Will you get the NAC


Schipper HM, Arnold D, GrandʼMaison F, Melmed C, Moore F, Levental M, Su H, Constantin M, Stril JL, Godin J.Tolerability and Safety of Combined Glatiramer Acetate and N-Acetylcysteine in Relapsing-RemittingMultiple Sclerosis. Clin Neuropharmacol. 2015 . [Epub ahead of print]

INTRODUCTION:Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system where inflammation and neurodegeneration play key roles. Mounting evidence implicates oxidative stress in the development of irreversible neuronal and glial injury in this condition. N-acetylcysteine (NAC) is a sulfhydryl amino acid derivative with anti-oxidant and anti-apoptotic properties. Administration of NAC to mice attenuated the induction of or improved experimental autoimmune encephalomyelitis (an MS model).
METHODS: We performed an open-label study to explore the tolerability and safety of the combination of glatiramer acetate (GA) and NAC in patients with relapsing-remitting multiple sclerosis. Seven patients with relapsing-remitting multiple sclerosis with at least one T1 gadolinium-enhancing lesion on screening magnetic resonance imaging were recruited. Treatment consisted of a 10-week run-in period followed by 36-week treatment with a combination of GA 20 mg subcutaneously once daily plus NAC 2.5 g orally twice daily. Outcome measures included safety and tolerability, redox biochemistry, and magnetic resonance imaging effect.
RESULTS:Treatment with the combination of GA and NAC was safe and well tolerated.
CONCLUSIONS:In light of the favourable safety profile, an efficacy-demonstrating study may be considered.
N-acetylcysteine is a pharmaceutical drug and nutritional supplement used primarily as a mucolytic agent and in the management of paracetamol(acetaminophen) overdose. Other uses include sulfate repletion in conditions, such as autism, where cysteine and related sulphur amino acids may be depleted. This compound is sold as a dietary supplement commonly claiming antioxidant and liver protecting effects. It is used as a cough medicine because it breaks disulfide bonds in mucus and liquefies it, making it easier to cough up. MAC serves as a prodrug to L-cysteine which is a precursor to the biologic antioxidant, glutathione and hence administration of NAC replenishes glutathione stores. Glutathione (GSH) is an important antioxidant in plants, animals, fungi, and some bacteria and archaea, preventing damage to important cellular components caused by reactive oxygen species such as free radicals, peroxides, lipid peroxides. Now there is a interest in affecting this oxidative stress to protect nerves.

Many, many years ago this bloke called Mark Nobel who was working on the development of oligodenrocytes came up to me and he said I have this idea for treating MS and it is very safe and I’ve been taking it for months. He asked will you have a look in EAE to see what it does…so being inquisitive and willing to give anything a go (even to spend 3 days & nights giving drug hourly to unblock veins for Andrew Wakefield-yes that Andrew Wakefield of autism infamy and yes it was a bust but that’s another story), I said yes.

We planned the experiment and it was done. I was looking at this data the other day written up on a type writer it did absolutely nothing to EAE in ABH mice. Mark left London and is a neuroscientist professor at the University of Rochester who now works on stem cells (watch his TEDtalk). 

Later, out came a study by Lehman D et al. 1994. Oral administration of the oxidant-scavenger N-acetyl-L-cysteine inhibits acute experimental autoimmune encephalomyelitis. It apparently worked in early EAE…I was very sceptical. Move-on a decade or more and now we know that MS and EAE is not just autoimmunity and now I realise that we did the wrong experiments years earlier. We should have targeted nerve loss not the T cell. It was never going to inhibit autoimmunity…so sorry Mark we botched your idea, because the idea was ahead of its time.

An emient MRI Prof Neuro said this to me “Your idea its ahead of its time” when we tried in vane to get progression studies years off the ground years, before the penny dropped. 

The pressing need is to strive for NEDA and saving brain…when will this penny drop with neurologists….or certain neurologists?

Anyway back to the story. So now we know more, and a few years ago I said to one of the guys in the lab why don’t we do a neuroprotection study with NAC, so she went off to do a bit of reading and came back and said why would we use NAC, as an anti-oxidant for MS as it does not penetrate into the CNS very well, based on some papers. However there was a NAC-amide that did penetrate the CNS, being made by a company. We wrote to them a number of times to try and get our hands on the drug, and we didn’t get anywhere and time passed and we just moved on. We later saw Offen D et al. 2004. A low molecular weight copper chelator crosses the blood-brain barrier and attenuates experimental autoimmune encephalomyelitis.

