The image above presents a ‘before treatment’ (left) and ‘after treatment’ (right) brain scan image from a recent research report of a clinical study that looked at the use of Acetylcysteine (also known as N-acetylcysteine or simply NAC) in Parkinson’s disease.
DaTscan brain imaging technique allows us to look at the level of dopamine processing in an individual’s brain. Red areas representing a lot; blue areas – not so much. The image above represents a rather remarkable result and it certainly grabbed our attention here at the SoPD HQ (I have never seen anything like it!).
In today’s post, we will review the science behind this NAC and discuss what is happening with ongoing clinical trials.
Source: The Register
Let me ask you a personal question:
Have you ever overdosed on Paracetamol?
Regardless of your answer to that question, one of the main treatments for Paracetamol overdose is administration of a drug called ‘Acetylcysteine’.
Why are you telling me this?
Because acetylcysteine is currently being assessed as a potential treatment for Parkinson’s disease.
Oh I see. Tell me more. What is acetylcysteine?
Acetylcysteine. Source: Wikimedia
Acetylcysteine (N-acetylcysteine or NAC – commercially named Mucomyst) is a prodrug – that is a compound that undergoes a transformation when ingested by the body and then begins exhibiting pharmacological effects. Acetylcysteine serves as a prodrug to a protein called L-cysteine, and – just as L-dopa is an intermediate in the production of dopamine – L-cysteine is an intermediate in the production of another protein called glutathione.
Take home message: Acetylcysteine allows for increased production of Glutathione.
What is glutathione?
Glutathione. Source: Wikipedia
Glutathione (pronounced “gloota-thigh-own”) is a tripeptide (a string of three amino acids connected by peptide bonds) containing the amino acids glycine, glutamic acid, and cysteine. It is produced naturally in nearly all cells. In the brain, glutathione is concentrated in the helper cells (called astrocytes) and also in the branches of neurons, but not in the actual cell body of the neuron.
It functions as a potent antioxidant.
We have previously discussed antioxidants (click here to read that post). An antioxidant is simply a molecule that prevents the oxidation of other molecules. Which begs the question:
What is oxidation?
Oxidation is the loss of electrons from a molecule, which in turn destabilises the molecule. Think of iron rusting. Rust is the oxidation of iron – in the presence of oxygen and water, iron molecules will lose electrons over time. Given enough time, this results in the complete break down of objects made of iron.
Rusting iron. Source: Thoughtco
The exact same thing happens in biology. Molecules in your body go through a similar process of oxidation – losing electrons and becoming unstable. This chemical reaction leads to the production of what we call free radicals, which can then go on to damage cells.
What is a free radical?
A free radical is an unstable molecule – unstable because they are missing electrons. They react quickly with other molecules, trying to capture the needed electron to re-gain stability. Free radicals will literally attack the nearest stable molecule, stealing an electron. This leads to the “attacked” molecule becoming a free radical itself, and thus a chain reaction is started. Inside a living cell this can cause terrible damage, ultimately killing the cell.
Antioxidants are thus the good guys in this situation. They are molecules that neutralize free radicals by donating one of their own electrons. The antioxidant don’t become free radicals by donating an electron because by their very nature they are stable with or without that extra electron.
How free radicals and antioxidants work. Source: h2miraclewater
When the brain is affected by free radicals or any other toxic agent, astrocytes can release their store of glutathione into the space outside of neurons to help defend those them from any attack, and glutathione within the branches of the neurons deals with anything that actually manages to enter the cell.
Thus, glutathione plays an important in removing free radicals.
Do we know anything about glutathione with regards to Parkinson’s disease?
Yes we do.
First, glutathione appears to be reduced in many important areas of the Parkinsonian brain:
Title: Parkinson’s disease: a disorder due to nigral glutathione deficiency?
Authors: Perry TL, Godin DV, Hansen S.
Journal: Neurosci Lett. 1982 Dec 13;33(3):305-10.
The investigator who conducted this study began by analysing levels of glutathione in autopsied human brain. They found that in general glutathione content is significantly lower in the substantia nigra (the region where the dopamine neurons live) than in other brain regions. But when they looked at glutathione levels in the substantia nigra of people who died with Parkinson’s disease, they barely detected any glutathione at all.
This result has been subsequently repeated by several other independent groups (Click here, here and here to see some of those reports). The initial discovery, though, led the investigators to excitedly question whether the Parkinson’s disease was partly the result of a glutathione deficiency.
