Category Archives: Complementary and Alternative Medicine

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.

Screen Shot 2017-05-25 at 3.43.19 PM

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.

Screen Shot 2017-05-25 at 3.47.06 PM

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

Save

Parkinson’s Treatment With Dopamine Agonist, Complementary and Alternative Medicine (CAM), and Exercise

“Stop taking identity in illness and start taking identity in wellness” Nina Leavins

“The thought of hope is the seed to healing.” Shilpa Menon

Précis: Several of you have asked for an update on my strategy for treating my  Parkinson’s.  My current plan consists of traditional Parkinson’s medication,  augmented by a complementary and alternative medicine (CAM) approach, and supplemented by exercise.

Is current Parkinson’s therapy similar to the new models of personalized medicine?:  Those of us with Parkinson’s have a  constellation of symptoms that vary from person-to-person.   There is no doubt that people with Parkinson’s have a movement disorder with unifying clinical features. However, expression and rate of progression of the common physical symptoms (rigidity; slowness of movement; postural instability and gait problems; and tremor) differ in each of us. This degree-of-difference in how we express our Parkinson’s is likely a combination of environmental  influences [both internal (physiologic) and external (life-style)] and genetics.

Ask 10 people with Parkinson’s to describe their symptoms and their therapy; I wouldn’t be surprised if you get 10 (slightly) different answers. In someway we are lucky (okay, relieved is likely a better word choice) because we received the diagnosis, we began being treated, and probably we started feeling better.

There is a new (and developing) trend in treating patients using a more personalized approach aimed at preventing disease with individualized treatment once the disease is diagnosed (and includes individual genetic tests). This is called personalized medicine or precision medicine (‡given at the bottom is a fuller definition).   Although there is no specific genetic test for the most common form of Parkinson’s (termed idiopathic or sporadic), I believe our neurologists are already using a form of personalized medicine to manage our individual and varied (but still somewhat similar) symptoms.

“When you got a condition, it’s bad to forget your medicine.”  Frank Miller

“If you suspect that you have Parkinson’s, knowing for certain will be much better than uncertainty.” Glenna Wotton Atwood

My Parkinson’s treatment strategy involves traditional drugs, complementary and alternative medicine (CAM), and  exercise: Compared to others, my treatment plan may seem relatively simple. It has been devised by many conversations with my Neurologist and Internist. Combined with a lot of reading and internet searching of the medical literature on what has worked in Parkinson’s treatment, the CAM list continues to evolve and be refined [e.g., I believe that NAC travels to the brain in a usable form to then boost intracellular  glutathione levels.].  The diagram below  presents an overview of the strategy for treating my Parkinson’s.

16.04.28.Brain.Med.CAM.Exercise

-Dopamine agonists: For the past two years I’ve been taking the dopamine agonist Ropinirole. Recently, we decided to add the Neupro transdermal patch, which is another dopamine agonist (Rotigotine).  By  using the dopamine agonist patch, the thought is to normalize the amount of dopamine agonist in my body throughout the day (i.e., smooth out the peaks and valleys). I have tried to  draw it schematically below.

16.05.02.Normalizing.DA.Levels

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 altering the progression of my Parkinson’s. [Please consult with your physician before taking any type of new medication.]

-Complementary and Alternative Medicine (CAM): “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.”  (http://www.cancer.gov/cancertopics/cam). My CAM strategy for treating Parkinson’s goes as follows: compounds (reportedly) able to penetrate the blood brain barrier; compounds (possibly) able to slow progression of the disorder; compounds that are anti-oxidative and anti-inflammatory; compounds that don’t adversely alter dopamine synthesis/activity; and compounds that support general brain/nervous system health. [Please consult with your physician before taking any type of supplements.]

-Exercise: Exercise improves flexibility, builds muscle mass,  aids sleep, and reduces stress. Exercise is neuroprotective in Parkinson’s (see: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136051/ and http://www.neurology.org/content/77/3/288 and http://www.ncbi.nlm.nih.gov/pubmed/21375602 ).  For anyone with Parkinson’s, it is important to stretch and exercise on a very regular basis. Brian Lambert remarked: “With Parkinson’s, exercise is better than taking a bottle of pills. If you don’t do anything you’ll just stagnate.”  My strategy is relatively simple, make time in each day to exercise (it’s that important): stretch every couple of hours (the exercises in LSVT BIG are fantastic); and try to exercise every day for 30-60 minutes (playing/walking 18 holes of golf takes ~4-5 hr). I do a lot of exercises with range of motion sports like golf and boxing on a reflex bag (more tennis this summer).  Most importantly, I do exercises that I really enjoy doing and it brings a lot of enjoyment to the way my body feels. [Please consult with your physician before beginning any new exercise routine.]

 -The Table below summarizes my  approach to managing my Parkinson’s:

16.05.04.DailyTherapy*Footnote to Table: Medical (MED), Experimental (EXP), Complementary and alternative medicine (CAM), Exercise (EXERC).

 -Past References: In previous posts linked here, I have described various aspects of my treatment strategy (click on word/phrase):  first treatment plan; complementary and alternative medicine (CAM); Isradipine; exercise-1; exercise-2; exercise-3; LSVT BIG.

“Exercise is king. Nutrition is queen. Put them together and you’ve got a kingdom.”   Jack LaLanne

“There’s always a moment that separates the past from the future, and that moment is now.” Aniekee Tochukwu

Managing Parkinson’s: While we wait for a cure, we manage our disorder by many methods. While we wait for the potion that slows progression, we exercise and remain hopeful. While we live with a neurodegenerative disorder, we strive to remove the label and we stay positive.
Please stay involved in managing your disorder.
Please work with your Neurologist to develop your own ideal strategy.
Please stretch and exercise, it’ll make a difference.
Please use hope and positivity to remain focused and persistent.
Please use loved ones and support team to help sustain your treatment plan.
What you do in managing your disorder will help you today and for many more future days.

 “We look for medicine to be an orderly field of knowledge and procedure. But it is not. It is an imperfect science, an enterprise of constantly changing knowledge, uncertain information, fallible individuals, and at the same time lives on the line. There is science in what we do, yes, but also habit, intuition, and sometimes plain old guessing. The gap between what we know and what we aim for persists. And this gap complicates everything we do.” Atul Gawande

‡”Personalized medicine is a medical model that separates patients into different groups—with medical decisions, practices, interventions and/or products being tailored to the individual patient based on their predicted response or risk of disease.” (https://www.google.com/search?q=personalied+medicine&ie=utf-8&oe=utf-8#q=personalized+medicine)

Cover photo credit: http://az616578.vo.msecnd.net/files/2016/03/19/635940149667803087959444186_6359344127228967891155060939_nature-grass-flowers-spring-2780.jpg

Brain image modified from: http://cdn.playbuzz.com/cdn/bb0810a8-aeff-403b-b38a-e1e9fc9f7c81/79502c61-ec41-4802-8e22-92a0ddc0cc20.jpg