa, these drugs are commonly known as Sinemet, Sinemet CR, and Parcopa;
  7.  To review, we ingest carbidopa/levodopa, the carbidopa inhibits tissue enzymes that would break down the levodopa, this allows the levodopa to reach the blood-brain barrier, and then get converted to dopamine in the brain.
  8. Important side-note: Levodopa is an amino acid that crosses the blood brain barrier through a molecular amino acid transporter that binds amino acids.  Thus, eating and digestion of a protein-rich meal (also to be broken down to amino acids) either before or with your carbidopa/levodopa dose would competitively lower transport of levodopa across the blood brain barrier.  You should have been advised to take your carbidopa/levodopa doses (i) on an empty stomach, (ii) ~1 hr before eating or (iii) ~1-2 hr after eating (assuming you can tolerate it and the drug doesn’t cause nausea); this would insure your dose of levodopa gets across the blood brain barrier.

Here are the structures of the main players (top-left panel is levodopa; top-right panel is carbidopa; and the most commonly used dose is 25/100 immediate release carbidopa-levodopa (tablet with 25 mg carbidopa and 100 mg levodopa) on the bottom panel.

“The quality of your life is dependent upon the quality of the life of your cells. If the bloodstream is filled with waste products, the resulting environment does not promote a strong, vibrant, healthy cell life-nor a biochemistry capable of creating a balanced emotional life for an individual.” Tony Robbins

What’s the big deal about homocyteine (Hcy)?  Homocysteine is a sulfur-containing amino acid formed by demethylation of the essential amino acid methionine. Methionine is first modified to form S-adenosylmethionine (SAM), the direct precursor of Hcy,  This is important because SAM serves as a methyl-group “donor” in almost all biochemical pathways that need methylation (see figure below).  There are pathways that Hcy follows; importantly, the B vitamins of B6, B12 and folic acid are required for proper recycling/processing of Hcy.   An abnormal increase in levels of Hcy says that some disruption of this cycle has occurred.     Elevated Hcy is associated with a wide range of clinical manifestations, mostly affecting the central nervous system. Elevated Hcy has also been associated with an increased risk for atherosclerotic and thrombotic vascular diseases.  The mechanism for how Hcy damages tissues and cells remains under study; however, many favor the notion that excess Hcy increases oxidative stress.  As you might see why from the figure below, Hcy concentrations may increase as a result of deficiency in folate, vitamin B6 or B12. To recap, Hcy is a key biochemical metabolite focused in the essential methyl-donor pathway, whereby successful utilization of Hcy requires a role for complex B vitamins.  By contrast,  there is substantial evidence for a role of elevated Hcy as a disease risk factor for the cardiovascular and central nervous systems.

SAM+HCY


“We need truth to grow in the same way that we need vitamins, affection and love.” Gary Zukav

Sustained use of carbidopa/levodopa can result in elevated levels of homocysteine: As shown below, one of the reactions on levodopa involves methylation to form a compound named 3-O-methyldopa (3-OMD).   The reaction involves the enzyme catechol-O-methyl-transferase (COMT) and requires SAM as the methyl group donor. There is evidence that plasma Hcy levels are higher in carbidopa/levodopa-treated Parkinson’s patients when compared to controls and untreated Parkinson’s patients.  Interpretation of these results suggest the elevated Hcy levels is due to the drug itself and not from Parkinson’s.

Levodopa-3MO

B vitamins (folate, B6, B12) reduce homocysteine produced by carbidopa/levodopa therapy:   Based on the cycle and loops drawn below, they are not strictly one-way in  that theoretically you can drive the reaction in the reverse direction by using an excess amount of folate (NIH fact sheet, click here), vitamin B6 (NIH fact sheet, click here) and vitamin B12 (NIH fact sheet, click here) to reduce levels of Hcy. Folate supplementation was  previously found to reduces Hcy levels when used to treat an older group of people with vascular disease. Using the scheme depicted below as given in the slideshow there are four points I’d like to make:

  1. One might envision the brain is constantly processing a very small amount of levodopa to dopamine throughout the day. By contrast, we take 100’s of         milligram quantities of levodopa several times a day almost as if  we are giving ourselves a bolus of the precursor that reaches the brain. This scheme suggests that L-DOPA + SAM by COMT will produce Hcy; Over time ↑Hcy levels would be generated, leading to hyper-Hcy. Implied by hyper-Hcy is the consumption of B vitamins like folate, B12 and B6; deficiency of these vitamins would contribute to the body being unable to metabolize the excess Hcy.
  2. The folate/vitamin B12 cycle is crucial for DNA synthesis in our body.  This cycle verifies the essential role of folate and vitamin B12 in our diet and demonstrates their function in a key biochemical pathway. This also suggests that making too much Hcy could potentially consume both folate and B12, which would be detrimental to you. By contrast, the cycle also implies that by taking excess  folate and vitamin B12 you might drive the reaction the other direction and reduce the amount of Hcy generated,  and preserve the biochemical integrity of the cycle.
  3.  The processing of HCy is somewhat dependent on vitamin B6.  In the presence of excess Hcy you would consume the vitamin B6 ; however, the cycle also implies in the presence of an excess of vitamin B6 would allow the processing of Hcy further downstream.
  4.  Finally, unrelated to the B vitamins, the addition of N-Acetyl-cysteine (NAC) to the pathway would generate glutathione, which would help consume the excess Hcy  and also generate a very potent antioxidant compound.

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“1914…Dr. Joseph Goldberger had proven that (pellagra) was related to diet, and later showed that it could be prevented by simply eating liver or yeast. But it wasn’t until the 1940’s…that the ‘modern’ medical world fully accepted pellagra as a vitamin B deficiency.” G. Edward Griffin

Beware of taking a huge excess of vitamin B6 in the presence of carbidopa/levodopa, a cautionary tale: I started taking a supplement that had relatively large amounts of complex B vitamins  (specifically the one labeled number two below) had 100% (400 mcg) folate, 1667% (100 mcg) vitamin B12 and 5000% (100 mg) of vitamin B6 (based on daily requirement from our diet).   Over a period of several days I started feeling stiffer, weaker as if  my medicine had stopped treating my Parkinson’s. I especially noticed it one day while playing golf because I had lost significant yardage on my shots, I was breathing heavily, and I was totally out of sync with my golf swing.  Just in general, my entire body was not functioning well.  Timing wise, I was taking the complex B vitamin pill with my early morning carbidopa/levodopa pill on an empty stomach. Something was suddenly (not subtly) wrong with the way I was feeling, and the only new addition to my treatment strategy was this complex B  vitamin pill. There had to be an explanation.