Unfortunately for those excited investigators, glutathione deficiency is not specific to Parkinson’s disease:
Title: Nigral glutathione deficiency is not specific for idiopathic Parkinson’s disease.
Authors: Fitzmaurice PS, Ang L, Guttman M, Rajput AH, Furukawa Y, Kish SJ.
Journal: Mov Disord. 2003 Sep;18(9):969-76.
In this study, the researchers found that decreased levels of glutathione in the substantia nigra is a common feature across several neurodegenerative conditions, including progressive supranuclear palsy (PSP) and multiple system atrophy (MSA).
Interestingly they also saw a trend towards decreased levels of uric acid (another antioxidant that we have previously discussed – Click here to read that post) in the substantia nigra of all the neurodegenerative groups analysed (a decrease of -19 to -30%). In addition, previous reports have indicated that glutathione levels in the brains of people with Alzheimer’s disease are significantly reduced (click here for more on this). Thus, reduced levels of glutathione appears to be a common feature of neurodegenerative conditions.
Researchers have subsequently found that decreased levels of glutathione does not directly result in dopamine cell loss (Click here to read more about this), but it does make the cells more vulnerable to damaging agents (such as neurotoxins, etc – Click here and here to read more about this). This has lead investigators to ask whether administering glutathione to people with Parkinson’s disease would slow done the condition.
Has glutathione ever been tested in clinical studies for Parkinson’s disease?
Yes it has. At least four times in fact!
Title: Reduced intravenous glutathione in the treatment of early Parkinson’s disease.
Authors: Sechi G, Deledda MG, Bua G, Satta WM, Deiana GA, Pes GM, Rosati G.
Journal: Prog Neuropsychopharmacol Biol Psychiatry. 1996 Oct;20(7):1159-70.
In the first clinical trial to test glutathione in Parkinson’s disease, the investigators recruited nine people with recently diagnosed (and untreated) Parkinson’s disease. Glutathione was administered intravenous twice per day (600 mg each time) for 30 days. The drug was then discontinued and the participants were followed up for 4 months.
All of the participants in this study improved significantly after glutathione treatment (an average of 42% decline in disability) and the beneficial effects lasted for 2-4 months after the treatment was stopped at the end of the study. Particularly, interesting was the change in resting tremor intensity:
Intensity of the resting tremor of a subject with PD at baseline (A), after 30 day of glutathione treatment (B), 60 days after stopping glutathione treatment (C), and 30 days after returning to L-dopa (D). Source: Sciencedirect
Following this study, a series of videos were placed online which caused a lot of excitement within the Parkinson’s community:
A second video demonstrated some beneficial effects in three other people with Parkinson’s disease:
One cautionary note regarding the first glutathione study and these subsequent videos, however, is that in all of these cases, the investigators and the subjects were not blind – they all knew who was getting the treatment and what the treatment was. Thus, investigator bias and the placebo effect could have been at work.
To deal with this possibility a randomised, double blind clinical study was organised by Dr David Perlmutter (one of the investigators who first posted the videos online):
Title: Randomized, double-blind, pilot evaluation of intravenous glutathione in Parkinson’s disease.
Authors: Hauser RA, Lyons KE, McClain T, Carter S, Perlmutter D.
Journal: Mov Disord. 2009 May 15;24(7):979-83.
The investigators of this study randomly assigned 20 subjects with Parkinson’s disease to receive intravenous glutathione (1,400 mg) or a placebo treatment (10 people in each group). Both were administered three times a week for 4 weeks. The investigators found that glutathione was well tolerated and there were no withdrawals due to any adverse events of the treatment.
Importantly, there were no significant differences in changes in Unified Parkinson’s Disease Rating Scale (UPDRS) scores. The UPDRS is a universally utilised method of scoring the severity of Parkinson’s disease features/symptoms. Over the 4 weeks of study, the glutathione group exhibited only a mild improvement when compared to the control. That trend did continue, however, over a subsequent 8 week follow up period, which saw the control group worsened by an average of 3.5 points more than the glutathione-treated group. The researchers concluded by suggesting that further evaluation was required in a larger, longer study.
Intravenous delivery of glutathione is not an ideal treatment approach for a community that has movement issues, and this was taken into consideration when the next clinical trial of glutathione was conducted:
Title: A randomized, double-blind phase I/IIa study of intranasal glutathione in Parkinson’s disease.