Maybe this was why we could not get our hands on the drug, but they had not done the right EAE experiments to properly look at neuroprotection. I recently looked and I could get my hands on the drug, but can we justify the expense and is it worth it as how is this going to be developed?

However, now we have this study they give NAC to someone on copaxone. They conclude it is safe (NSS!)…surprise, surprise it’s an ingredient of cough medicine. However, as the sample size is only seven people it is not going to tell use anything useful. The question I would want to know…is does much of the NAC or the active ingedient gets into the CNS in  humans? If not, it is not going to be a very good neuroprotective. 

Likewise we, can ask the same question about BG-12/tecfidera.

Does anyone know if the active ingredient of BG-12 gets into the CNS in any appreciable amount? I’ve seen a poster on Dimethyl fumarate indicating that most of it doesn’t get in the CNS.

Next what is the pathway to get NAC or NAC + copaxone approved? 

Who is going to spend millions on a trial for a drug costing pennies…Maybe a candidate for MS SMART-2. 

Have you signed up to MS SMART 1(click here).

You are going to say that there are some papers reporting brain effects of NAC….yes there are some. There is the metsbolite permeability and we have also shown that CNS exclusion can be use to good advantage, to target drugs to where they are needed.

Remember Biogen are testing a remyelination treatment that is according to Biogen people 99.9% excluded from the CNS (this is anti-Lingo-1 not BG-12). But is this a good starting point when most of your drug is doing nothing?

Likewise, there are also studies of human beta interferon and cladribine working in rodent when neither of them cross-react to a targets in rodents and so a bit of reading tells you that the experiments have no validity, so why would you do them?

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  • I think it can deliver the cysteine part as this does cross the BBB, not sure if why you don't try just cysteine? Or NAC Ethyl ester?

  • Good point maybe we missed an opertunity and maybe we should have done a suck it and see. This would not be very 3Rs and it was one of mNy ideas at the time and we had more ideas than time and money to do the experiments.

    I would have to look back on the papers to see what happened to cysteine and maybe the metabolite gets into the CNS with BG12. It is all relative, some drug gets in CNS but should you start with a sub optimal condition.

    • Worth a look, from what I've read, though personally I stopped using this years ago, as I became aware of the fact it doesn't all cross the BBB except the cysteine part and too expensive for only a potentially small benefit. These days I take n-acetyl l carnatine (may just be anti-inflammatory, but possibly improves nerve regeneration/possibly nerve pain and anti-depressant) and alpha lipoic acid (also anti- inflammatory as well as an anti-oxidant), which do and *may* also have a beneficial affect on cognition. Combined with lots of leafy green veggies, peppers and asparagus (natural source of NAC)! I don't buy the hype around all supposed neutraceuticals but a few are certainly worth investigating.

  • Is there proof that NAC doesn't cross the bbb?
    I read a number of papers on NAC and how it affects ocidative stress also how it's been used in ocd where oxidative stress has been implicated (ocd and EBV also linked in some papers)
    Would this suggest it crosses the bbb? I've been taking Swanson NAC 1800 a day for about a month. No side effects low risk and high gain should it work I guess.
    Is there another form of NAC you believe works better

    • read the papers to get the links. on evidence we can not support this as a useful treatment and likewise we have no evidence it is useless.

  • MD looks "coincidence" but yesterday I was consulting with my nutritionist. She had passed me a series of blood tests. She looked for all, and as I returned to physical activity (weight training) she spent a specific diet and still went on to supplement N-acetyl-Cysteine, Lysine and Carnitine … I never question because the "expert" is ver, not me …

  • A quick look retrieved the following recent review on NAC and some of its derivatives:
    It has some refs on NAC, NAC-amide, and NAC – ethyl ester crossing the blood brain barrier
    As far as the "copper chelator" 2004 paper is concerned, the authors may have hoped to improve complexation with copper by having an extra amide group – but I really doubt amide will bind well at neutral pH

  • MD, it's really trivial to make an amide from cysteine or N-acetylcysteine. Your chemistry collaborators can do this very quickly if the compounds are not commercially available and/or cheap

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