17.08.16.B_Vitamins

I went home and started thinking like a biochemist, started searching the Internet as an academic scientist, and found the answer in the old archives of the literature.  The older literature says taking more than 15 mg of vitamin B6 daily could compromise the effectiveness of carbidopa to protect levodopa from being activated in the tissues. Thus, I may have been compromising at least one or more doses of levodopa daily by taking 100 mg of vitamin B6 daily.  Let me further say I found that the half-life of vitamin B6 was 55 hours; furthermore, assuming 3L of plasma to absorb the vitamin B6, and a daily dose of 100 mg I plotted the vitamin B6 levels in my bloodstream. The calculation is based on a simple, single compartment elimination model assuming 100% absorbance that happens immediately. The equation is: concentration in plasma (µg/ml vitamin B6) = dose/volume * e^(-k*t) :

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And further inspection of the possible reaction properties between vitamin B6, carbidopa and even levodopa suggests that vitamin B6 could be forming a Schiff Base, which would totally compromise the ability of either compound to function biologically (this is illustrated below).   And I should have known this because some of my earliest publications studied the binding site of various proteins and they were identified using vitamin B6 modifying the amino groups of the proteins (we were mapping heparin-binding sites):

Church, F.C., C.W. Pratt, C.M. Noyes, T. Kalayanamit, G.B. Sherrill, R.B. Tobin, and J.B. Meade (1989) Structural and functional properties of human α-thrombin, phosphopyridoxylated-α-thrombin and γT-thrombin: Identification of lysyl residues in α-thrombin that are critical for heparin and fibrin(ogen) interactions.  J. Biol. Chem. 264: 18419-18425.

Peterson, C.B., C.M. Noyes, J.M. Pecon, F.C. Church and M.N. Blackburn (1987)  Identification of a lysyl residue in antithrombin which is essential for heparin binding.  J. Biol. Chem.  262: 8061-8065.

Whinna, H.C., M.A. Blinder, M. Szewczyk, D.M. Tollefsen and F.C. Church (1991) Role of lysine 173 in heparin binding to heparin cofactor II.  J. Biol. Chem.  266: 8129-813

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“…The Chinese in the 9th century AD utilized a book entitled The Thousand Golden Prescriptions, which described how rice polish could be used to cure beri~beri, as well as other nutritional approaches to the prevention and treatment of disease. It was not until twelve centuries later that the cure for beri~beri was discovered in the West, and it acknowledged to be a vitamin B-1 deficiency disease.” Jeffrey Bland

To take or not to take, complex B vitamin supplementation:  I literally have been writing and working on this post since July; it started as a simple story about the use of complex B vitamins to reduce homocysteine levels as a consequence of chronic carbidopa/levodopa use to manage Parkinson’s.   If you eat a good healthy diet you’re getting plenty of B vitamins. Do you need mega-doses of complex B vitamins? My cautionary note described taking very large amounts of vitamin B6 may be compromising both carbidopa and/or levodopa. You should talk with your Neurologist because it’s straightforward to measure folate, vitamin B6 and B12, and homocysteine levels to see if they are in the normal range if you are taking carbidopa/levodopa. The hidden subplot behind the story is the growing awareness and importance of managing homocysteine levels and also knowing the levels of folate, B6 and B12 to help maintain your neurological health.  Bottom line, if you need it, take a multiple vitamin with only 100 to 200% of your daily need of vitamin B6 (what is shown in panel three and four above). And please be careful if you decide to take a larger dose of vitamin B6 (between 10-100 mg/day).

“A risk-free life is far from being a healthy life. To begin with, the very word “risk” implies worry, and people who worry about every bite of food, sip of water, the air they breathe, the gym sessions they have missed, and the minutiae of vitamin doses are not sending positive signals to their cells. A stressful day sends constant negative messaging to the feedback loop and popping a vitamin pill or choosing whole wheat bread instead of white bread does close to zero to change that.” Deepak Chopra

Cover photo credit:

photos.smugmug.com/Kure-Beach-NC/i-QS7T6sW/2/df8e6878/L/kbp3-L.jpg

 

The Yack on NAC (N-Acetyl-Cysteine) and Parkinson’s

“Once you choose hope, anything’s possible.” Christopher Reeve

“Hope is like a road in the country; there was never a road, but when many people walk on it, the road comes into existence.” Lin Yutang

Introduction: N-Acetyl-Cysteine (or N-acetylcysteine, usually abbreviated NAC and frequently pronounced like the word ‘knack’) is an altered (modified by an N-acetyl-group) form of the sulfur-containing amino acid cysteine (Cys).  NAC is one of the building blocks for the all important antioxidant substance glutathione (GSH).   GSH is a powerful reagent that helps cells fight oxidative stress.  One of the putative causes of Parkinson’s is oxidative stress on dopamine-producing neurons (see figure below). This post summarizes some of the biochemistry of NAC and GSH.  Furthermore, NAC may provide some neuroprotective benefit as a complementary and alternative medicine (CAM) approach to treating Parkinson’s.

“Losing the possibility of something is the exact same thing as losing hope and without hope nothing can survive.” Mark Z. Danielewski

17.05.24.Causes_PD

 Glutathione (GSH):  GSH is a 3-amino acid substance (tripeptide) composed of Cys linked to glutamate (Glu) and followed by glycine (Gly). NAC would need to be de-acetylated to provide Cys and that would feed in to the reaction synthesis. Importantly, Cys is the rate limiting reactant, which means without adequate amounts of Cys you do not make GSH.   The schematic below gives the orientation and order of addition of the three amino acid components to give you GSH.

NACtoGSH

There are two advantages of NAC over Cys for making GSH: (i) the sulfhydryl group of NAC remains reduced (that is as an SH group) more so than the SH group of Cys; and (ii) the NAC molecule appears to transport itself through cell membranes much more easily than Cys.  The reduced (i.e.,  free SH group) form of GSH, once synthesized within the cell, has several key functions that range from antioxidant protection to protein thiolation to drug detoxification in many different tissues.   The key function of GSH is to provide what is known as “reducing equivalents” to the cell, which implies an overall key antioxidant effect.

The schematic below shows NAC transport from extracellular to intracellular (inside the cell), and the primary reactions for detoxification and thiolation from GSH. Implied by this figure below is that GSH is not easily transported into the cell. Furthermore, in a more toxic/hostile environment outside of the cell, you can easily oxidize 2 GSH molecules to become GSSG (the reduced SH group gets oxidized to form an S-S disulfide bond) and GSSG does not have the antioxidant effect of GSH.   However, inside the cell, GSH is a very potent antioxidant/detoxifying substance. And the beauty of being inside the cell, there is an enzyme called GSH-reductase that regenerates GSH from GSSG.

Rushworth-NAC.review-4.2

To recap and attempt to simplify what I just said, NAC gets delivered into a cell, which then allows the cell to generate intracellular GSH.  The presence of intracellular GSH gives a cell an enormous advantage to resist potentially toxic oxidative agents. By contrast, extracellular GSH has a difficult path into the cell; and is likely to be oxidized to GSSG and rendered useless to help the cell.

“Just remember, you can do anything you set your mind to, but it takes action, perseverance, and facing your fears.”  Gillian Anderson

One of many biological functions of NAC:   Perhaps the most important medical use of NAC is to help save lives in people with acetaminophen toxicity, in which the liver is failing.  How does NAC do this?  Acetaminophen is sold as Tylenol.  It is also added to compounds that are very important for pain management ()analgesics), including Vicodin and Percocet. Acetaminophen overdose is the leading cause of acute liver failure in the USA.   This excess of acetaminophen rapidly consumes the GSH in the liver, which then promotes liver death.  NAC quickly restores protective levels of GSH  to the liver, which hopefully reverses catastrophic liver failure to prevent death.

Systemically, when taken either orally or by IV injection, NAC would have 2 functions.  First, NAC replenishes levels of Cys to generate the intracellular antioxidant GSH (see schemes above).  Second, NAC has been shown to regulate gene expression of several pathways that link oxidative stress to inflammation.  Since the primary goal of this post relates to NAC as a CAM in Parkinson’s, I will not expand further on the many uses of NAC in other disease processes.  However, listed at the end are several review articles detailing the numerous medicinal roles of NAC.