Authors: Mischley LK, Leverenz JB, Lau RC, Polissar NL, Neradilek MB, Samii A, Standish LJ.
Journal: Mov Disord. 2015 Oct;30(12):1696-701. doi: 10.1002/mds.26351. Epub 2015 Jul 31.
PMID: 26230671 (This article is OPEN ACCESS if you would like to read it)
In this study, the researchers utilised a nasal spray approach to get glutathione into the body. The goal of the study was to test the safety and tolerability of intranasal delivery of glutathione in people with Parkinson’s disease. The investigators recruited 30 individuals with Parkinson’s disease, who were randomly assigned to either a placebo/control group (saline) or to a treatment group (two doses were tested on the treatment group – 300 mg/day or 600 mg/day of intranasal glutathione). The study was conducted over 3 months and found little difference between the groups with regards to the clinical features of Parkinson’s disease, but did find that intranasal glutathione was well tolerated by all of those involved in the study.
This first trial has subsequently led to a phase II study to look more carefully at the effectiveness of intranasal delivery of glutathione.
Title: Phase IIb Study of Intranasal Glutathione in Parkinson’s Disease
Authors: Mischley LK, Lau RC, Shankland EG, Wilbur TK, Padowski JM.
Journal: J Parkinsons Dis. 2017 Apr 20. doi: 10.3233/JPD-161040.
PMID: 28436395 (This article is OPEN ACCESS if you would like to read it)
Curiously in this double-blind, placebo-controlled clinical trial, all of the 45 individuals (averaging 3.5 years since diagnosis) involved in the study improved during the study (including the control group), suggesting that there was some kind of placebo effect at play within the cohort. The subjects were divided into three groups: a control group, a low dose treatment group, and a high dose treatment group for the intranasal glutathione treatment.
The high-dose group demonstrated improvement in total UPDRS score over their baseline scores, but neither treatment group improved more than the placebo control group (who also improved). It was therefore difficult for the researchers to conclude that glutathione is superior to placebo after a three month intervention (although obviously there may have been a placebo effect occurring in the control).
So glutathione treatment doesn’t work?
I would not interpret the results that way.
Firstly, none of these clinical studies have recruited enough participants for major conclusions to be made of their results, except that collectively they indicate that glutathione appears to be safe for use in folks with Parkinson’s disease.
In addition, they have all been rather short studies (conducted over a matter of weeks or months) which makes determining changes in UPDRS scores or simply disease progression rather difficult. Parkinson’s is a slow progressive condition. Therapies that slow or halt the disease require longer periods to demonstrate efficacy.
Are there any clinical trials being conducted at the moment for glutathione in Parkinson’s disease?
There have been quite a few clinical trials involving glutathione, but currently there is only one that is recruiting, and that study is only a brain imaging study that will be investigating glutathione levels using magnetic resonance spectroscopy imaging, to determine if quantitative measures can be made. The hope is that glutathione can be used as a biomarker – allowing for measurements of disease progression.
So there are no clinical trials for glutathione at the moment?
Not that I’m aware of (and happy to be corrected on this). And this is a shame. It would be good to have a proper, large, double-blind clinical trial to evaluate the potential of glutathione, ideally over 6-12 months.
There are, however, other ongoing clinical studies that are investigating drugs that indirectly influence this glutathione pathway:
Edison Pharmaceuticals is a biotech company taking a drug (EPI-589) to the clinic for Parkinson’s disease. EPI-589 (also known as Troloxamide quinone) is a redox (meaning reduction–oxidation reaction) active molecule, that has significant effects on increasing glutathione levels.
Exactly what EPI-589 does is a bit of a mystery (there is very little preclinical data available regarding it – even on the company’s own website). It is described online as an “NAD(P)H dehydrogenase (quinone) modulator” (which basically translates to: an antioxidant.
In this phase IIa clinical trial, investigators are recruiting 40 individuals who have recently been diagnosed with Parkinson’s (and are currently not being treated with any drugs such as L-dopa), and they are also recruiting subjects with genetic forms of Parkinson’s (such as mutations in genes such as PARKIN, PINK, and LRRK2).
The trial will run for 5 months and all of the participants will be taking the drug EPI-589 (it will be an open-label study – Click here for more information regarding this trial). You can also find more information on the CureParkinson’s Trust website.
Ok, and what about the clinical study of NAC in Parkinson’s disease you mentioned at the start of the post?
Ah yes. I almost forgot.
