Trial for progressive MS will it get in the brain?

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Glutathione is a substance made from the amino acids glycine, cysteine, and glutamic acid. It is produced by the liver and is involved in many body processes. Glutathione is involved in tissue building and repair, making chemicals and proteins needed in the body, and in immune system function. Glutathione is an antioxidant in plants, animals, fungi, and some bacteria Glutathione is capable of preventing damage to important cellular components caused by reactive oxygen species such as free radicals, peroxides, lipid peroxides, and heavy metals. So inhibitors of glutathione should be good for progressive MS if part of the problem is due to reactive oxygen species.

When I was a scientific ameoba about thirty-forty years ago someone came to me with the idea that inhibiting glutathione would be useful. Would I have a go in EAE to see if it was useful? I was always willing to give stuff a try in those days and I said yes.

The person was so convinced it “was a goer” that they were taking the solution themselves. How were they going to do it?

Compounds such as N-acetylcysteine (NAC) and alpha lipoic acid are both capable of helping to regenerate glutathione levels. You may have heard of lipoic acid and its potential for treating progressive MS. You can read here if interested. It has been identified as a potential useful target for progressive MS

Cunniffe N, Vuong KA, Ainslie D, Baker D, Beveridge J, Bickley S, Camilleri P, Craner M, Fitzgerald D, de la Fuente AG, Giovannoni G, Gray E, Hazlehurst L, Kapoor R, Kaur R, Kozlowski D, Lumicisi B, Mahad D, Neumann B, Palmer A, Peruzzotti-Jametti L, Pluchino S, Robertson J, Rothaul A, Shellard L, Smith KJ, Wilkins A, Williams A, Coles A. Systematic approach to selecting licensed drugs for repurposing in the treatment of progressive multiple sclerosis. J Neurol Neurosurg Psychiatry. 2021 Mar;92(3):295-302

Now the approach suggested to me many years ago was to test N-acetyl-cysteine.  I did it in the early stages of EAE and in my hands it did nothing (It is possible my dose used was not good enough)…I didn’t published it and I am sorry that it gave little info to help the person with the idea the option to develop it.. Eventually, it was dropped and the person stopped doing MS research and went back to the country where they were born. Sadly I, and they, did not understand the nuissances of relapsing and progressive MS at the time, like all of my peers.

The person wanted to treat progressive MS but we were using a model that was approriate for relapsing MS and so no wonder it didn’t do anything in our hands. However, when I did understand it and thought that it may work in progression and was gearing up to do some progression studies we did a literature review and we found this paper.

Offen D, Gilgun-Sherki Y, Barhum Y, Benhar M, Grinberg L, Reich R, Melamed E, Atlas D. A low molecular weight copper chelator crosses the blood-brain barrier and attenuates experimental autoimmune encephalomyelitis. J Neurochem. 2004; 89:1241-51

In that paper it said “In the present study, we characterize the chemical and redox properties of N-acetylcysteine amide (AD4), a low molecular weight thiol-compound that, unlike N-acetyl cysteine, readily crosses the BBB”. In the present study, we characterize the chemical and redox properties of N-acetylcysteine amide (AD4), a low molecular weight thiol-compound that, unlike N-acetyl cysteine, readily crosses the BBB” and also “In contrast, N-acetylcysteine (10–30mg/kg) that was injected intraperitoneally or administered orally (160 mg/kg) did not appear in the brain extracts indicating no entry into the brain”.

We wrote to the group producing the AD4 numerous times to try and get the drug but nothing was forthcoming. So with this information of poor penetration it was difficult for us to justify blindly doing the animal studies in progressive EAE, which would take months and cost alot….So there the story stopped for us.

They followed the study up Gilgun-Sherki Y, Barhum Y, Atlas D, Melamed E, Offen D. Analysis of gene expression in MOG-induced experimental autoimmune encephalomyelitis after treatment with a novel brain-penetrating antioxidant. J Mol Neurosci. 2005;27:125-35

However, I did remember this and in 2020, I was taking N-acetyl cysteine. This is a medication that is used to treat paracetamol overdose and to loosen thick mucus in individuals with chronic bronchopulmonary disorders like pneumonia and bronchitis. Some people use it as a dietary supplement. That’s how I got my hands on it. Early on in COVID-19 there was a suggestion that reactive oxygen species were going to be bad, so I thought I would take an anti-oxidant along with some other anti-COVID concoctions I thought would be useful. So I took my pills every day…However, I must admit NAC tasted awful and I am sure it gave me “Heartburn” and so I stopped it. It may be too acidic.

However, NAC may not be optimum for MS because it is said “Over six decades, numerous studies involving NAC therapy have yielded inconsistent results, and this could be due to low bioavailability.” This may mean a lot of what you swallow does not reach the blood stream, which would limit it’s activity. However, others have other views . Now NAC has been tried in MS and there was not much to write about in relapsing MS, based on imaging It was also tried in MS related fatigue and blood flow. However, it has suggested that NAC can be neuroprotective in animals…one has to hope sufficient will enter the MS for progressive MS. Therefore,maybe the person was right and they were just ahead of their time.

Anyway a trial in progressive MS is now planned. Will it work?

I hope so and I hope it is not too late for the person so see if their ideas come to fruition

There is evidence for neuroprotective effects in animals,

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