Saturday, 2 August 2014

Gilenya may affect astrocyte function

Colombo E, Dario MD, Capitolo E, Chaabane L, Newcombe J, Martino G, Farina C. Fingolimod may support neuroprotection via blockade of astrocyte nitric oxide. Ann Neurol. 2014 Jul . doi: 10.1002/ana.24217.

Objective: Although astrocytes participate in glial scar formation and tissue repair, dysregulation of the NFκB pathway and of nitric oxide (NO) production in these glia cells contributes to neuroinflammation and neurodegeneration. Here we investigated the role of the crosstalk between sphingosine-1-phosphate (S1P) and cytokine signaling cascades in astrocyte activation and inflammation-mediated neurodegeneration, and addressed the effects of fingolimod on astrocyte-neuron interaction and NO synthesis in vivo. 

Methods: Immunohistochemistry, immunofluorescence and confocal microscopy were used to detect S1P receptors, IL1R, IL17RA and nitrosative stress in multiple sclerosis (MS) plaques, experimental autoimmune encephalomyelitis (EAE) spinal cord and the spinal cord of fingolimod-treated EAE mice. An in vitro model was established to study the effects of S1P, IL1 and IL17 stimulation on NFkB translocation and NO production in astrocytes, on spinal neuron survival, and astrocyte-neuron interaction. Further, fingolimod efficacy in blocking astrocyte-mediated neurodegeneration was evaluated. 
Results: We found coordinated upregulations of IL1R, IL17RA, S1P1 and S1P3 together with nitrosative markers in astrocytes within MS and EAE lesions. In vitro studies revealed that S1P, IL17 and IL1 induced NFκB translocation and NO production in astrocytes, and astrocyte conditioned media triggered neuronal death. Importantly, fingolimod blocked the two activation events evoked in astrocytes by either S1P or inflammatory cytokines resulting in inhibition of astrocyte-mediated neurodegeneration. Finally, therapeutic administration of fingolimod to EAE mice hampered astrocyte activation and NO production. 
Interpretation: A neuroprotective effect of fingolimod in vivo may result from its inhibitory action on key astrocyte activation steps.
Astrocytes are a very ignored player in the potential to damage or maintain the CNS environment. In this study there is a suggestion that gilenya may block astrocyte activation to block their neurodegenerative potential. This study shows that it blocks cytokines. The dice is now cast and we should know very soon if gilenya blocks progressive MS, if it does then this may be a mechanism but if it does then this is just hypothectical.

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