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Title: Inhibition of autophagy by CRMP2-derived peptide ST2-104 (R9-CBD3) via a CaMKKβ/AMPK/mTOR pathway contributes to ischemic postconditioning-induced neuroprotection against cerebral ischemia-reperfusion injury. Author: Yao Y, Ji Y, Ren J, Liu H, Khanna R, Sun L. Journal: Mol Brain; 2021 Aug 06; 14(1):123. PubMed ID: 34362425. Abstract: Cerebral ischemia, a common cerebrovascular disease, is characterized by functional deficits and apoptotic cell death. Autophagy, a type of programmed cell death, plays critical roles in controlling neuronal damage and metabolic homeostasis, and has been inextricably linked to cerebral ischemia. We previously identified a short peptide aptamer from collapsin response mediator protein 2 (CRMP2), designated the Ca2+ channel-binding domain 3 (CBD3) peptide, that conferred protection against excitotoxicity and traumatic brain injury. ST2-104, a nona-arginine (R9)-fused CBD3 peptide, exerted beneficial effects on neuropathic pain and was neuroprotective in a model of Alzheimer's disease; however, the effect of ST2-104 on cerebral ischemia and its mechanism of action have not been studied. In this study, we modeled cerebral ischemia-reperfusion injury in rats with the middle cerebral artery occlusion (MCAO) as well as challenged SH-SY5Y neuroblastoma cells with glutamate to induce toxicity to interrogate the effects of ST2-104 on autophagy following ischemic/excitotoxic insults. ST2-104 reduced the infarct volume and improved the neurological score of rats subjected to MCAO. ST2-104 protected SH-SY5Y cells from death following glutamate exposure via blunting apoptosis and autophagy as well as limiting excessive calcium entry. 3-Methyladenine (3-MA), an inhibitor of autophagy, promoted the effects of ST2-104 in inhibiting apoptosis triggered by glutamate while rapamycin, an activator of autophagy, failed to do so. ST2-104 peptide reversed glutamate-induced apoptosis via inhibiting Ca2+/CaM-dependent protein kinase kinase β (CaMKKβ)-mediated autophagy, which was partly enhanced by STO-609 (an inhibitor of CaMKKβ). ST2-104 attenuated neuronal apoptosis by inhibiting autophagy through CaMKKβ/AMPK/mTOR pathway. Our results suggest that the neuroprotective effect of ST2-104 are due to actions on the crosstalk between apoptosis and autophagy via the CaMKKβ/AMPK/mTOR signaling pathway. The findings present novel insights into the potential neuroprotection of ST2-104 in cerebral ischemia.[Abstract] [Full Text] [Related] [New Search]