The Neuroprotective Effect of Losartan through Inhibiting AT 1/ ASK 1/ MKK 4/ JNK 3 Pathway Following Cerebral I/R in Rat Hippocampal CA 1 Region

Summary Aims It has been well documented that angiotensin II type 1 ( AT 1 ) receptor blockers ( ARB s) are known to attenuate neural damage and the c‐Jun N ‐terminal protein kinase 3 ( JNK 3) pathway and caspase‐3 signal are involved in neuronal cell death following cerebral ischemia/reperfusion ( I / R ). In this study, we first showed that losartan could protect neurons against cerebral I / R ‐induced injury. Methods Cerebral ischemia model was induced by four‐vessel occlusion. Antisense oligodeoxynucleotides ( ODN s) against AT 1 receptor and losartan were used to detect whether the AT 1 receptor implicated in cerebral I / R . Immunoprecipitation ( IP ) and immunoblotting ( IB ) were used to detect the interactions between β‐arrestin‐2 and AT 1/apoptosis signal‐regulating kinase 1 ( ASK 1)/ MAP kinase kinase 4 ( MKK 4) signaling module following cerebral I / R . Results First, losartan decreased cerebral I / R ‐induced neuronal death. Second, losartan depressed the β‐arrestin‐2‐assembled AT 1/ ASK 1/ MKK 4 signaling module. Third, losartan depressed the activation of c‐jun, JNK 3, B cl‐2, caspase‐3 and the release of cytochrome c from mitochondria to cytoplasm. Conclusion Taken together, losartan could attenuate neural damage following the cerebral I/R via inhibiting the β‐arrestin‐2‐assembled AT 1/ ASK 1/ MKK 4 signaling module and depressing the activation of c‐jun, JNK 3, and caspase‐3 and the release of cytochrome c .