“Love, we say, is life; but love without hope and faith is agonizing death.” Elbert Hubbard

Use of NAC as a CAM in Parkinson’s:   This is what we know about oxidative stress in Parkinson’s and the potential reasons why NAC could be used as a CAM in this disorder, it goes as follows  (it’s also conveniently shown in the figure at the bottom):

1. Substantia nigra dopamine-producing neurons die from oxidative stress, which can lead to Parkinson’s.

2.What is oxidative stress? Oxidative stress happens when your cells in your body do not make/have enough antioxidants to reduce pro-oxidants like free radicals. Free radicals cause cell damage/death when they attack proteins/cell membranes.

3.We speak of oxidative stress in terms of redox imbalance (which means the balance between increased amounts of oxidants or  decreased amounts of antioxidants).

4.Glutathione (GSH) is a key substance used by cells to repair/resist oxidatively damaged cells/proteins.

5.”Forces of evil” in the brain that make it difficult to resist oxidative stress:  decreased levels of GSH,  increased levels of iron and  increased polyunsaturated fatty acids.

6.Extracellar GSH cannot be transported easily into neurons, although there is evidence GSH gets past the blood brain barrier;

7.N-acetyl Cysteine (NAC), is an anti-oxidant and a precursor to GSH.  NAC gets through the blood brain barrier and can also be transported into neurons.

8.Cysteine is the rate-limiting step for GSH synthesis (NAC would provide the cysteine and favor synthesis of GSH).

9.Animal model studies have shown NAC to be neuroprotective.

10. Recent studies have shown NAC crosses the human blood brain barrier and may be a useful PD-modifying therapy.

 

17.05.26.OX_Stress

“You cannot tailor-make the situations in life but you can tailor-make the attitudes to fit those situations.”  Zig Ziglar

Scientific and clinical support for NAC in treating Parkinson’s: Content presented here is meant for informational purposes only and not as medical advice.  Please remember that I am a basic scientist, not a neurologist, and any use of these compounds should be thoroughly discussed with your own personal physician. This is not meant to be an endorsement  because it would be more valuable and important for your neurologist to be in agreement with the interpretation of these papers.

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To evaluate the use of NAC in Parkinson’s, Katz et al. treated 12 patients with Parkinson’s with oral doses of NAC twice a day for two days.   They studied three different doses of 7, 35, and 70 mg per kilogram. For example, in a person weighing 170 pounds, from a Weight Based Divided Dose Calculator (click here), this would be 540, 2700, and 5400 mg/day of NAC for 7, 35, and 70 mg/kg, respectively. Using cerebral spinal fluid (CSF), they measured levels of  NAC, Cys, and GSH at baseline and 90 minutes after the last dose. Their results showed that there was a dose-dependent range of NAC as detected by CSF. And they concluded that oral administration of NAC produce biologically relevant CSF levels of NAC at the three doses examined; the doses of oral NAC were also well-tolerated.  Furthermore, the patients treated with NAC had no change in either motor or cognitive function. Their conclusions support the feasibility of using oral NAC as a CAM therapy for treatment of Parkinson’s.

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In a separate study, Monti at al  presented some preliminary evidence for the use of NAC in Parkinson’s. The first part of their study consisted of a neuronal cell system that was pre-treated with NAC in the presence of the pesticide rotenone as a model of Parkinson’s.   These results showed that with NAC there was more neuronal cell survival after exposure to rotenone compared to the rotenone-treated cells without NAC. The second part of the study was a small scale clinical evaluation using NAC in Parkinson’s. These patients were randomized and given either NAC or nothing and continued to use their traditional medical care. The patients were evaluated at the start and after three months of receiving NAC; they measured dopamine transporter binding and  performed the unified Parkinson’s disease rating scale  (UPDRS) to measure clinical symptoms. The clinical study revealed an increase in dopamine transporter binding in the NAC treatment group and no measurable changes in the control group. Furthermore UPDRS scores were significantly improved in the NAC treatment group compared to the control patient group.   An interesting feature of this study was the use of pharmaceutical NAC, which is an intravenous (IV) medication and they also used 600 mg NAC tablets. The dose used was 50 mg per kg mixed into sterile buffer and infused over one hour one time per week. In the days they were not getting the IV NAC treatment, subjects took 600 mg NAC tablets twice per day.

 Okay, what did I just say? I will try to summarize both of these studies in a more straightforward manner.   The results above suggest that NAC crosses the blood brain barrier and does offer some anti-oxidative protection. In one study, this was shown by increased levels of both GSH and Cys dependent on the NAC dose. In another study, they directly measured dopamine transporter binding, which was increased in the presence of NAC. In the second study using a three month treatment strategy with NAC, there was a measurable positive effect on disease progression as measured by UPDRS scores.  

“Our greatest weakness lies in giving up. The most certain way to succeed is always to try just one more time.” Thomas A. Edison

Potential for NAC in treating Parkinson’s: Overall, both studies described above suggest the possibility that NAC may be useful in treating Parkinson’s. However, in both cases these were preliminary studies that would require much larger randomized double-blind placebo-controlled trials to definitively show a benefit for using NAC in treating Parkinson’s. On a personal note, I have been taking 600 mg capsules of NAC three times a day for the past year with the hope that it is performing the task as outlined in this post. Using information from the first study that would be a NAC dose of 24 mg per kilogram body weight. In conclusion, the information described above suggests that NAC may be useful in regulating oxidative stress, one of the putative causes of Parkinson’s. As with all studies, time will tell if ultimately there is a benefit for using NAC in Parkinson’s.

“I am not an optimist, because I am not sure that everything ends well. Nor am I a pessimist, because I am not sure that everything ends badly. I just carry hope in my heart. Hope is the feeling that life and work have a meaning. You either have it or you don’t, regardless of the state of the world that surrounds you. Life without hope is an empty, boring, and useless life. I cannot imagine that I could strive for something if I did not carry hope in me. I am thankful to God for this gift. It is as big as life itself.” Vaclav Havel

References Used:
Katz M, Won SJ, Park Y, Orr A, Jones DP, Swanson RA, Glass GA. Cerebrospinal fluid concentrations of N-acetylcysteine after oral administration in Parkinson’s disease. Parkinsonism Relat Disord. 2015;21(5):500-3. doi: 10.1016/j.parkreldis.2015.02.020. PubMed PMID: 25765302.

Martinez-Banaclocha MA. N-acetyl-cysteine in the treatment of Parkinson’s disease. What are we waiting for? Med Hypotheses. 2012;79(1):8-12. doi: 10.1016/j.mehy.2012.03.021. PubMed PMID: 22546753.

Monti DA, Zabrecky G, Kremens D, Liang TW, Wintering NA, Cai J, Wei X, Bazzan AJ, Zhong L, Bowen B, Intenzo CM, Iacovitti L, Newberg AB. N-Acetyl Cysteine May Support Dopamine Neurons in Parkinson’s Disease: Preliminary Clinical and Cell Line Data. PLoS One. 2016;11(6):e0157602. doi: 10.1371/journal.pone.0157602. PubMed PMID: 27309537; PMCID: PMC4911055.

Mosley RL, Benner EJ, Kadiu I, Thomas M, Boska MD, Hasan K, Laurie C, Gendelman HE. Neuroinflammation, Oxidative Stress and the Pathogenesis of Parkinson’s Disease. Clin Neurosci Res. 2006;6(5):261-81. doi: 10.1016/j.cnr.2006.09.006. PubMed PMID: 18060039; PMCID: PMC1831679.

