Katepsin B İnhibitörü olan CA074'ün Serebral İskemi Modelinde Apoptoz ve Hücre Ölümü Üzerine Etkisi

Abstract

Lysosomes and cathepsins, the most common hydrolytic enzymes in lysosomes, are available in the different models of cell death as necrosis and apoptosis. This study investigated the effect of cathepsin B-selective inhibitor CA-074 on apoptotic and necrotic neuronal cell death. Focal cerebral ischemia which has been formed by occlusion of the three-vessel consisting permanent middle cerebral artery occlusion and temporary bilateral common carotid artery occlusion for 60 minutes was selected as ischemia model. Two sets of rats were used in this study. The rats in the first set were used formeasurement of sulfhydryl groups in the lysosomal membrane, lysosomal integrity, cathepsins B and L activities and caspase-3 activity. The rats in the second set were used as histological study including "hematoxylin and eosin" for the detection of necrotic neuronal deathand "TUNEL" staining for the detection of apoptotic neuronal death. 4 mg/kg CA-074 was administered intravenouslyin the treatment group. CA-074 has substantially reduced levels of cathepsins B and L compared to ischemia and solvent groups (respectively, p<0.05 and p<0.01). Similarly, CA-074 has reduced increase in caspase-3 activity compared to ischemia and solvent groups (p<0.05). While the number of eosinophilic (necrotic) and apoptotic neurons has highly increased in post-ischemic cerebral tissue in middle cerebral artery feeding area (p<0.001), CA-074 could only reduce significantly the number of apoptotic neurons (p<0.05). CA-074 has reduced apoptotic neuronal death by inhibiting caspase and cathepsin activity. It may be useful that CA074 is used with other therapeutic drugs in stroke patients.