title: Neurovascular and neuronal protection by E64d after focal cerebral ischemia in rats.
abstract: Calpains and cathepsins are two families of proteases that play an important role in ischemic cell death. In this study, we investigated the effect of E64d, a mu-calpain and cathepsin B inhibitor, in the prevention of neuronal and endothelial apoptotic cell death after focal cerebral ischemia in rats. Rats underwent 2 hr of transient focal ischemia from middle cerebral artery occlusion (MCAO) and were sacrificed 24 hr later. E64d (5 mg/ kg intraperitoneally) was administered 30 min before MCAO. Assessment included neurological function, infarction volume, brain water content, blood-brain barrier permeability, histology, and immunohistochemistry. The E64d-treated rats had significant brain protection against ischemic damage. We observed a reduction of infarction volume, brain edema, and improved neurological scores in E64d-treated rats compared with the nontreated control. Furthermore, there was a remarkable reduction in both proteases and caspase-3 activation and apoptotic changes in both neurons and endothelial cells in E64d-treated rats. These results suggest that E64d protects the brain against ischemic/reperfusion injury by attenuating neuronal and endothelial apoptosis.
authors.affiliation: Department of Physiology and Pharmacology, Loma Linda University School of Medicine, California 92354, USA.
authors.forename: Tamiji
authors.initials: T
authors.lastname: Tsubokawa
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Yamaguchi-Okada
authors.forename: John W
authors.initials: JW
authors.lastname: Calvert
authors.forename: Ihsan
authors.initials: I
authors.lastname: Solaroglu
authors.forename: Norihito
authors.initials: N
authors.lastname: Shimamura
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Yata
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001929:Brain Edema / Q000188:drug therapy; D020520:Brain Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D002545:Brain Ischemia / Q000209:etiology / Q000517:prevention & control*; D002154:Calpain / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002403:Cathepsins / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects*; D007839:Functional Laterality / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000473:pathology; D007930:Leucine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008297:Male; D009460:Neurologic Examination / Q000379:methods; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013778:Tetrazolium Salts
chemical_list: D018696:Neuroprotective Agents; D013778:Tetrazolium Salts; C009591:triphenyltetrazolium; D002403:Cathepsins; D002154:Calpain; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; C449002:mu-calpain; D010751:Phosphopyruvate Hydratase; D007930:Leucine; C108192:aloxistatin