title: 2-(4-Methoxyphenyl)ethyl-2-acetamido-2-deoxy-β-d-pyranoside confers neuroprotection in cell and animal models of ischemic stroke through calpain1/PKA/CREB-mediated induction of neuronal glucose transporter 3.
abstract: Salidroside is proven to be a neuroprotective agent of natural origin, and its analog, 2-(4-Methoxyphenyl)ethyl-2-acetamido-2-deoxy-β-d-pyranoside (named SalA-4g), has been synthesized in our lab. In this study, we showed that SalA-4g promoted neuronal survival and inhibited neuronal apoptosis in primary hippocampal neurons exposed to oxygen and glucose deprivation (OGD) and in rats subjected to ischemia by transient middle cerebral artery occlusion (MCAO), respectively, and that SalA-4g was more neuroprotective than salidroside. We further found that SalA-4g elevated glucose uptake in OGD-injured primary hippocampal neurons and increased the expression and recruitment of glucose transporter 3 (GLUT3) in ischemic brain. Signaling analysis revealed that SalA-4g triggered the phosphorylation of CREB, and increased the expression of PKA RII in primary hippocampal neurons exposed to OGD injury, while inhibition of PKA/CREB by H-89 alleviated the elevation in glucose uptake and GLUT3 expression, and blocked the protective effects of SalA-4g. Moreover, SalA-4g was noted to inhibit intracellular Ca(2+) influx and calpain1 activation in OGD-injured primary hippocampal neurons. Our results suggest that SalA-4g neuroprotection might be mediated by increased glucose uptake and elevated GLUT3 expression through calpain1/PKA/CREB pathway.
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Co-innovation Center of Neuroregeneration, 19 Qixiu Road, Nantong JS 226001, PR China.
authors.forename: Shu
authors.initials: S
authors.lastname: Yu
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Co-innovation Center of Neuroregeneration, 19 Qixiu Road, Nantong JS 226001, PR China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Co-innovation Center of Neuroregeneration, 19 Qixiu Road, Nantong JS 226001, PR China.
authors.forename: Lu
authors.initials: L
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Co-innovation Center of Neuroregeneration, 19 Qixiu Road, Nantong JS 226001, PR China.
authors.forename: Mei
authors.initials: M
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Co-innovation Center of Neuroregeneration, 19 Qixiu Road, Nantong JS 226001, PR China.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Co-innovation Center of Neuroregeneration, 19 Qixiu Road, Nantong JS 226001, PR China. Electronic address: dingfei@ntu.edu.cn.
authors.forename: Fei
authors.initials: F
authors.lastname: Ding
mesh_terms: D000117:Acetylglucosamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy*; D002154:Calpain / Q000235:genetics / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D051274:Glucose Transporter Type 3 / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D051379:Mice; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000188:drug therapy* / Q000209:etiology
chemical_list: C000589286:2-(4-methoxyphenyl)ethyl-2-acetamido-2-deoxyglucopyranoside; D017362:Cyclic AMP Response Element-Binding Protein; D051274:Glucose Transporter Type 3; D018696:Neuroprotective Agents; D017868:Cyclic AMP-Dependent Protein Kinases; D002154:Calpain; D000117:Acetylglucosamine
keywords: 2-(4-Methoxyphenyl)ethyl-2-acetamido-2-deoxy-β-d-pyranoside; CREB; Ischemic stroke models; Neuronal glucose transporter 3; Neuroprotection; PKA