Upregulating the Expression of Survivin-HBXIP Complex Contributes to the Protective Role of IMM-H004 in Transient Global Cerebral Ischemia/Reperfusion

Abstract

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.

Ginsenoside Rg1 protects against ischemic/reperfusion-induced neuronal injury through miR-144/Nrf2/ARE pathway

“…PC12 cell culture and OGD/R Rat pheochromocytoma PC12 cells were obtained from Peking Union Medical College. The OGD/R was performed as previously described [34]. In brief, PC12 cells were cultured in DMEM with 10% fetal bovine serum, 5% embryonic stem, 100 U/mL penicillin, and 100 U/mL streptomycin at 37°C under a humidified atmosphere containing 5% CO 2 .…”

Pelargonidin Ameliorates MCAO-Induced Cerebral Ischemia/Reperfusion Injury in Rats by Action on the Nrf2/HO-1 Pathway

“…When cerebral ischemia develops at the reperfusion stage, the compensation provided by pre-existing nerve cells in the ischemic and hypoxic brain tissues rises abruptly, and is accompanied by a dramatic increase in free radicals that mediate oxidative damage in the affected areas [22,23]. As an end product of oxidation, MDA further aggravates any damage to cellular membranes.…”

Combined Neuroprotective Action of JWH-015 and AM251 in the CA1 Hippocampal Area of Transient Global Cerebral Ischemia

“…To explain, pyramidal neurons of the CA1 hippocampal area are particularly sensitive to ischemia, and their apoptosis is an outcome of transient GCI [20]. Therefore, memory deficit is one of the outcomes of transient GCI [5], as in the study carried out by Movassaghi et al who found that exposure of rats to BCCAO could impair spatial memory [21]. To evaluate learning and memory, MWM was used.…”

“…reduces brain blood flow [4]. TGCI mediates neuronal cell death resulting in severe neurological and neurobehavioral dysfunction [5]. Among various areas in brain, neurons of CA1 hippocampal area are highly vulnerable to ischemia [6] so that apoptosis of these neurons is an important phenomenon of brain ischemia/reperfusion injury [7].…”