Premium
Fingolimod may support neuroprotection via blockade of astrocyte nitric oxide
Author(s) -
Colombo Emanuela,
Di Dario Marco,
Capitolo Eleonora,
Chaabane Linda,
Newcombe Jia,
Martino Gianvito,
Farina Cinthia
Publication year - 2014
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.24217
Subject(s) - astrocyte , fingolimod , neurodegeneration , neuroprotection , experimental autoimmune encephalomyelitis , microglia , neuroinflammation , neuroscience , multiple sclerosis , biology , pharmacology , medicine , inflammation , immunology , pathology , central nervous system , disease
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, interleukin (IL) 1R, 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 on astrocyte–neuron interaction. Furthermore, fingolimod efficacy in blocking astrocyte‐mediated neurodegeneration was evaluated. Results We found coordinated upregulation 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 2 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. Ann Neurol 2014;76:325–337