Remote Limb Ischemic Preconditioning Protects Rats Against Cerebral Ischemia via HIF-1α/AMPK/HSP70 Pathway

Remote limb ischemic preconditioning (RIPC) is a clinically feasible strategy to protect against ischemia/reperfusion injury, but the knowledge concerning the mechanism underlying RIPC is scarce. This study was performed to examine the effect of RIPC on brain tissue suffering from ischemia challenge and explore its underlying mechanism in a rat model. The animals were divided into four groups: Sham, middle cerebral artery occlusion (MCAO), RIPC, and MCAO+RIPC. We found that previous exposure to RIPC significantly attenuated neurological dysfunction and lessened brain edema in MCAO+RIPC group. Moreover, other important events were observed in MCAO+RIPC group, including substantial decrements in the concentrations of oxidative response indicators [malondialdehyde (MDA), 8-hydroxy-2-deoxyguanosine (8-OHdG), and protein carbonyl], significant reductions in levels of inflammation mediators [myeloperoxidase (MPO), tumor necrosis factor-a (TNF-a), interleukin-1β (IL-1β), and IL-6], and significant decline in neuronal apoptosis revealed by a smaller number of TUNEL-positive cells. Interestingly, both MCAO and RIPC groups exhibited meaningful elevations in the levels of HIF-1a, HSP70, and AMP-activated protein kinase (AMPK) compared to Sham group, and previous exposure to RIPC further elevated the levels of HIF-1a, HSP70, and AMPK in MCAO+RIPC group. Furthermore, the administration of YC-1 (HIF-1 inhibitor), 8-bAMP (AMPK inhibitor), and Quercetin (HSP70 inhibitor) to MCAO+RIPC rats demonstrated that HIF-1α/AMPK/HSP70 was involved in RIPC-mediated protection against cerebral ischemia.