So in addition to treating paracetamol (acetaminophen) overdose (as discussed above), acetylcysteine is also used to loosen up thick mucus in conditions such as cystic fibrosis or chronic obstructive pulmonary disease. It can be taken intravenously, by mouth (in pill form), or inhaled as a mist.
One of the big issues with using glutathione as a treatment is that glutathione can not be taken up by neurons. It is generally made inside the cell. NAC, on the other hand is readily taken up by neurons and it can help to boost neuronal GSH levels. NAC has been shown to be neuroprotective in animal models of Parkinson’s disease (Click here to read more on this), which has led researchers to investigate its use as a potential treatment for Parkinson’s disease:
Title: N-Acetyl Cysteine May Support Dopamine Neurons in Parkinson’s Disease: Preliminary Clinical and Cell Line Data.
Authors: 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.
Journal: PLoS One. 2016 Jun 16;11(6):e0157602.
PMID: 27309537 (This article is OPEN ACCESS if you would like to read it)
The researchers in this study began their investigation by looking at the effect of NAC on the survival of dopamine neurons (made from human embryonic stem cells) in culture after exposure to a neurotoxin (rotenone; which is a pesticide/insecticide that has been associated with Parkinson’s disease – click here to read more on this).
They found that NAC treatment resulted in significantly more dopamine neurons surviving the exposure to rotenone when compared to cultures that received no NAC. Armed with this result, the investigators boldly moved straight into the clinic and started a clinical study (click here for the details of that trial). They took 23 people with Parkinson’s disease (average time since diagnosis was approx. 3 years) and randomly assigned them to either the NAC group (12 subjects) or the control group (11 subjects). The study was not blinded, so both the investigators and the participants knew which treatment they were being administered. And the NAC was administered intravenously and orally.
At the start of the study, all of the subjects were assessed using the UPDRS scoring system and imaging of the brain was conducted using DaTscan. During the study, both groups continued their normal treatment for their Parkinson’s symptoms, with the experimental group also receiving NAC (50mg/kg) once per week. After approximately 90 days of NAC treatment, all of the subjects underwent a follow up evaluation, which included another UPDRS assessment and DaTscan brain image.
After the study, the UPDRS score of the NAC treated group dropped from an average of 25.6 to 22.3, while the control group increased from 20.2 to 22.2. The UPDRS has a list of 55 items that are graded 0-4 depending on level of severity. A lower score indicates a more normal level of activity. Thus, any decrease in UPDRS score can be seen as a positive outcome – in this case the treated group improved by 12.9% on average.
Importantly, the brain imaging also showed a significantly increase in DAT binding in the caudate and putamen in the brain. The investigators wrote that the increase ranged from 4.4% to 7.8%….
…which does bring into question the image at the top of this post….
That would be this image here:
Now,…. call me me crazy, but the increase in the level of red between the left (before NAC treatment) and right (after NAC treatment) brain scans strikes me as sliiiightly more than an 8% increase! No?
Either way, the investigators saw beneficial effects from using NAC in subjects with Parkinson’s disease. Yes, the study was not blinded, but it is intriguing that the benefits were observed in brain imaging assessments as well as clinical scores – it is harder to suggest any placebo effect is occurring when brain imaging suggests improvements.
Two clinical trials following up these results. One study is being conducted at Thomas Jefferson University by the researchers who conducted the study reviewed above. This study is recruiting participants by invitation only – click here to read more about this. The second study is being conducted by the National Institute of Neurological Disorders and Stroke (NINDS) (Click here for more information about this).
Is this the first time NAC has been tested in people with Parkinson’s disease?
Wow, this sounds good. Where can I get me some of this NAC stuff?
NAC is widely available as a dietary supplement.
But… there is just one slight problem with it: NAC is poorly absorbed when taken orally. Only about 6–10% of it passes through to the blood stream, and this can vary between individuals (Click here and here to read more on this).
But NAC is an interesting molecule that warrants further research. Some investigators have suggested that NAC may have a direct role in neuroprotection as a scavenger of oxygen radicals by itself (Click here for more on this). And it has been shown to be a modulator of the immune system and mitochondrial processing (Click here and here for more on this).
Thus I think it deserves more attention.
What does it all mean?
A recent clinical study has suggested some positive benefits to using acetylcysteine (or NAC) – a supplement that stimulates the production of an antioxidant called glutathione. This study and other previous clinical studies investigating glutathione production, indicate that NAC is worthy of further investigation (both in the lab and the clinic).
