Sunday, 4 May 2014

Are Neuroprotectants already Prescribable?

Gilani AA, Dash RP, Jivrajani MN, Thakur SK, Nivsarkar M. Evaluation of GABAergic Transmission Modulation as a Novel Functional Target for Management ofMultiple Sclerosis: Exploring Inhibitory Effect of GABA on Glutamate-Mediated Excitotoxicity. Adv Pharmacol Sci. 2014;2014:632376

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS) where the communication ability of nerve cells in the brain and spinal cord with each other gets impaired. Some current findings suggest the role of glutamate excitotoxicity in the development and progression of MS. An excess release of glutamate leads to the activation of ionotropic and metabotropic receptors, thus resulting in accumulation of toxic cytoplasmic Ca(2+) and cell death. However, it has been observed that gamma-aminobutyric acid-A (GABA-A) receptors located in the nerve terminals activate presynaptic Ca(2+)/calmodulin-dependent signaling to inhibit depolarization-evoked Ca(2+) influx and glutamate release from isolated nerve terminals, which suggest a potential implication of GABA receptor in management of MS. With this proof of concept, we tried to explore the potential of selective GABA receptor agonists or positive allosteric modulators (diazepam and phenobarbitone sodium) and GABA level enhancer (sodium valproate) for management of MS by screening them for their activity in experimental autoimmune encephalomyelitis (EAE) model in rats and cuprizone-induced demyelination model in mice. In this study, sodium valproate was found to show the best activity in the animal models whereas phenobarbitone sodium showed moderate activity. However, diazepam was found to be ineffective.

We do not often comment of EAE papers and their "cure of the week potential" . This report demonstrates that stimulators of GABA receptor which inhibits nerve transmission can control some of the signs of EAE. 

This idea is not new and has been reported before and maybe debatable ( 

Maybe there is disease modifying potential but we have to be sure that the animals are not too whacked out because it could be the stress of the side-effects that could control disease. Being near a building site does this to animals it is probably the frequency of noise and vibration that we can't sense or do not worrying about, as I don't think living near a building site eases your MS.

However this post raises an interesting point.

What causes damage in progressive and relapsing MS possibly many different things but one thought is too much nerve excitation.

The major excitatory nerve transmitting molecule that helps the nerve impulses travel along the nerves is called glutamate. We need this for life to makes nerve work but too much glutamate can cause the nerve to let too much calcium (Please note this is not a dietary thing and we need calcium to survive) to enter and this triggers cell suicide. So too much glutamate is not good.

 However nerve transmitting molecules exist in a balance an Yin and Yang (hows that for spellin) and there is an inhibitory transmitter called GABA. This works by stimulating GABA receptors and there are a number of them such as GABA-A and GABA-B. Drugs that stimulate these receptors are used to control some symptoms of MS such as diazepam for GABA-A and baclofen for GABA-B. This quells the symtoms caused by too much glutamate such as spasticity where the muscles get too excited and stay contracted.

In this study they report that drugs that stimulate GABA-A may have some disease modifying potential. But could it mean that symptom control drugs can slow down progression. We think this is possible. It was almost shown in the Cannabis studies, look at the people who were EDSS <5.5ers and it did.

Does GABA receptor stimulation affect the rate of progression?
I have asked the question before and the answer is we don't really know?  We don't have the data. Who is going to do the study for a generic drug costing not that much...I suspect no one.

This is where a comprehensive register may be of value to look at the disease course of a large number of people and this type of data may be found.

A phase III drug trial for progressive MS takes 5-7 years for a DMT but a symptom control drug trial takes 1-2 years. So you could be on drug 5 years quicker. Is it a no brainer for pharma to target the lower hanging fruit to get at a bigger fish, and once you can have a drug there is no incentive to test to see if it affects progression.

However a symptomatic drug gets a lower price than a DMT (about 10-20 times less) so I wonder what would happen?


  1. I, a RRMSers for two years, am taking valproate acid (DepakoteTM) initially for mood disorders. My mood is now stabilized but Depakote interacts with Tecfidera in an interesting way. I turn red quasi instantly if I take the Depakote after the Tecfidera and I have nausea (the most common side effect of Depakote) at the same time. More interesting, my nystagmus disappeared. I stopped taking the Tecfidera, afraid of more important side effects (severe lymphocytopenia for instance). I am taking 500 mg of Depakote morning and evening. My plan is to reduce to dose to 250 mg morning/night and restart the Tecfidera (first 250mg one per day midday). Do you think it is a good idea?

    1. Valproate inhibits enzymes in the liver that are involved in the breakdown of other drugs and one wonders if this interacts with tecfidera

      As to a good or bad idea...I suggest that you consult with you physician before starting or stopping treatments or experimenting

  2. Thank you for your answer. My neuro opinion is to wait (I stopped Tecfi) until sept and change of treatment. I might do that and try Cladribine. Do you think that such interactions would exist in this case?


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