Novel protective effect of mifepristone on detrimental GABA A receptor activity to immature Purkinje neurons

ABSTRACT Immature Purkinje neurons are particularly vulnerable cells. They survive in cerebellar slice cultures under treatment by the synthetic steroid mifepristone (RU486) that depolarizes them at this age. The present study aims at understanding the mechanism underlying this neuroprotective effect. In the developing cerebellum, the role of γ‐aminobutyric acid (GABA) in neuron survival is unknown. In 3‐d‐old mouse cerebellar slice cultures, we show that GABA A receptor activation is depolarizing and excitatory. Antagonists of GABA A receptors rescue Purkinje neurons, demonstrating that GABA is endogenously released in this preparation and is toxic. Mifepristone likely protects these neurons by reversing GABA A receptor‐mediated chloride fluxes and reducing their driving force. Neuroprotection by mifepristone is dose‐dependently decreased by the agonist of GABA A receptors muscimol and by caffeine, an agonist of internal calcium store release. Moreover, the survival induced by neomycin, an inhibitor of calcium release, is partially reversed by muscimol. The p38 mitogen‐activated protein kinase (MAPK) inhibitor SB239063 also rescues Purkinje neurons. In summary, we propose that when GABA is depolarizing, mifepristone protects Purkinje neurons by shunting GABA responses and probably chloride fluxes, by inhibiting p38 MAPK activity and likely internal calcium store release. A new and nonhormonal effect of mifepristone is thus revealed.—Rakotomamonjy, J., Levenes, C., Baulieu, E. E., Schumacher, M., Ghoumari, A. M. Novel protective effect of mifepristone on detrimental GABA A receptor activity to immature Purkinje neurons. FASEB J. 25, 3999–4010 (2011). www.fasebj.org