title: Insulin receptor A and Sirtuin 1 synergistically improve learning and spatial memory following chronic salidroside treatment during hypoxia.
abstract: Hypoxia has been reported to cause hippocampal neurodegeneration resulting in learning and memory deficits. In the present study, we investigated the potential of salidroside, a glucoside derivative of tyrosol, in ameliorating hypoxia-induced neurodegeneration and memory impairment. Morris water maze test showed improvement in learning and spatial memory of salidroside-treated hypoxic rats correlating with increased dendritic intersections and arborization. Salidroside administration increased phosphorylation of insulin receptor subunit A (IRA) at Y972, Y1162/63, and Y1146 sites and subsequent activation of AMP-activated protein kinase (AMPK) α subunit isoforms pAMPKα1 and pAMPKα2 resulting in mitochondrial biogenesis. Contrarily, silencing of IRA in salidroside-supplemented hypoxic hippocampal cells could not improve cell viability or alter pAMPKα1 and pAMPKα2 expression. Rats administered with salidroside showed elevated expression of phosphorylated cAMP response element-binding protein in the hippocampus. Salidroside administration also resulted in increased sirtuin 1 (SIRT1) activity through a cytochrome P4502E1 (CYP2E1)-regulated mechanism that was independent of pIRA. Taken together, these findings suggest a synergistic role of pIRA and SIRT1 in salidroside-mediated neuroprotection, mitochondrial biogenesis, and cognitive improvement during hypoxia. We propose a novel mechanism for salidroside-mediated neuroprotection in hypoxia.
authors.affiliation: Defence Institute of High Altitude Research, Leh-Ladakh, Jammu and Kashmir, India.
authors.forename: Kalpana
authors.initials: K
authors.lastname: Barhwal
authors.affiliation: Defence Institute of High Altitude Research, Leh-Ladakh, Jammu and Kashmir, India.
authors.forename: Saroj K
authors.initials: SK
authors.lastname: Das
authors.affiliation: Defence Institute of High Altitude Research, Leh-Ladakh, Jammu and Kashmir, India.
authors.forename: Ashish
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Defence Institute of High Altitude Research, Leh-Ladakh, Jammu and Kashmir, India.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Hota
authors.affiliation: Defence Institute of High Altitude Research, Leh-Ladakh, Jammu and Kashmir, India.
authors.forename: Ravi B
authors.initials: RB
authors.lastname: Srivastava
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D002470:Cell Survival; D017362:Cyclic AMP Response Element-Binding Protein; D004272:DNA, Mitochondrial / Q000235:genetics; D005960:Glucosides / Q000493:pharmacokinetics / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D000860:Hypoxia / Q000523:psychology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000473:pathology; D010636:Phenols / Q000493:pharmacokinetics / Q000494:pharmacology*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000187:drug effects*; D056564:Sirtuin 1 / Q000494:pharmacology*; D065852:Spatial Memory / Q000187:drug effects*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D004272:DNA, Mitochondrial; D005960:Glucosides; D010636:Phenols; D011972:Receptor, Insulin; D055372:AMP-Activated Protein Kinases; D056564:Sirtuin 1; C009172:rhodioloside
keywords: Sirtuin 1; hypoxia; insulin receptor; memory; mitochondrial biogenesis; salidroside