The Neuroprotective Mechanism Of Cortical Spreading Depression Preconditioning In A Rat Ischemic/reperfusion Injury Model

Cortical spreading depression(CSD), based on its similarities with peri-infarct depolarization(PID), is an ideal model for investigating transformation from the ischemic penumbra to infarct core. However, the underlying mechanisms remain unclear. To our knowledge, this is the first study to use a middle cerebral artery occlusion(MCAO) ischemic-reperfusion(I/R) injury model to determine whether AMP-activated protein kinase(AMPK)-dependent autophagy contributes to the neuroprotection of CSD preconditioning in rat cortex. The results demonstrated that CSD preconditioning significantly decreased the infarct volume, neurological deficits and apoptosis, inhibited unfolded protein response(UPR) in the cortical penumbra of MCAO rats, which was inhibited by the autophagy inhibitor 3-methyladenine(3-MA, 200 nmol). Furthermore, CSD increased the protein levels of the autophagy markers LC3-II, Beclin-1, and the p-AMPK(Thr172)/AMPK ratio at 12 h and decreased P62 and p-P70S6K(Thr389). Moreover, the AMPK inhibitor Compound C(CC, 20 mg/kg) down-regulated the LC3-II, p-AMPK(Thr172)/AMPK and ULK1 levels, up-regulated the P62 and p-P70S6K(Thr389) levels induced by CSD. Meanwhile, CSD preconditioning could partly inhibit the excessive activation of endoplasmic reticulum stress(ERS). However, Connexin 36 exerts no influence in the protection of CSD preconditioning. The neuroprotection of CSD preconditioning is likely a result of AMPK-mediated autophagy activity and autophagy-induced apoptosis inhibition. These novel findings support a central role for AMPK and autophagy in CSD-induced ischemic tolerance. AMPK-mediated autophagy may represent a new target for stroke.