Protecting oligodendrocytes

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Many years ago we were interested in cannabis as a nerve protector and one way we thought that it worked was to control nerve excitability. Nerve excitation is associated with electrically charged calcium and sodium entry into the cell making the inside cell more positive and if you get too much excitation it triggers cells to die by cell suicide. As a result of cannabinoid receptor stimulation, chemicals in cannabis block calcium entry into the cell and moves potassium out of the cell making the inside less electrically positive and so could stop the cell suicide. MD2 showed this worked in the beasties and we maintain it occurred in human trials also, but because this trial contained a large number of slow progressors it was classed as a failure. We also wondered if baclofen did the same. There was no data on the disease modifying potential. This works in the same way as the cannabinoid receptor it worked via the GABA B receptor….GABA-A receptor could do the same thing but it does this by allowing chloride to enter the cell. As chloride ions are more electrically negative this reduces the positive charge. This works to block spasticity by the same mechanism.

Although this activity is at the level of the nerve, more recently it was recognised that oligodentrocyte precursors also express these channels. One suspects that it may be something to do with nerves stimulating the precursors to make myelin. Once the nerve is myelinated they lose alot of the channels through which these charged chemicals move.

In this study they note that too much excitation damages myelin forming cells due to the action of stimulation of glutamate. There are different glutamate receptors simulated by AMPA, NMDA and kainate and this acts as calcium channel. Remember too much calcium is damaging. Here they suggest that a glutamate receptor subtype oligodndrocyte survival and suggest that MS-spasticity drugs can affects oligodendrocyte damage. I wonder if we can find out if this benfits the course of MS.This info sort of suggests it could

Bayón-Cordero L, Ochoa-Bueno BI, Ruiz A, Ozalla M, Matute C, Sánchez-Gómez MV. GABA Receptor Agonists Protect From Excitotoxic Damage Induced by AMPA in Oligodendrocytes. Front Pharmacol. 2022 Jul 26;13:897056. doi: 10.3389/fphar.2022.897056. eCollection 2022

Oligodendrocytes are the myelin forming cells of the central nervous system, and their vulnerability to excitotoxicity induced by glutamate (Excitatory neurotransmitter) contributes to the pathogenesis of neurological disorders including brain ischemia (lack of oxygen) and neurodegenerative diseases, such as multiple sclerosis. In addition to glutamate receptors, oligodendrocytes express GABA receptors (GABAR) (GABA is a major inhibitor neurotransmitter) that are involved in their survival and differentiation. The interactions between glutamate and GABAergic systems are well documented in neurons, under both physiological and pathological conditions, but this potential crosstalk in oligodendrocytes has not been studied in depth. Here, we evaluated the protective effect of GABAR agonists, baclofen (GABAB) and muscimol (GABAA), against AMPA-induced (Type of Glutamate) excitotoxicity in cultured rat oligodendrocytes. First, we observed that both baclofen and muscimol reduced cell death and caspase-3 activation (triggers cell suicide) after AMPA insult, proving their oligoprotective potential. ….. We determined that baclofen and muscimol also impaired AMPA-induced intracellular calcium increase and subsequent mitochondrial membrane potential alteration and other elements…. Overall, our results suggest that GABAR activation initiates alternative molecular mechanisms that attenuate AMPA-mediated apoptotic excitotoxicity in oligodendrocytes by interfering with expression of glutamate receptor subunits GluR subunits in membranes and with calcium-dependent intracellular signaling pathways. Together, these findings provide evidence of GABAR agonists as potential oligodendroglial protectants in central nervous system disorders.

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7 comments

  • I was recently directed to take a 500mg calcium supplement daily for osteopenia by a primary care doc. Is this much calcium risky for pwMS?

    • No…dietry calcium is part of daily life just as is salt and sodium chloride, I am talking about sodium and calcium ions which are in the fluids that bathe our cells and are found inside and outside. So not taking calcium does not mean you will save nerves, it would mean your teeth and bones go etc

      • Wasn’t there a study in ECTRIMS about high VitD dosage and calcium absorption that might affect neuro inflammation?

        • There are lots of studies on vitamin D claiming this and that and taking high levels calcium with vitamin D should be avoided, there is a risk of kidney stones

    • There are at least fifty poptassium channels expressed at some stage in oligos, potassium channel biology is very complex.
      Yes 4-AP acts on some but there are many more different types

  • Hi! In patients with a baclofen implant, isn’t the drug going straight into the nervous system? Would ‘monitoring’ these ppl help getting answers?
    Thanks

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