Saturday, 17 May 2014

Neuroprotection by Memantine

Sühs KW, Fairless R, Williams SK, Heine K, Cavalié A, Diem R. N-Methyl-D-Aspartate Receptor Blockade Is Neuroprotective in Experimental Autoimmune Optic NeuritisJ Neuropathol Exp Neurol. 2014 May 6. [Epub ahead of print]
Optic neuritis is a common clinical manifestation of the chronic inflammatory CNS disease multiple sclerosis that can result in persistent visual impairment caused by degeneration of optic nerve axons and apoptosis of retinal ganglion cells (RGCs). Using a model of experimental autoimmune encephalomyelitis with optic neuritis (Brown Norway rats), we show that administration of the N-methyl-D-aspartate (NMDA) receptor antagonists memantine or MK801 results in RGC protection, axon protection, and reduced demyelination of optic nerves. Calcium imaging revealed that RGC responses to glutamate stimulation predominantly occurred via NMDA receptors and were inhibited by memantine in a dose-dependent manner. In contrast, oligodendrocytes were mainly responsive through the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptor. This suggests that NMDA receptor blockade protected RGCs directly and that the protection was independent of effects on oligodendrocytes. Moreover, increased RGC survival was observed before the onset of optic nerve demyelination-when RGC degeneration had already started. These results indicate an important pathophysiologic role for NMDA receptor-mediated glutamate toxicity during the induction phase of this disease model and highlight a potential target for therapeutic neuroprotection in human optic neuritis.
This study shows that drugs like memantine are neuroprotective in optic neuritis. 

I would also add that it can be neuroprotective in EAE also..we really should publish this!  It is one of the many generic drugs we have found that can influence nerve loss,without affecting the autoimmunity. This blocks the influence of the glutamate the excitatory neurotransmitter stimulating too much influx of calcium that in excess is deadly to cells. 

The problem of blocking the NMDA receptor like the AMPA receptor another glutamate receptor is the development of side effects. This will be exaggerated in MSers with less nerve circuitry because we need NMDA and AMPA signalling for normal nerve function,block them and normal function can be lost.
Therefore the NMDA receptors blockers that can be used in man have to be very weak blockers. Memantine is one. It is used to slow cognitive problems in Alzheimer's disease. 

The problem is it has been used in so many MS studies and has not shown much improvement. However  until a trial design is found that can really work out if drugs are neuroprotective then potentially useful drugs will continue to be thrown away. 

It is a cheap and chips drug that is unlikely to be developed. 
Maybe one could think about trying in in a neuroprotective study in optic neuritis before too much damage has accumulated.


1 comment:

  1. Amantadine is a known NMDA receptor antagonist and also a symptomatic treatment for fatigue. Can this compound be neuroprotective?

    ReplyDelete

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