Nolan YM, Sullivan AM, Toulouse A. Parkinson’s disease in the nuclear age of neuroinflammation. Trends Mol Med. 2013;19(3):187-96. doi: 10.1016/j.molmed.2012.12.003. PubMed PMID: 23318001.

Rushworth GF, Megson IL. Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits. Pharmacol Ther. 2014;141(2):150-9. doi: 10.1016/j.pharmthera.2013.09.006. PubMed PMID: 24080471.

Taylor JM, Main BS, Crack PJ. Neuroinflammation and oxidative stress: co-conspirators in the pathology of Parkinson’s disease. Neurochem Int. 2013;62(5):803-19. doi: 10.1016/j.neuint.2012.12.016. PubMed PMID: 23291248.

Cover photo credit: https://s-media-cache-ak0.pinimg.com/originals/e8/33/ae/e833aeb408a432d419628c803bf14498.jpg

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Parkinson’s Disease Research: A Commentary from the Stands and the Playing Field

“You can have a very bad end with Parkinson’s, but on the other hand, you can be like me, because I’m lucky. I’m not having a bad end.” Margo MacDonald

“My age makes me think how valuable life is. How bad is something like Parkinson’s in relation to not having life at all?” Michael J. Fox

Introduction: Last month, together with Dr. Simon Stott and his team of scientists (The Science of Parkinson’s Disease), we co-published a historical timeline of Parkinson’s disease beginning with the description of the ‘shaking palsy’ from James Parkinson in 1817. My post entitled “Milestones in Parkinson’s Disease Research and Discovery” can be read here (click this link). The Science of Parkinson’s Disease post entitled “Milestones in Parkinson’s Disease Research and Discovery” can be read here (click this link).

We spent a lot of time compiling and describing what we felt were some of the most substantial findings during the past 200 years regarding Parkinson’s disease.  I learned a lot; truly amazing what has been accomplished in our understanding of  such a complex and unique disorder.  Simon posted a follow-up note entitled “Editorial: Putting 200 years into context” (click this link). I have decided to also post a commentary from the standpoint of (i) being someone with Parkinson’s and (ii) being a research scientist.

“Every strike brings me closer to the next home run.” Babe Ruth

Baseball: I want to use the analogy of a baseball game to help organize my commentary. Baseball fans sit in the stands and have fun watching the game, thinking about the strategy behind the game, eating/drinking, and sharing the experience with family/friends/colleagues.   Most baseball players begin playing early in life and the ultimate achievement would be to reach the major leagues. And this would usually have taken many years of advancing through different levels of experience on the part of the ballplayer. How does how this analogy work for me in this blog? Stands: I am a person-with-Parkinson’s watching the progress to treat and/or cure this disorder. Playing field: I am a research scientist in a medical school (click here to view my training/credentials).

“Never allow the fear of striking out keep you from playing the game!”  Babe Ruth

Observation from the stands:
I am a spectator like everyone else with Parkinson’s. I read much of the literature available online.  Like you, I think about my disorder; I think about how it’s affecting me every day of my life. Yes, I want a cure for this disease.  Yes, I’m rather impatient too.  I understand the angst and anxiety out there with many of the people with Parkinson’s. In reality, I would not be writing this blog if I didn’t have Parkinson’s. Therefore, I truly sense your frustration that you feel in the presence of Parkinson’s, I do understand.  Given below are examples of various organizations and ads and billboards in support of finding a cure for Parkinson’s.  Some even suggest that a cure must come soon.   However, the rest of my post is going to be dedicated to trying to explain why it’s taking so long; why I am optimistic and positive a cure and better treatment options are going to happen.  And it is partly based on the fact that there really are some amazing people working to cure Parkinson’s and to advance our understanding of this disorder.

“When you come to a fork in the road take it.” Yogi Berra

Observations from the playing field (NIH, war on cancer, research lab, and advancing to a cure for Parkinson’s):

National Institutes of Health (NIH) and biomedical research in the USA: Part of what you have to understand, in the United States at least, is that a large portion of biomedical research is funded by the NIH (and other federally-dependent organizations), which receives a budget from Congress (and the taxpayers). What does it mean for someone with Parkinson’s compared to someone with cancer or diabetes? The amount of federal funds committed to the many diseases studied by NIH-funded-researchers are partly divvied up by the number of people affected. I have prepared a table from the NIH giving the amount of money over the past few years for the top four neurodegenerative disorders, Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis (ALS), and Huntington’s Disease, respectively [taken from “Estimates of Funding for Various Research, Condition, and Disease Categories” (click here)]. And this is compared to cancer and coronary arterial disease and a few other major diseases. Without going into the private organizations that fund research, a large amount of money comes from the NIH. Unfortunately, from 2003-2015, the NIH lost >20% of its budget for funding research (due to budget cuts, sequestration, and inflationary losses; click here to read further).   Therefore,  it is not an overstatement to say getting  funded today by the NIH is fiercely competitive.  From 1986 to 2015, my lab group was supported by several NIH grants and fellowships  (and we also received funding from the American Heart Association and Komen for the Cure).

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“In theory, there is no difference between theory and practice. But in practice, there is.” Yogi Berra

War against cancer: In 1971, Pres. Richard Nixon declared war against cancer and Congress passed the National Cancer Act.  This created a new national mandate “to support research and application of the results of research to reduce the incident, morbidity, and mortality from cancer.” Today, cancer is still the second leading cause of death in the USA; however, we’ve come such a long way to improving this statistic from when the Cancer Act was initiated.

Scientifically, in the 1970’s, we were just learning about oncogenes and the whole field of molecular biology was really in its infancy. We had not even started sequencing the human genome, or even of any organism.  We discovered genes that could either promote or suppress cellular growth.   We began to delineate the whole system of cell signaling and communications with both normal and malignant cells. We now know there are certain risk factors that allow us to identify people that may have increased risk for certain cancers. Importantly,  we came to realize that not all cancers were alike,  and it offered the notion to design treatment strategies for each individual cancer.  For example,  we now have very high cure rates for childhood acute leukemia and Hodgkin’s lymphoma and we have significantly improved survival statistics for women with breast cancer. Many might say this was a boondoggle and that we wasted billions of dollars  funding basic biomedical research on cancer; however, basic  biomedical research is expensive and translating that into clinical applications is even more expensive.  [ For a  very nice short review on cancer research please see the following article, it may be freely accessible by now: DeVita Jr, Vincent T., and Steven A. Rosenberg. “Two hundred years of cancer research.” New England Journal of Medicine 366.23 (2012): 2207-2214.]

“One of the beautiful things about baseball is that every once in a while you come into a situation where you want to, and where you have to, reach down and prove something.” Nolan Ryan

The biomedical research laboratory environment:  A typical laboratory group setting is depicted in the drawing below. The research lab usually consists of the lead scientist who has the idea to study a research topic, getting grants funded and in recruiting a lab group to fulfill the goals of the project.  Depending on the philosophy of the project leader the lab may resemble very much like the schematic below or may be altered to have primarily technicians or senior postdoctoral fellows working in the lab  (as two alternative formats). A big part of academic research laboratories is education and training the students and postdocs to go on to advance their own careers; then you replace the people that have left and you continue your own research.  Since forming my own lab group in 1986, I have helped train over 100 scientists in the research laboratory: 17 graduate students, 12 postdoctoral fellows, 17 medical students, and 64 undergraduates. The lab has been as large as 10 people and a small as it is currently is now with two people. People come to your lab group because they like what you’re doing scientifically and this is where they want to belong for their own further training and advancement.  This description is for an academic research  laboratory; and  I should also emphasize that many people get trained in federal government-supported organizations, private Pharma and other types of research environments that may differ in their laboratory structure and organizational format.

