Inhibitory effect of Notch1 on cell apoptosis during acute phase of focal cerebral ischemic injury

Abstract

Objective To study the dynamic changes of Notch1 activity in penumbra area and its role in cell apoptosis during acute phase of cerebral ischemic injury and explore new therapeutic target for ischemia cerebrovascular disease. Methods Focal cerebral ischemic model was established by intraluminal middle cerebral artery occlusion (MCAO) method. Adult male SD rats were randomly divided into sham group (Sham), MCAO+ Notch1 inhibitor group (DAPT group), and MCAO+ vehicle control group (Vehicle group). Cell apoptotic index was analyzed by TdT-mediated dUTP nick end labeling (TUNEL) staining. The poly adenosine diphosphate-ribose polymerase (PARP) cleavage fragment, activated Notch1 fragment, phosphorylation of protein kinase B (Akt) and Bad were detected by Western blotting. Results The Notch1 activity in ischemic penumbra area at 1, 3, 7 d after ischemia was increased by 2.1, 4.6, 3.8 folds, respectively, in comparison to sham group. Consecutive DAPT injection significantly reduced Notch1 activity. The apoptotic indices in DAPT group at 1, 3, 7 d [(32.71±5.20)%, (52.58±9.20)%, (49.53±8.40)%, respectively] were significantly higher than those in Vehicle group [(23.21±4.66)%, (37.86±8.12)%, (34.87±7.30)%, respectively], and the phosphorylation levels of Akt and Bad in DAPT group were lower than those in Vehicle group. Conclusion Increased Notch1 activity in ischemic penumbra following ischemic stroke maybe inhibit cell apoptosis and inhibition of Notch1 activity may exacerbate ischemic injury. Key words: Cerebral ischemic injury; Notch1; Apoptosis