Two structurally different T-type Ca2+ channel inhibitors, mibefradil and pimozide, protect CA1 neurons from delayed death after global ischemia in rats

作者：Bancila M; Copin J C; Daali Y; Schatlo B; Gasche Y; Bijlenga Philippe^*

来源：Fundamental & Clinical Pharmacology, 2011, 25(4): 469-478.

DOI：10.1111/j.1472-8206.2010.00879.x

• ischemia
• mibefradil
• neuroprotection
• pimozide
• stroke
• T-type calcium channel

Recent in vitro evidence suggests that T-type Ca2+ channels are implicated in the mechanisms of ischemia-induced delayed neuronal cell death. The aim of this work was to study the neuroprotective potential of mibefradil and pimozide, both T-type Ca2+ channel inhibitors, in an in vivo rat model of global ischemia. We performed blinded and randomized placebo vs. treatment experiments using 57 animals to test mibefradil and fourteen animals to test pimozide. Each treated animal received a single stereotactic intraventricular injection of mibefradil or intraperitoneal injection of pimozide prior to transient global cerebral ischemia. The primary endpoint was the number of neurons surviving in the CA1 region 72 h after insult as evaluated by NeuN-labeled cell counts. All physiological variables monitored immediately before and after ischemic insult were equivalent between all groups. Surviving neurons in the CA1 region were significantly more frequent in the treated groups compared to the placebo group (mibefradil: 36.8 +/- 2.8 cells in a 200 x 100 mu m counting area vs. placebo: 25.2 +/- 3.2 [P < 0.01]; pimozide: 39.4 +/- 1.12 vs. placebo: 27.8 +/- 0.7 [P < 0.0001]). Thus, administration of mibefradil or pimozide effectively prevents neuronal death after ischemia in a rat model of global ischemia. This study provides further support for a neuroprotective effect of T-type Ca2+ current inhibition during ischemia.

• 出版日期2011-8