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“Hitting is 50% above the shoulders.” Ted Williams

 In search of the cure for Parkinson’s:    First, I understand the situation you’re in with Parkinson’s because I’m living through the same situation.   But when people find out I’m a research scientist they always wonder why aren’t we doing more to find a cure, and I  hear the sighs of frustration and I see the anxiety in their faces. Second, the previous three sections are not meant to be an excuse for why there is still no cure for Parkinson’s. It is presented in the reality of what biomedical research scientists must undergo to study a topic.  Third, the experiments that take place in basic biomedical research laboratory may happen over weeks to months if successful. Taking that laboratory data to the clinic and further takes months and years to succeed if at all.   The section on cancer reminds me a lot of where we are going with Parkinson’s and trying to advance new paradigms in the treatment and curative strategies.  Professionally, I have even decided  to pursue research funding in the area of Parkinson’s disease.   Why not spend the rest of my academic career studying my own disease; in the least I can help educate others about this disorder. Furthermore, I can assure you from my reading and meeting people over the last couple of years, there are many hundreds of scientists and clinicians throughout this world studying Parkinson’s and trying to advance our understanding and derive a cure.  I see their devotion, I see their commitment to helping cure our disorder.

The science behind Parkinson’s is quite complicated. These complications suggest that Parkinson’s may be more of a syndrome rather than a disease. Instead of a one-size-fits-all like a disease would be classified; Parkinson’s as a syndrome would be a group of symptoms which consistently occur together.  What this might imply is that some treatment strategy might work remarkably well on some patients but have no effect on others. However, without a detailed understanding and advancement of what Parkinson’s really is we will never reach the stage where we can cure this disorder.

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In a recent blog from the Science of Parkinson’s disease, Simon nicely summarized all the current research in 2017 in Parkinson’s disease (click here to read this post). To briefly summarize what he said is that there are multiple big Pharma collaborations occurring to study Parkinson’s.  There are more than 20 clinical trials currently being done in various stages of completion to prevent disease progression but also to try to cure the disorder.  From a search of the literature, there are literally hundreds of research projects going on that promise to advance our understanding of this disorder. With the last point, it still will take time to happen. Finally, I am a realist but I’m also optimistic and positive that we’re making incredible movement toward much better therapies, which will eventually lead to curative options for Parkinson’s.

And a final analogy to baseball and Parkinson’s, as Tommy Lasorda said “There are three types of baseball players: those who make it happen, those who watch it happen, and those who wonder what happens.”  I really want to be one of those scientists that help make it happen (or at least to help advance our understanding of the disorder).

“You can’t expect life to play fair with your heart or your brain or your health. That’s not the nature of the game we call life. You have to recognize the nature of the game and know that you can do your best to make the right choices, but life if going to do whatever the hell it pleases to you anyway. All you can control is how you react to whatever life throws at you. You can shut down or you can soar.” Holly Nicole Hoxter

Cover photo credit: PNC Park photo: i.imgur.com/32RWncK

Sign post scienceofparkinsons.com/

Milestones in Parkinson’s Disease Research and Discovery

“The real voyage of discovery consists not in seeking new landscapes, but in having new eyes.” Marcel Proust

“The process of scientific discovery is, in effect, a continual flight from wonder.” Albert Einstein

Preface:  Happy birthday to James Parkinson (neurologist, geologist, scientist, activist),  born April 11, 1755 and died December 21, 1824.  World Parkinson’s Day April 11, 2017.

Introduction to the historical timeline on Parkinson’s disease: This historical description of Parkinson’s is a joint venture/adventure between Frank and Simon . The idea for this project started as a conversation during a recent North Carolina beach weekend for Frank and Barbara: “Wouldn’t it be cool to publish a Parkinson’s historical timeline for Parkinson’s awareness month?” However, to complete this project I needed a Parkinson’s expert. As a follower of his outstanding blog ‘Science of Parkinson’s’, I approached Simon about helping out on this timeline project; and to my delight he said yes. Therefore, we are happy to present the milestones in Parkinson’s disease research and discovery. We do apologize to the clinicians, scientists, health-care specialists, and their projects that were not cited here but we limited the timeline to ~50 notations.

The entire historical timeline can be downloaded (click here for the PowerPoint file) and we encourage you to view it in ‘presentation’ mode. Each individual page of the timeline is presented below along with a brief explanation for each of the highlighted events. And Simon and I will be sharing the historical timeline in our own individual blogs.

“I want to see books taken out of historical time and placed into a different timeline, such as evolutionary or geological time, as a means of putting the human experience in context.” Douglas Coupland

1817-1919, Milestones in Parkinson’s Disease Research and Discovery (Part 1a: Historical):
Slide1

First description of Parkinson’s disease:
In 1811, Mr James Parkinson of no. 1 Hoxton Square (London) published a 66 page booklet called an ‘An Essay on the Shaking Palsy’. At the date of printing, it sold for 3 shillings (approx. £9 or US$12). The booklet was the first complete description of a condition that James called ‘Paralysis agitans’ or shaking palsy. In his booklet, he discusses the history of tremor and distinguishes this new condition from other diseases. He then describes three of his own patients and three people who he saw in the street.

The naming of Parkinson’s disease:
Widely considered the ‘Father of modern neurology’, the importance of Jean-Martin Charcot’s contribution to modern medicine is rarely in doubt. From Sigmund Freud to William James (one of the founding fathers of Psychology), Charcot taught many of the great names in the early field of neurology. Between 1868 and 1881, Charcot focused much of his attention on the ‘paralysis agitans’. Charcot rejected the label ‘Paralysis agitans’, however, suggesting that it was misleading in that patients were not markedly weak and do not necessarily have tremor. Rather than Paralysis Agitans, Charcot suggested that Maladie de Parkinson (or Parkinson’s disease) would be a more appropriate name, bestowing credit to the man who first described the condition. And thus 70 years after passing away, James Parkinson was immortalized with the disease named after him.

The further clinical characterization of Parkinson’s disease:
British neurologist Sir William Gowers published a two-volume text called the Manual of Diseases of the Nervous System (1886, 1888). In this book he described his personal experience with 80 people with Parkinson’s disease in the 1880s. He also identified the subtle male predominance of the disorder and provided illustrations of the characteristic posture. In his treatment of Parkinson’s tremor, Gower used hyoscyamine, hemlock, and hemp (cannabis) as effective agents for temporary tremor abatement.

The discovery of the chemical dopamine:
In the Parkinsonian brain there is a severe reduction in the chemical dopamine. This chemical was first synthesized in 1910 by George Barger and James Ewens at the Wellcome labs in London, England.

The discovery of Lewy bodies:
One of the cardinal features of Parkinson’s disease in the brain is the presence of Lewy bodies – circular clusters of protein. In 1912, German neurologist Friedrich Lewy, just two years out of medical school and still in his first year as Director of the Neuropsychiatric Laboratory at the University of Breslau (now Wroclaw, Poland) Medical School discovered these ‘spherical inclusions’ in the brains of a people who had died with Parkinson’s disease.

