Two structurally different T-type Ca 2+ channel inhibitors, mibefradil and pimozide, protect CA1 neurons from delayed death after global ischemia in rats.

Abstract

Recent in vitro evidence suggests that T-type Ca(2+) 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 Ca(2+) 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 × 100 μm 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 Ca(2+) current inhibition during ischemia.

• Authors: M Bancila, J-C Copin, Y Daali, B Schatlo, Y Gasche, Philippe Bijlenga
• Journal: Fundamental & clinical pharmacology (Fundam Clin Pharmacol) Vol. 25 Issue 4 Pg. 469-78 (Aug 2011) ISSN: 1472-8206 [Electronic] England
• PMID: 21039820 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2010 The Authors Fundamental and Clinical Pharmacology © 2010 Société Française de Pharmacologie et de Thérapeutique.

Chemical References

• CACNA1H protein, human
• Calcium Channel Blockers
• Calcium Channels, T-Type
• Neuroprotective Agents
• Pimozide
• Mibefradil
• Lactic Acid
• Glucose

Topics

• Animals
• Brain (drug effects, metabolism)
• CA1 Region, Hippocampal (drug effects, pathology)
• Calcium Channel Blockers (metabolism, pharmacokinetics, pharmacology, therapeutic use)
• Calcium Channels, T-Type (drug effects, genetics, metabolism)
• Cell Death (drug effects)
• Cell Survival (drug effects)
• Electrophysiological Phenomena (drug effects, physiology)
• Glucose (deficiency)
• HEK293 Cells
• Humans
• Hypoxia
• Ischemic Attack, Transient (blood, drug therapy, mortality, pathology)
• Lactic Acid (blood)
• Male
• Membrane Potentials (physiology)
• Mibefradil (metabolism, pharmacokinetics, pharmacology, therapeutic use)
• Neurons (drug effects, pathology)
• Neuroprotective Agents (metabolism, pharmacokinetics, pharmacology, therapeutic use)
• Pimozide (pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Survival Analysis
• Tissue Culture Techniques
• Transfection