The effects of monobromobimane on neuronal cell death in the hippocampus after transient global cerebral ischemia in rats.
Calcium accumulation and free radical formation in the mitochondria are suggested to result in opening of the mitochondrial permeability transition pore that may be an initial step in neuronal cell death. The purpose of the present study was to determine whether monobromobimane (MBM) was a possible protective agent against neuronal cell death after transient global ischemia and the swelling of isolated hippocampal mitochondria. Infusion of MBM (1 or 3 microg) to cerebral ventricles 30 min before ischemia attenuated the expression of TUNEL-labeled cells and neuronal cell death in the hippocampal CA1 region at 72 h of reperfusion dose-dependently. Treatment with MBM inhibited an increase in caspase-3-like activity at 48 h of reperfusion in the hippocampus. MBM (30-300 microM) also inhibited an enhanced swelling rate induced by Ca2+ and phenylarsineoxide in the isolated hippocampal mitochondria. These results suggest that in vivo treatment with MBM may protect against neuronal cell death through inhibition of the mitochondrial swelling and caspase-3-dependent apoptotic pathway.
Department of Pharmacology, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Tsutomu
T
Abe
Norio
N
Takagi
Midori
M
Nakano
Satoshi
S
Takeo
D000818:Animals; D001152:Arsenicals / Q000494:pharmacology; D002545:Brain Ischemia / Q000517:prevention & control; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D002122:Calcium Chloride / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000473:pathology*; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D002546:Ischemic Attack, Transient / Q000473:pathology*; D008297:Male; D008928:Mitochondria / Q000187:drug effects; D008933:Mitochondrial Swelling / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D015424:Reperfusion / Q000379:methods; D013997:Time Factors
D001152:Arsenicals; D001643:Bridged Bicyclo Compounds; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; C029341:oxophenylarsine; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D002122:Calcium Chloride; C028381:monobromobimane