The importance of the substantia nigra in Parkinson’s disease:
The first brain structure to be associated with Parkinson’s disease was the substantia nigra. This region lies in an area called the midbrain and contains the majority of the dopamine neurons in the human brain. It was in 1919 that a Russian graduate student working in Paris, named Konstantin Tretiakofirst demonstrated that the substantia nigra was associated with Parkinson’s disease. Tretiakoff also noticed circular clusters in the brains he examined and named them ‘corps de Lewy’ (or Lewy bodies) after the German neurologist Friedrich Lewy who first discovered them.

“Everyone wants answers and wants to know what the timeline is. Unfortunately, it’s a complex situation, and we don’t have the final answers yet.” Dennis Miller

1953-1968, Milestones in Parkinson’s Disease Research and Discovery (Part 1b: Historical):

Slide2

The first complete pathologic analysis of the Parkinsonian brain:
The most complete pathologic analysis of Parkinson’s disease with a description of the main sites of damage was performed in 1953 by Joseph Godwin Greenfield and Frances Bosanquet.

The discovery of a functional role for dopamine in the brain:
Until the late 1950s, the chemical dopamine was widely considered an intermediate in the production of another chemical called norepinephrine. That is to say, it had no function and was simply an ingredient in the recipe for norepinephrine. Then in 1958, Swedish scientist Arvid Carlsson discovered that dopamine acts as a neurotransmitter – a discovery that won Carlsson the 2000 Nobel prize for Physiology or Medicine.

The founding of the Parkinson’s Disease Foundation:
In 1957, a nonprofit organization called the Parkinson’s Disease Foundation was founded by William Black. It was committed to finding a cure for Parkinson’s Disease. Since its founding in 1957, PDF has funded more than $115 million worth of scientific research in Parkinson’s disease. The National Parkinson Foundation (NPF), was also founded in 1957 by Jeanne C. Levey. NPF is a national organization whose mission is to make life better for people with Parkinson’s through expert care and research. The foundation has funded more than $208 million in care, research and support services.

The discovery of the loss of dopamine in the brain of people with Parkinson’s disease:  In 1960, Herbert Ehringer and Oleh Hornykiewicz demonstrated that the chemical dopamine was severely reduced in brains of people who had died with Parkinson’s disease.

The first clinical trials of Levodopa:
Knowing that dopamine can not enter the brain and armed with the knowledge that the chemical L-dopa was the natural ingredient in the preoduction of dopamine, Oleh Hornykiewicz & Walther Birkmayer began injecting people with Parkinson’s disease with L-dopa in 1961. The short term response to the drug was dramatic: “Bed-ridden patients who were unable to sit up, patients who could not stand up when seated, and patients who when standing could not start walking performed all these activities with ease after L-dopa. They walked around with normal associated movements and they could even run and jump.” (Birkmayer and Hornykiewicz 1961).

The first internationally-used rating system for Parkinson’s disease:
In 1967, Melvin Yahr and Margaret Hoehn published a rating system for Parkinson’s disease in the journal Neurology. It involves 5 stages, ranging from unilateral symptoms but no functional disability (stage 1) to confinement to wheel chair (stage 5). Since then, a modified Hoehn and Yahr scale has been proposed with the addition of stages 1.5 and 2.5 in order to help better describe the intermediate periods of the disease.

Perfecting the use of L-dopa as a treatment for Parkinson’s disease:
In 1968, Greek-American scientist George Cotzias reported dramatic effects on people with Parkinson’s disease using oral L-dopa. The results were published in the New England Journal of Medicine. and L-dopa becomes a therapeutic reality with the Food and Drug Administration (FDA) approving the drug for use in Parkinson’s disease in 1970. Cotzias and his colleagues were also the first to describe L-dopa–induced dyskinesias.

“Nothing in life is to be feared, it is only to be understood. Now is the time to understand more, so that we may fear less.” Marie Curie

1972-1997, Milestones in Parkinson’s Disease Research and Discovery (Part 1c: Historical):

Levodopa + AADC inhibitors (carbidopa or benserazide:
 When given alone levodopa is broken down to dopamine in the bloodstream, which leads to some detrimental side effects.  By including an aromatic amino acid decarboxylase (AADC) inhibitor with levodopa allows the levodopa to get to the blood-brain barrier in greater amounts for better utilization by the neurons. In the U.S., the AADC inhibitor of choice is carbidopa and in other countries it’s benserazide.

The discovery of dopamine agonists:
Dopamine agonists are ‘mimics’ of dopamine that pass through the blood brain barrier to interact with target dopamine receptors. Since the mid-1970’s, dopamine agonists are often the first medication given most people to treat their Parkinson’s; furthermore, they can be used in conjunction with levodopa/carbidopa. The most commonly prescribed dopamine agonists in the U.S. are Ropinirole (Requip®), Pramipexole (Mirapex®), and Rotigotine (Neupro® patch). There are some challenging side effects of dopamine agonists including compulsive behavior (e.g., gambling and hypersexuality),  orthostatic hypotension, and hallucination.

The clinical use of MAO-B inhibitors:
In the late-1970’s, monoamine oxidase-B (MAO-B) inhibitors were created to block an enzyme in the brain that breaks down levodopa. MAO-B inhibitors have a modest effect in suppressing the symptoms of Parkinson’s.  Thus, one of the functions of MAO-B inhibitors is to prolong the half-life of levodopa to facilitate its use in the brain.  Very recently in clinical trials, it’s been shown that MAO-B inhibitors have some neuroprotective effect when used long-term.  The most widely used MAO-B inhibitors in the U.S. include Rasagiline (Azilect®) and Selegiline (Eldepryl® and Zelpar®); MAO-B inhibitors may reduce “off” time and extend “on” time of levodopa.

Fetal Cell transplantation:
After successful preclinical experiments in rodents, a team of researchers in Sweden, led by Anders Bjorklund and Olle Lindvall, began the first clinical trials of fetal cell transplantation for Parkinson’s disease. These studies involved taking embryonic dopamine cells and injecting them into the brains of people with Parkinson’s disease. The cells then matured and replaced the cells that had been lost during the progression of the disease.

The discovery of MPTP:
In July of 1982, Dr. J. William Langston of the Santa Clara Valley Medical Center in San Jose (California) was confronted with a group of heroin addicts who were completely immobile. A quick investigation demonstrated that the ‘frozen addicts’ had injected themselves with a synthetic heroin that had not been prepared correctly. The heroin contained a chemical called MPTP, which when injected into the body rapidly kills dopamine cells. This discovery provided the research community with a new tool for modeling Parkinson’s disease.

LSVT LOUD®:
LSVT stands for Lee Silverman Voice Treatment for use by speech pathologists; she was the first patient treated by this innovative therapeutic technique in 1985.   LSVT LOUD® was one of the first treatment strategies used for boosting the voice and sound levels of patients with Parkinson’s.   It is set up to be one hour per day for four days per week for four weeks of treatment, and it’s typically very effective in boosting volume and clarity of someone’s voice. LSVT LOUD® led to LSVT BIG®, developed by Dr. Becky Farley and others and it focused on improving movement, mobility, stiffness and stability in Parkinson’s.