For those folks who are interested in learning more about NAC, you should definitely read a recent post on Prof Frank Church’s blog Journey with Parkinson’s.
Hope you liked it Don.
This additional section has been added following a question asked by a reader in the comments section below. The question was:
“If PD patients ONLY take the NAC pills (no intravenous, due to the problems associated with intravenous administration), and 1) only 6-10% of oral NAC makes it to the blood stream, and 2) the experiment did not specifically test for oral only NAC;
we do not know if NAC pill only patients would that see the same positive results?
It’s a good question, addressing an issue I basically avoided in the post to save space (the post was getting long and unwieldy). Plus, I’m not sure that we really know the answer.
A couple of years ago this research report was published:
Title: Cerebrospinal fluid concentrations of N-acetylcysteine after oral administration in Parkinson’s disease.
Authors: Katz M, Won SJ, Park Y, Orr A, Jones DP, Swanson RA, Glass GA.
Journal: Parkinsonism Relat Disord. 2015 May;21(5):500-3.
PMID: 25765302 (This article is OPEN ACCESS if you would like to read it)
In this study, the investigators recruited 12 people with Parkinson’s disease and gave them oral NAC twice daily for 2 days. Three different doses of NAC were compared (7 mg/kg, 35 mg/kg, and 70 mg/kg), and cerebrospinal fluid (the liquid that your brain sits in) was collected before the start of the study and then again at 90 min after the last dose of NAC, to analyse levels of NAC reaching the brain and the amount of glutathione subsequently produced.
The results showed that the lowest dose (7mg/kg) had little effect, but the highest dose (70mg/kg) significantly increased NAC levels in the cerebrospinal fluid. This means that NAC is getting into the brain after oral treatment. One issue arising from this study however, was that this increase in NAC levels had little/no effect on the levels of glutathione circulating in the spinal fluid (see image below).
No change in glutathione (GSH) levels. Source: rxlist
Now, this lack of glutathione increase could simply be due to the short time frame of the study (just 2 days). Or it could be that glutathione is principally produced and housed inside neurons and helper cells (like astrocytes) in the brain, and not much of it is floating around for investigators to detect.
What was really missing from this study was an analysis of some actual brain tissue, and it would appear that the participants were not too willing to have samples taken (understandable I guess).
Luckily for us, these same scientists followed up that first study and published a report recently about a study addressing exactly how much NAC in cerebrospinal fluid was required to affect glutathione levels in neurons:
Title: Neuronal Glutathione Content and Antioxidant Capacity can be Normalized In Situ by N-acetyl Cysteine Concentrations Attained in Human Cerebrospinal Fluid.
Authors: Reyes RC, Cittolin-Santos GF, Kim JE, Won SJ, Brennan-Minnella AM, Katz M, Glass GA, Swanson RA.
Journal: Neurotherapeutics. 2016 Jan;13(1):217-25.
PMID: 26572666 (This article is OPEN ACCESS if you would like to read it)
In this study, healthy mice were treated with NAC over a range of doses, and then the researchers measured neuronal glutathione levels and neuronal antioxidant capacity in pieces of brain tissue. Glutathione levels (and the antioxidant capacity) was augmented by NAC at doses that produced peak cerebrospinal fluid NAC concentrations of ≥50 nM. This is far below the 10mM levels achieved using 70mg/kg of NAC in the first study, suggesting that “oral NAC administration can surpass the levels required for biological activity in brain”. In other words, not much oral NAC is required for beneficial levels to be achieved.
Re-reading through this now, I guess this last section would have rounded off the post quite nicely and maybe I should have added it (Blame my poor judgement on limited ability and writing this stuff in the wee small hours). But one important question remains: does this last finding in the mice apply in a situation like Parkinson’s disease where there is already a reduction in glutathione levels in the brain? (see top of the post) Further research is required looking that NAC and Parkinson’s disease.
So my answer is we simply don’t know.
EDITOR’S NOTE: Under absolutely no circumstances should anyone reading this material consider it medical advice. The material provided here is for educational purposes only. Before considering or attempting any change in your treatment regime, PLEASE consult with your doctor or neurologist. While some of the drugs discussed on this website are clinically available, they may have serious side effects. We therefore urge caution and professional consultation before any attempt to alter a treatment regime. SoPD can not be held responsible for any actions taken based on the information provided here.
The banner for today’s post was sourced from PLOSONE