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

Article Article scientifique Article Two structurally different T-type Ca<sup>2+</sup> channel inhibitors, mibefradil and pimozide, protect CA1 neurons from delayed death after global ischemia in rats eng 2010-10-06 2011-08 author Bancila Mircea Service de Neurochirurgie, Département des Neurosciences Cliniques, Hôpitaux Universitaires de Genève et Université de Genève, 1211 Geneva, Switzerland. 135742 author Copin Jean-Christophe 524456 author Daali Youssef 46042 Département d'anesthésiologie, pharmacologie et soins intensifs (APSIC) author Schatlo Bawarjan 673588 author Gasche Yvan 32923 Département d'anesthésiologie, pharmacologie et soins intensifs (APSIC) author Bijlenga Philippe Alexandre Pierre 0000-0002-3586-2757 104899 Département des neurosciences cliniques (OTONO) 469-478 10.1111/j.1472-8206.2010.00879.x 21039820 0767-3981 https://onlinelibrary.wiley.com/doi/10.1111/j.1472-8206.2010.00879.x 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. Animals Brain / drug effects Brain / metabolism CA1 Region, Hippocampal / drug effects CA1 Region, Hippocampal / pathology Calcium Channel Blockers / metabolism Calcium Channel Blockers / pharmacokinetics Calcium Channel Blockers / pharmacology Calcium Channel Blockers / therapeutic use Calcium Channels, T-Type / drug effects Calcium Channels, T-Type / genetics Calcium Channels, T-Type / metabolism Cell Death / drug effects Cell Survival / drug effects Electrophysiological Phenomena / drug effects Electrophysiological Phenomena / physiology Glucose / deficiency HEK293 Cells Humans Hypoxia Ischemic Attack, Transient / blood Ischemic Attack, Transient / drug therapy Ischemic Attack, Transient / mortality Ischemic Attack, Transient / pathology Lactic Acid / blood Male Membrane Potentials / physiology Mibefradil / metabolism Mibefradil / pharmacokinetics Mibefradil / pharmacology Mibefradil / therapeutic use Neurons / drug effects Neurons / pathology Neuroprotective Agents / metabolism Neuroprotective Agents / pharmacokinetics Neuroprotective Agents / pharmacology Neuroprotective Agents / therapeutic use Pimozide / pharmacology Pimozide / therapeutic use Rats Rats, Sprague-Dawley Survival Analysis Tissue Culture Techniques Transfection Dewey 616.8 Dewey 617 Swiss National Science Foundation Inhibition of T-type calcium voltage gated channels as a neuroprotective strategy 116770 CH Projects Swiss National Science Foundation Brain hemorrhage and edema after reperfusion with issue plasminogen activator in thrombo-embolic stroke 116774 CH Projects 61 Département des neurosciences cliniques 226 53 Département de neurosciences fondamentales 21A 63 Département d'anesthésiologie, pharmacologie, soins intensifs et urgences 229 16 Centre interfacultaire de neurosciences 0D9 false 513 Groupe Schaller Karl Lothard (neurochirurgie) 851 1280 Pharmaco-omiques et médecine de précision 1003 Fundamental & clinical pharmacology 25 4 1c439e8d-f1a0-46b2-abc5-e5f691c5e12d Article (Published version) Restricted file.pdf 572833 application/pdf e398f2033a63ec935346bcbc40cc54de0a815e5b7adba14154c5d0f064d583dc restrictedAccess Faculté de médecine / Section de médecine clinique / Département des neurosciences cliniques Faculté de médecine / Section de médecine fondamentale / Département de neurosciences fondamentales Faculté de médecine / Section de médecine clinique / Département d'anesthésiologie, pharmacologie, soins intensifs et urgences Centres et instituts / Centre interfacultaire de neurosciences

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