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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Di Menna, Luisa Molinaro, Gemma Di Nuzzo, Luigi Riozzi, Barbara Zappulla, Cristina Pozzilli, Carlo Turrini, Renato Caraci, Filippo Copani, Agata Battaglia, Giuseppe Nicoletti, Ferdinando Bruno, Valeria |
| Description | Country affiliation: Italy Author Affiliation: Di Menna L ( I.R.C.C.S. Neuromed, 86077 Pozzilli (IS), Italy.) |
| Abstract | 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 10 min, and neuronal death was assessed 20 h later. FTY720, FTY720-P, and S1P were all neuroprotective when applied 18-20 h 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. |
| File Format | HTM / HTML |
| ISSN | 10436618 |
| Issue Number | 1 |
| Volume Number | 67 |
| e-ISSN | 10961186 |
| Journal | Pharmacological Research |
| Language | English |
| Publisher | Elsevier |
| Publisher Date | 2013-01-01 |
| Publisher Place | Netherlands |
| Access Restriction | One Nation One Subscription (ONOS) |
| Subject Keyword | Discipline Pharmacology Immunosuppressive Agents Pharmacology Neurons Drug Effects Neuroprotective Agents Organophosphates Propylene Glycols Sphingosine Analogs & Derivatives Animals Astrocytes Cell Death Cells, Cultured Female Fingolimod Hydrochloride Lysophospholipids Mice Rats Journal Article |
| Content Type | Text |
| Resource Type | Article |
| Subject | Pharmacology |
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