Inhibition of T-type calcium channels protects neurons from delayed ischemia-induced damage.
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 Ca(V)3.1 and Ca(V)3.2 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.
Nikonenko
I
I
Département des Neurosciences Cliniques, Hôpital Universitaire de Genève CH 1211 Genève, Suisse.
Bancila
M
M
Bloc
A
A
Muller
D
D
Bijlenga
P
P
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009924:Organ Culture Techniques; D010477:Perfusion; D051381:Rats
D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D018696:Neuroprotective Agents