Retracted: 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) a subunit isoforms pAMPKa1 and pAMPKa2 resulting in mitochondrial biogenesis. Contrarily, silencing of IRA in salidroside-supplemented hypoxic hippocampal cells could not improve cell viability or alter pAMPKa1 and pAMPKa2 expression. Rats administered with salidroside showed elevated expression of phosphorylated cAMP response elementbinding 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 salidrosidemediated neuroprotection, mitochondrial biogenesis, and cognitive improvement during hypoxia.

Insulin prevents aberrant mitochondrial phenotype in sensory neurons of type 1 diabetic rats

“…Insulin interaction with the AMPK pathway is multifaceted (Towler and Hardie, 2007) and adipocytes maintained under conditions of ongoing fatty acid metabolism, insulin can activate AMPK over a period of 40 min via elevation in the AMP/ATP ratio (Hebbachi and Saggerson, 2012; Liu et al, 2010). In hippocampal neurons, compounds that activate the insulin receptor also mobilize the AMPK-SIRT signaling axis with associated enhancement of mitochondrial function (Barhwal et al, 2015). Insulin can also boost intracellular Ca 2+ ion concentration (Contreras-Ferrat et al, 2014) which could trigger activation of an upstream activator of AMPK, namely Ca 2+ /calmodulin-dependent protein kinase kinase β (CaMKKβ) (Hawley et al, 2005; Hurley et al, 2005; Woods et al, 2005).…”

SIRT1 mediates salidroside‐elicited protective effects against MPP+‐induced apoptosis and oxidative stress in SH‐SY5Y cells: involvement in suppressing MAPK pathways

“…In present study, we found that MPP + treatment obviously decreased the SIRT1 activity, SIRT1 mRNA and protein levels in SH‐SY5Y cells, which is also consistent with the research done by Dong et al (), Tao et al (), and Zou et al (). Remarkably, some researchers reveal that SIRT1 contributes to the protective effects of salidroside against kainic acid‐induced status epilepticus (Si et al, ), d ‐galactose‐induced rat model of Alzheimer's disease (AD) (Gao et al, ), and hypoxia‐induced neurodegeneration (Barhwal et al, ). However, the role of SIRT1 in salidroside‐induced neuroprotection against injury in PD was not yet explored.…”

The Role of CYP2E1 in the Drug Metabolism or Bioactivation in the Brain

“…MPP+ also stimulates the release of DA [119], and autooxidation of dopamine results in the formation of cytotoxic quinones and highly reactive hydroxyl radicals, generating biomolecular damage [120]. In contrast to this, neuroprotection CYP2E1-regulated mechanism has been observed in a hypoxia model [121]. …”