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
| العنوان: | 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 |
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| المؤلفون: | Yingshi Ji, Jinghong Ren, Li Sun, Huanyu Liu, Yuan Yao, Rajesh Khanna |
| المصدر: | Molecular Brain, Vol 14, Iss 1, Pp 1-20 (2021) Molecular Brain |
| بيانات النشر: | BMC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Male, Programmed cell death, Neurotoxins, Excitotoxicity, Glutamic Acid, Calcium-Calmodulin-Dependent Protein Kinase Kinase, Nerve Tissue Proteins, Apoptosis, AMP-Activated Protein Kinases, Pharmacology, medicine.disease_cause, Neuroprotection, Brain Ischemia, Rats, Sprague-Dawley, Cellular and Molecular Neuroscience, Cell Line, Tumor, Autophagy, Animals, Humans, Medicine, Ischemic Postconditioning, RC346-429, Molecular Biology, PI3K/AKT/mTOR pathway, CaMKKβ/AMPK/mTOR pathway, business.industry, Research, Glutamate receptor, AMPK, Infarction, Middle Cerebral Artery, medicine.disease, Peptide Fragments, Cerebral ischemia injury, CRMP2, Reperfusion Injury, Intercellular Signaling Peptides and Proteins, Calcium, Neurology. Diseases of the nervous system, Glutamate, business, Reperfusion injury, Signal Transduction |
| الوصف: | 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. |
| اللغة: | English |
| تدمد: | 1756-6606 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ecc441d25f3b491b6f926bc51332bd85Test https://doaj.org/article/1b51f0a80ad6417c8a7c616f6dc23fdcTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....ecc441d25f3b491b6f926bc51332bd85 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17566606 |
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