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Département des Neurosciences Cliniques, Hôpital Universitaire de Genève CH 1211 Genève, Suisse (M.B., A.B., P.B.); and Département des Neurosciences Fondamentales, Centre Médical Universitaire CH 1211 Genève, Suisse (I.N., D.M.)
Intracellular calcium increase is an early key event triggering ischemic neuronal cell damage. The role of T-type voltage-gated calcium channels in the neuronal response to ischemia, however, has never been studied. Using an in vitro model of ischemia-induced delayed cell death in rat organotypic hippocampal slice cultures, we show that T-type calcium channels inhibitors drastically reduce ischemic cell damage. Immunostaining studies reveal the existence of CaV3.1 and CaV3.2 types of low-voltage-activated calcium channels in rat organotypic hippocampal cultures. Low extracellular calcium (100 nM) or increase of intracellular calcium buffering ability by BAPTA-acetoxymethyl ester significantly reduced ischemia-induced neuronal damage. Pharmacological inhibition of the T-type calcium current by mibefradil, kurtoxin, nickel, zinc, and pimozide during the oxygen-glucose deprivation episode provided a significant protection against delayed neuronal death. Mibefradil and nickel exerted neuroprotective effects, not only if administrated during the oxygen-glucose deprivation episode but also in conditions of postischemic treatment. These data point to a role of T-type calcium currents in ischemia-induced, calcium-mediated neuronal cell damage and suggest a possible new pharmacological approach to stroke treatment.
Address correspondence to: Dr. Philippe Bijlenga, Neurochirurgie, Hôpital Universitaire de Genève, 24 rue Micheli-du-Crest, 1211 Geneva 14, Switzerland. E-mail: philippe.bijlenga{at}hcuge.ch
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