Deep-brain stimulation (DBS) surgery becomes a treatment for Parkinson’s disease:
DBS is a surgical procedure used to treat some of the disabling neurological symptoms of Parkinson’s when drug therapy has failed to help the patient’s tremor, rigidity, stiffness, slowed movement, and walking problems.  There are three components in DBS surgery, the electrode, the extension from the electrode to the neurostimulator, which is also called the battery pack. The subthalamic nucleus and the globus pallidus are FDA-approved target sites in the brain for stimulation by the electrode. Although most patients still need to take medication after DBS, many patients experience considerable reduction of their  symptoms and are able to greatly reduce their medications.

“Imagination will often carry us to worlds that never were. But without it we go nowhere.” Carl Sagan

1997-2006, Milestones in Parkinson’s Disease Research and Discovery (Part 1d: Historical):

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Alpha synuclein becomes the first gene associated with familial cases of Parkinson’s disease and its protein is found in Lewy bodies:
In 1997, a group of researchers at the National institute of Health led by Robert Nussbaum reported the first genetic aberration linked to Parkinson’s disease. They had analyzed DNA from a large Italian family and some Greek familial cases of Parkinson’s disease.

The gene Parkin becomes the first gene associated with juvenile Parkinson’s disease:
The gene Parkin provides the instructions for producing a protein that is involved with removing rubbish from within a cell. In 1998, a group of Japanese scientists identified mutations in this gene that resulted in affected individuals being vulnerable to developing a very young onset (juvenile) version of Parkinson’s disease.

The first use of PET scan brain imaging for Parkinson’s disease:
Using the injection of a small amount of radioactive material (known as a tracer), the level of dopamine present in an area of the brain called the striatum could be determined in a live human being. Given that amount of dopamine in the striatum decreases over time in Parkinson’s disease, this method of brain scanning represented a useful diagnostic aid and method of potentially tracking the condition.

The launch of Michael J Fox Foundation:
In 1991, actor Michael J Fox was diagnosed with young-onset Parkinson’s disease at 29 years of age. Upon disclosing his condition in 1998, he committed himself to the campaign for increased Parkinson’s research. Founded on the 31st October, 2000, the Michael J Fox Foundation has funded more than $700 million in Parkinson’s disease research, representing one of the largest non-governmental sources of funding for Parkinson’s disease.

The Braak Staging of Parkinson’s pathology:
In 2003, German neuroanatomist Heiko Braak and colleagues presented a new theory of how Parkinson’s disease spreads based on the post mortem analysis of hundreds of brains from people who had died with Parkinson’s disease. Braak proposed a 6 stage theory, involving the disease spreading from the brain stem (at the top of the spinal cord) up into the brain and finally into the cortex.

The gene DJ1 is linked to early onset PD:
DJ1 (also known as PARK7) is a protein that inhibits the aggregation of Parkinson’s disease-associated protein alpha synuclein. In 2003, researchers discovered mutations in the DJ1 gene that made people vulnerable to a early-onset form of Parkinson’s disease.

The first GDNF clinical trial indicates neuroprotection in people with Parkinson’s disease:
A small open-label clinical study involving the direct delivery of the chemical Glial cell-derived neurotrophic factor (GDNF) into the brains of people with Parkinson’s disease indicated that neuroprotection. The subjects involved in the study exhibited positive responses to the treatment and postmortem analysis of one subjects brain indicated improvements in the brain.

The genes Pink1 and LRRK2 are associated with early onset PD:
Early onset Parkinson’s is defined by age of onset between 20 and 40 years of age, and it accounts for <10% of all patients with Parkinson’s.  Genetic studies are finding a causal association for Parkinson’s with five genes: α-synuclein (SNCA), parkin (PARK2), PTEN-induced putative kinase 1 (PINK1), DJ-1 (PARK7), and Leucine-rich repeat kinase 2 (LRRK2). However it happens, and at whatever age it occurs, there is no doubt that genetics and environment combine together to contribute to the development of Parkinson’s.

The discovery of induced pluripotent stem (IPS) cells:
In 2006, Japanese researchers demonstrated that it was possible to take skin cells and genetically reverse engineer them into a more primitive state – similar to that of a stem cell. This amazing achievement involved a fully mature cell being taken back to a more immature state, allowing it to be subsequently differentiated into any type of cell. This research resulted in the discoverer, Shinya Yamanaka being awarded the 2012 Nobel prize for Physiology or Medicine.

“Science is organized knowledge. Wisdom is organized life.” Immanuel Kant

2007-2016, Milestones in Parkinson’s Disease Research and Discovery (Part 1e: Historical):

Slide5

The introduction of the MDS-UPDRS revised rating scale:
The Movement Disorder Society (MDS) unified Parkinson’s disease rating scale (UPDRS) was introduced in 2007 to address two limitations of the previous scaling system, namely a lack of consistency among subscales and the low emphasis on the nonmotor features. It is now the most commonly used scale in the clinical study of Parkinson’s disease.

The discovery of Lewy bodies in transplanted dopamine cells:
Postmortem analysis of the brains of people with Parkinson’s disease who had fetal cell transplantation surgery in the 1980-1990s demonstrated that Lewy bodies are present in the transplanted dopamine cells. This discovery (made by three independent research groups) suggests that Parkinson’s disease can spread from unhealthy cells to healthy cells. This finding indicates a ‘prion-like’ spread of the condition.

SNCA, MAPT and LRRK2 are risk genes for idiopathic Parkinson’s disease:
Our understanding of the genetics of Parkinson’s is rapidly expanding. There is recent evidence of multiple genes linked to an increase the risk of idiopathic Parkinson’s. Interestingly, microtubule-associated protein tau (MAPT) is involved in microtubule assembly and stabilization, and it can complex with alpha-synuclein (SNCA).  Future therapies are focusing on  the reduction and clearance of alpha-synuclein and inhibition of Lrrk2 kinase activity.

 IPS derived dopamine neurons from people with Parkinson’s disease:
The ability to generate dopamine cells from skin cells derived from a person with Parkinson’s disease represents not only a tremendous research tool, but also opens the door to more personalized treatments of suffers. Induced pluripotent stem (IPS) cells have opened new doors for researchers and now that we can generate dopamine cells from people with Parkinson’s disease exciting opportunities are suddenly possible.

Neuroprotective effect of exercise in rodent Parkinson’s disease models:
Exercise has been shown to be both neuroprotective and neurorestorative in animal models of Parkinson’s. Exercise promotes an anti-inflammatory microenvironment in the mouse/rat brain (this is but one example of the physiological influence of exercise in the brain), which helps to reduce dopaminergic cell death.  Taking note of these extensive and convincing model system results, many human studies studying exercise in Parkinson’s are now also finding positive benefits from strenuous and regular exercise to better manage the complications of Parkinson’s.

Transeuro cell transplantation trial begins:
In 2010, a European research consortium began a clinical study with the principal objective of developing an efficient and safe treatment methodology fetal cell transplantation in people with Parkinson’s disease. The trial is ongoing and the subjects will be followed up long term to determine if the transplantation can slow or reverse the features of Parkinson’s disease.

Successful preclinical testing of dopamine neurons from embryonic stem cells:
Scientists in Sweden and New York have successfully generated dopamine neurons from human embryonic stem cells that can be successfully transplanted into animal models of Parkinson’s disease. Not only do the cells survive, but they also correct the motor deficits that the animals exhibit. Efforts are now being made to begin clinical trials in 2018.

