Author:
Yao Yuan,Ji Yingshi,Ren Jinghong,Liu Huanyu,Khanna Rajesh,Sun Li
Abstract
AbstractCerebral 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.
Funder
the Major Chronic Disease Program of the Ministry of Science and Technology of China
the General Program of the National Natural Science Foundation of China
Technology Foundation of Jilin Province
the Foundation of Health and Family Planning Commission of Jilin Province
Publisher
Springer Science and Business Media LLC
Subject
Cellular and Molecular Neuroscience,Molecular Biology
Reference56 articles.
1. Zhao ZQ. Postconditioning in reperfusion injury: a status report. Cardiovasc Drugs Ther. 2010;24(3):265–79.
2. Gao Y, Wen LL, Yang X, Wang J, Feng J. Pathological mechanism of focal cerebral ischemia and reperfusion injuries in mice. J Biol Regul Homeost Agents. 2019;33(5):1507–13.
3. Jung JE, Kim GS, Chen H, Maier CM, Narasimhan P, Song YS, et al. Reperfusion and neurovascular dysfunction in stroke: from basic mechanisms to potential strategies for neuroprotection. Mol Neurobiol. 2010;41(2–3):172–9.
4. Zheng Z, Zhao H, Steinberg GK, Yenari MA. Cellular and molecular events underlying ischemia-induced neuronal apoptosis. Drug News Perspect. 2003;16(8):497–503.
5. Peng K, Liu H, Yan B, Meng XW, Song SY, Ji FH, et al. Inhibition of cathepsin S attenuates myocardial ischemia/reperfusion injury by suppressing inflammation and apoptosis. J Cell Physiol. 2021;236(2):1309–20.