IMM-H004, a 3-piperazinylcoumarin compound derived from coumarin, has been proved effective against CA1 cell loss and spatial learning impairments resulting from transient global ischemia/reperfusion (TGCI/R), while the mechanism is still largely unknown. Here, we confirmed that treatment of rats with IMM-H004 immediately after TGCI/R ameliorated delayed neuronal death (DND) in the CA1 of hippocampus and cortex. Further study suggested that IMM-H004 contributed to the expression of antiapoptotic protein survivin through the activation of PI3K-dependent protein kinase B (PKB/Akt), which led to the phosphorylation of forkhead box O1 (FoxO1), then relieved the inhibiting effect on survivin promoter. Additionally, IMM-H004 also enhanced the expression of hepatitis B X-interacting protein (HBXIP), which formed a complex with survivin to prevent the activation of caspase death cascade, thereby halting apoptotic cell death. Finally, we injected a HBXIP siRNA into hippocampus and performed microelectroporation before ischemia/reperfusion, which abolished the protective effect of IMM-H004. Further study revealed that HBXIP maintained the high expression of Akt and survivin. Collectively, our findings demonstrated that DND after TGCI/R was alleviated by IMM-H004 through promoting the formation of survivin-HBXIP complex, which further emphasized the importance of endogenous protein involved in self-repair after stroke.
Keywords: Akt; Delayed neuronal death; Global cerebral ischemia; HBXIP; IMM-H004; Neuroprotective role; Survivin.