Fingolimod protects cultured cortical neurons against excitotoxic death

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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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.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalPharmacological Research
Volume67
Issue number1
DOIs
StatePublished - Jan 1 2013

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Neurons
Aspartic Acid
Phosphatidylinositol 3-Kinase
Lysosphingolipid Receptors
Relapsing-Remitting Multiple Sclerosis
Poisons
Pertussis Toxin
Fingolimod Hydrochloride
Autoimmunity
Mitogens
Protein Kinases
T-Lymphocytes
Pharmaceutical Preparations
FTY 720P
sphingosine 1-phosphate

Keywords

  • Cortical cultures
  • Excitotoxicity
  • FTY720
  • Neuroinflammation
  • Neuroprotection

ASJC Scopus subject areas

  • Pharmacology

Cite this

Di Menna, L., Molinaro, G., Di Nuzzo, L., Riozzi, B., Zappulla, C., Pozzilli, C., ... Bruno, V. (2013). Fingolimod protects cultured cortical neurons against excitotoxic death. Pharmacological Research, 67(1), 1-9. https://doi.org/10.1016/j.phrs.2012.10.004

Fingolimod protects cultured cortical neurons against excitotoxic death. / 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.

In: Pharmacological Research, Vol. 67, No. 1, 01.01.2013, p. 1-9.

Research output: Contribution to journalArticle

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 2013, 'Fingolimod protects cultured cortical neurons against excitotoxic death', Pharmacological Research, vol. 67, no. 1, pp. 1-9. https://doi.org/10.1016/j.phrs.2012.10.004
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. / Fingolimod protects cultured cortical neurons against excitotoxic death. In: Pharmacological Research. 2013 ; Vol. 67, No. 1. pp. 1-9.
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