Friday, 19 October 2012

Research: Gilenya could be useful for progressive MS

Di Menna L, Molinaro G, Di Nuzzo L, Riozzi B, Zappulla C, Pozzilli C, Turrini R, Caraci F, Copani A, Battaglia G, Nicoletti F, Bruno V. PROTECTS CULTURED CORTICAL NEURONS AGAINST EXCITOTOXIC DEATH. Pharmacol Res. 2012 Oct 13. pii: S1043-6618(12)00191-0. doi: 10.1016/j.phrs.2012.10.004.

Fingolimod (FTY720), a novel drug approved for the treatment of relapsing-remitting multiple sclerosis, activates different sphingosine-1-phosphate receptor (S1PR) subtypes. Its primary mechanism of action is to reduce the egress of T lymphocytes from secondary lymphoid organs, thus restraining neuroinflammation and autoimmunity. However, recent evidence suggests that the action of FTY720 involves S1PRs expressed by cells resident in the CNS, including neurons. Here, we examined the effect of FTY720, its active metabolite, FTY720-P, and sphingosine-1-phosphate (S1P) on neuronal viability using a classical in vitro model of excitotoxic neuronal death. Mixed cultures of mouse cortical cells were challenged with toxic concentrations of N-methyl-D-aspartate (NMDA) for 10min, and neuronal death was assessed 20-24h later. FTY720, FTY720-P, and S1P were all neuroprotective when applied 18-20h prior to the NMDA pulse. Neuroprotection was attenuated by pertussis toxin, and inhibited by the selective type-1 S1PR (S1P1R) antagonist, W146, and by inhibitors of the mitogen associated protein kinase (MAPK) and the phosphatidylinositol-3-kinase (PtdIns-3-K) pathways. Both FTY720 and FTY720-P retained their protective activity in pure cultures of mouse or rat cortical neurons. These data offer the first direct demonstration that FTY720 and its active metabolite protect neurons against excitotoxic death.

Although Gilenya and Spingolimod inhibit the white blood cell entry in the blood and stop them entering the brain, it is not clear how this action would affect progressive MS, yet the former is in trial in PPMS and the latter is about to go on trial in SPMS. S1P receptors are found in brain cells. In this study they looked at what happens when glutamate (NMDA) receptors are over stimulated. We believe that this is a cause of nerve loss following stroke where too much glutamate stimulation in areas outside the areas of damage caused by blockage of the blood vessel. This is known as excitotoxicity as the nerve is excited to death. This works in part because too much glutamate stimulation causes calcium levels within a cell to rise to such a level that cell suicide is triggered. In MS we think there there may also be glutamate induced excitoxity, due to loss of inhibitory nerve signals, too much nerve signals and glutamate production by inflammatory cells and altered glutamate removal processes by nerves and astrocytes. This study suggests that the active chemicals from gilenya (also called fingolimod also called FTY-720) can inhibit excitotoxicity and so this is the evidence to suggest that Gilenya, could be useful in controlling progression. It would have been good if this had been demonstrated in a living animal. This has been done and has shown beneficial effect in a model of stroke, however there it was suggested that anti-inflammatory mechanisms, and possibly vasculoprotection, rather than direct effects on neurons, underlie the beneficial effects of fingolimod after experimental stroke. Let us hope this is the case but let us wait to see what happens in the trials in humans

1 comment:

  1. I hope that there is a proven and measured positive effect of gilenya on progressive MS. By now and what I'm writing as obviously only anecdotal value, just seeing other fellow MSers that changed from tysabri to gilenya (mainly because JC virus tested positive, not because they and their doctors wanted), are not so well and their disease is either relapsing or progressive at sight :(
    I had to change too this year, and on the 2 month safety break between therapies, my right eye got worse (blurred again) and the worse part was the fatigue that rose abruptly. Now I am struggling to not give up the things I was used to do, emotionaly it is a tremendous challenge to accept to do less, because energy levels changed dramaticaly.
    I believe is not gilenya fault, perhaps it is only tysabri absence.... I wish that gilenya may already start doing its effect from now on, and compensate this gap.
    This makes any sense to anyone? Similar experiences?

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