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FINGOLIMOD PROTECTS CULTURED CORTICAL NEURONS AGAINST EXCITOTOXIC DEATH.
MedLine Citation:
PMID:  23073075     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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.
Authors:
Luisa Di Menna; Gemma Molinaro; Luigi Di Nuzzo; Barbara Riozzi; Cristina Zappulla; Carlo Pozzilli; Renato Turrini; Filippo Caraci; Agata Copani; Giuseppe Battaglia; Ferdinando Nicoletti; Valeria Bruno
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-10-13
Journal Detail:
Title:  Pharmacological research : the official journal of the Italian Pharmacological Society     Volume:  -     ISSN:  1096-1186     ISO Abbreviation:  Pharmacol. Res.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-17     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8907422     Medline TA:  Pharmacol Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012. Published by Elsevier Ltd.
Affiliation:
I.R.C.C.S. Neuromed, 86077 Pozzilli (IS), Italy.
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