The Neuroprotective Effect of Losartan through Inhibiting AT1/ASK1/MKK4/JNK3 Pathway Following Cerebral I/R in Rat Hippocampal CA1 Region

Aims It has been well documented that angiotensin II type 1 (AT1) receptor blockers (ARBs) are known to attenuate neural damage and the c-Jun N-terminal protein kinase 3 (JNK3) 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 (ODNs) against AT1 receptor and losartan were used to detect whether the AT1 receptor implicated in cerebral I/R. Immunoprecipitation (IP) and immunoblotting (IB) were used to detect the interactions between beta-arrestin-2 and AT1/apoptosis signal-regulating kinase 1 (ASK1)/MAP kinase kinase 4 (MKK4) signaling module following cerebral I/R. Results First, losartan decreased cerebral I/R-induced neuronal death. Second, losartan depressed the beta-arrestin-2-assembled AT1/ASK1/MKK4 signaling module. Third, losartan depressed the activation of c-jun, JNK3, Bcl-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 beta-arrestin-2-assembled AT1/ASK1/MKK4 signaling module and depressing the activation of c-jun, JNK3, and caspase-3 and the release of cytochrome c.