No abstract

Withania somnifera root extract has been used traditionally in ayurvedic system of medicine as a memory enhancer. Present study explores the ameliorative effect of withanolide A, a major component of withania root extract and its molecular mechanism against hypoxia induced memory impairment. Withanolide A was administered to male Sprague Dawley rats before a period of 21 days pre-exposure and during 07 days of exposure to a simulated altitude of 25,000 ft. Glutathione level and glutathione dependent free radicals scavenging enzyme system, ATP, NADPH level, γ-glutamylcysteinyl ligase (GCLC) activity and oxidative stress markers were assessed in the hippocampus. Expression of apoptotic marker caspase 3 in hippocampus was investigated by immunohistochemistry. Transcriptional alteration and expression of GCLC and Nuclear factor (erythroid-derived 2)–related factor 2 (Nrf2) were investigated by real time PCR and immunoblotting respectively. Exposure to hypobaric hypoxia decreased reduced glutathione (GSH) level and impaired reduced gluatathione dependent free radical scavenging system in hippocampus resulting in elevated oxidative stress. Supplementation of withanolide A during hypoxic exposure increased GSH level, augmented GSH dependent free radicals scavenging system and decreased the number of caspase and hoescht positive cells in hippocampus. While withanolide A reversed hypoxia mediated neurodegeneration, administration of buthionine sulfoximine along with withanolide A blunted its neuroprotective effects. Exogenous administration of corticosterone suppressed Nrf2 and GCLC expression whereas inhibition of corticosterone synthesis upregulated Nrf2 as well as GCLC. Thus present study infers that withanolide A reduces neurodegeneration by restoring hypoxia induced glutathione depletion in hippocampus. Further, Withanolide A increases glutathione biosynthesis in neuronal cells by upregulating GCLC level through Nrf2 pathway in a corticosterone dependenet manner.

Edited by Roger J. Colbran Homocysteine, a metabolite of the methionine cycle, is a known agonist of N-methyl-D-aspartate receptor (NMDAR), a glutamate receptor subtype and is involved in NMDAR-mediated neurotoxicity. Our previous findings have shown that homocysteine-induced, NMDAR-mediated neurotoxicity is facilitated by a sustained increase in phosphorylation and activation of extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK MAPK). In the current study, we investigated the role GluN1/GluN2A-containing functional NMDAR (GluN2A-NMDAR) and GluN1/GluN2B-containing functional NMDAR (GluN2B-NMDAR) in homocysteine-induced neurotoxicity. Our findings revealed that exposing primary cortical neuronal cultures to homocysteine leads to a sustained low-level increase in intracellular Ca 2؉ . We also showed that pharmacological inhibition of GluN2A-NMDAR or genetic deletion of the GluN2A subunit attenuates homocysteine-induced increase in intracellular Ca 2؉ . Our results further established the role of GluN2A-NMDAR in homocysteine-mediated sustained ERK MAPK phosphorylation and neuronal cell death. Of note, the preferential role of GluN2A-NMDAR in homocysteine-induced neurotoxicity was distinctly different from glutamate-NMDAR-induced excitotoxic cell death that involves overactivation of GluN2B-NMDAR and is independent of ERK MAPK activation. These findings indicate a critical role of GluN2A-NMDAR-mediated signaling in homocysteine-induced neurotoxicity.

No abstract

Chronic exposure to hypobaric hypoxia (HH) causes memory impairment and prolonged state of mental confusion. However, effect of high altitude exposure on mood state and its underlying mechanisms have been poorly studied. Present study was undertaken to investigate the mood state alteration following chronic exposure to HH. Male Sprague Dawley rats were divided into five groups and exposed to hypoxia for 3, 7, 14 and 21 days in an animal decompression chamber at an altitude of 25,000ft. Anxiety-and depression-like behaviors were assessed by using various mazes along with changes in serotonin and glutamate level. Our study revealed a decrease in exploratory, grooming and rearing behavior in open field test following initial exposure to HH for 7 days without affecting the locomotory behavior. Initial exposure to HH-decreased time spent in open arm of elevated plus maze indicating induction of anxiety-like behavior which normalized on prolonged hypoxic exposure for 21 days. Hypoxic exposure for 7 days induced anhedonia and increased despair behavior in rat while there was steady improvement in these behaviors when exposed for 21 days. Decrease in serotonin level was noted in hippocampus along with elevated corticosterone and glutamate level which gradually decreased on prolonged exposure to HH. These findings suggest that initial exposure to HH increases transient anxiety-like behavior in rats followed by gradual improvement in mood state on prolonged exposure. Further, the study also indicates the involvement of serotonergic system in mood state alteration at high altitude following chronic exposure and reoxygenation.