Microbiome of the gut influences Parkinson’s disease:
Several research groups have found the Parkinson’s disease-associated protein alpha synuclein in the lining of the gut, suggesting that the intestinal system may be one of the starting points for Parkinson’s disease. In 2016, researchers found that the bacteria in the stomachs of people with Parkinson’s disease is different to normal healthy individuals. In addition, experiments in mice indicated that the bacteria in the gut can influence the healthy of the brain, providing further evidence supporting a role for the gut in the development of Parkinson’s disease.

“Any fool can know. The point is to understand.” Albert Einstein

2016-2017, Milestones in Parkinson’s Disease Research and Discovery (Part 2: Clinical trials either recently completed or in progress)

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Safety, Tolerability and Efficacy Assessment of Dynacirc (Isradipine) for PD (STEADY-PD) III trial:
Isradipine is a calcium-channel blocker approved for  treating high blood pressure; however, Isradipine is not approved for treating Parkinson’s. In animal models, Isradipine has been shown to slow the progression of PD by protecting dopaminergic neurons.  This study is enrolling newly diagnosed PD patients not yet in need of symptomatic therapy. Participants will be randomly assigned Isradipine or given a placebo.

Treatment of Parkinson’s Psychosis with Nuplazid:~50% of the people with Parkinson’s develop psychotic tendencies. Treatment of their psychosis can be relatively difficult. However, a new drug named Nuplazid™ was recently approved by the FDA specifically designed to treat Parkinson’s psychosis.

Opicapone (COMT Inhibitor) as Adjunct to Levodopa Therapy in Patients With Parkinson Disease and Motor Fluctuations:
Catechol-O-methyl transferase (COMT) inhibitors prolong the effect of levodopa by blocking its metabolism. COMT inhibitors are used primarily to help with the problem of the ‘wearing-off’ phenomenon associated with levodopa. Opicapone is a novel, once-daily, potent third-generation COMT inhibitor.  It appears to be safer than existing COMT drugs. If approved by the FDA, Opicapone is planned for use in patients with Parkinson’s taking with levodopa who experience wearing-off issues.

Nilotinib (Tasigna® by Novartis) indicates positive results in phase I trial:
Nilotinib is a drug used in the treatment of leukemia. In 2015, it demonstrated beneficial effects in a small phase I clinical trial of Parkinson’s disease. Researchers believe that the drug activates the disposal system of cells, thereby helping to make cells healthier. A phase II trial of this drug to determine how effective it is in Parkinson’s disease is now underway.

ISCO cell transplantation trial begins:
International Stem Cell Corporation is currently conducting a phase I clinical cell transplantation trial at a hospital in Melbourne, Australia. The company is transplanting human parthenogenetic stem cells-derived neural stem cells into the brains of people with Parkinson’s disease. The participants will be assessed over 12 months to determine whether the cells are safe for use in humans.

Neuropore’s alpha-synuclein stabilizer (NPT200-11) passes phase I trial:
Neuropore Therapies is a biotech company testing a compound (NPT200-11) that inhibits and stablises the activity of the Parkinson’s disease-associated protein alpha synuclein. This alpha-synuclein inhibitor has been shown to be safe and well tolerated in humans in a phase I clinical trial and the company is now developing a phase II trial.

mGluR4 PAM  (PXT002331) well tolerated in phase I trial:
Prexton Therapeutics recently announced positive phase I clinical trial results for their lead drug, PXT002331, which is the first drug of its kind to be tested in Parkinson’s disease. PXT002331 is a mGluR4 PAM – this is a class of drug that reduces the level of inhibition in the brain. In Parkinson’s disease there is an increase in inhibition in the brain, resulting in difficulties with initiating movements. Phase II clinical trials to determine efficacy are now underway.

Initial results of Bristol GDNF trial indicate no effect:
Following remarkable results in a small phase I clinical study, the recent history of the neuroprotective chemical GDNF has been less than stellar. A subsequent phase II trial demonstrated no difference between GDNF and a placebo control, and now a second phase II trial in the UK city of Bristol has reported initial results also indicating no effect. Given the initial excitement that surrounded GDNF, this result has been difficult to digest. Additional drugs that behave in a similar fashion to GDNF are now being tested in the clinic.

Immunotherapies proves safe in phase I trials (AFFiRis & Prothena):
Immunotherapy is a treatment approach which strengthens the body’s own immune system. Several companies (particularly ‘AFFiRis’ in Austria and ‘Prothena’ in the USA) are now conducting clinical trials using treatments that encourage the immune system to target the Parkinson’s disease-associated protein alpha synuclein. Both companies have reported positive phase I results indicating the treatments are well tolerable in humans, and phase II trials are now underway.

Living Cell Technologies Limited continue Phase II trial of NTCELLA New Zealand company called Living Cell Technologies Limited have been given permission to continue their phase II clincial trial of their product NTCELL, which is a tiny capsule that contains cells which release supportive nutrients when implanted in the brain. The implanted participants will be blindly assessed for 26 weeks, and if the study is successful, the company will “apply for provisional consent to treat paying patients in New Zealand…in 2017”.

MAO-B inhibitors shown to be neuroprotective:
MAO-B inhibitors block/slow the break down of the chemical dopamine. Their use in Parkinson’s disease allows for more dopamine to be present in the brain. Recently, several longitudinal studies have indicated that this class of drugs may also be having a neuroprotective effect.

Inhalable form of L-dopa:
Many people with Parkinson’s disease have issues with swallowing. This makes taking their medication in pill form problematic. Luckily, a new inhalable form of L-dopa will shortly become available following recent positive Phase III clinical trial results, which demonstrated a statistically significant improvements in motor function for people with Parkinson’s disease during OFF periods.

Exenatide trial results expected:
Exenatide is a drug that is used in the treatment of diabetes. It has also demonstrated beneficial effects in preclinical models of Parkinson’s disease, as well as an open-label clinical study over a 14 month period. Interestingly, in a two year follow-up study of that clinical trial – conducted 12 months after the patients stopped receiving Exenatide – the researchers found that patients previously exposed to Exenatide demonstrated significant improvements compared to how they were at the start of the study. There is currently a placebo-controlled, double blind phase II clinical trial being conducted and the results should be reported before the end of 2017.

“This is where it all begins. Everything starts here, today.” David Nicholls

A personal reflection:
In my adult life as a scientist, I’ve studied the world of hematology and how your blood clots.   And as a lifelong medical educator, I’ve taught the principles of biomedical science/hematology/oncology/immunology.   But this thing with Parkinson’s,  this for the rest of your life disorder is still relatively new in my life-line. Making this historical timeline was very educational for me; I learned a tremendous amount of information about this disease.  This timeline would not exist without the help and guidance of Simon my friend in Cambridge, England. He has his own blog entitled the Science of Parkinson’s.  Simon went out of his way to help plan and expedite this calendar of Parkinson’s history; I am most thankful for his participation.

“I’m going to be totally honest with you. Dealing with a diagnosis of Parkinson’s is not easy and there is no one, single technique that will ease the pain and no magic pill that will miraculously enable you to cope with it. However … I sincerely hope that you are able to come to terms with the diagnosis and perhaps even come to view it as a positive life-changing experience.” John Baxter

Cover photo credit: http://www.hoasaigon.com.vn/kcfinder/upload/images/tu-van-tang-hoa-chuc-mung-ngay-10-10-cho-nhung-nguoi-phu-nu-than-yeu-14.jp

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