title: Naringenin and quercetin reverse the effect of hypobaric hypoxia and elicit neuroprotective response in the murine model.
abstract: Exposure to high-altitude results in hypobaric hypoxia which is considered as an acute physiological stress. This condition often leads to high-altitude illnesses such as high-altitude cerebral edema, high altitude pulmonary edema and hypoxic muscle weakness. Hypoxic injuries can be prevented by either preconditioning with cobalt chloride or treatment with drugs. The aim of current investigation was to evaluate the effect of naringenin (NGEN) and quercetin (QUR) against behavioral impairment and neuronal damage in hypoxia induced murine model. An oral administration of NGEN or QUR (10mg/kg each) was given to the animal prior to every hypoxic treatment. Behavioral changes were evaluated along with the hypoxia exposure for all the groups. After hypoxia exposure and drug administration, the mice were euthanized; brains were harvested and stored for further analysis. Expressions of hypoxia induced proteins were ensured by Western blotting. Our results demonstrate expression of hypoxia inducible factor 1α (HIF1α), vascular endothelial growth factor (VEGF), active caspase 3 and ubiquitin levels were significantly reduced upon drug treatment. However, expressions of chaperones (Hsp70, Hsp90 and C-terminus Hsp70 interacting protein) were moderately changed. We established our findings based on behavioral test, hematoxylin and eosin as well as amino-cupric silver stainings. In addition, the protective nature of these drugs was corroborated with immunoblot and immunofluorescence results, where we confirmed the down regulation of caspase 3 and ubiquitinated proteins. To conclude, treatment with NGEN and QUR alone substantially ameliorated hypoxia induced brain dysfunction and acts like a neuroprotectant.
authors.affiliation: Functional genomics and Cancer biology laboratory, Center for Medical Engineering, Vellore Institute of Technology, Vellore, TN, India.
authors.forename: Aditi
authors.initials: A
authors.lastname: Sarkar
authors.forename: M Sonia
authors.initials: MS
authors.lastname: Angeline
authors.forename: Kushi
authors.initials: K
authors.lastname: Anand
authors.forename: Rashmi K
authors.initials: RK
authors.lastname: Ambasta
authors.forename: Pravir
authors.initials: P
authors.lastname: Kumar
mesh_terms: D000208:Acute Disease; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001273:Atmosphere Exposure Chambers; D053148:Caspase 3 / Q000378:metabolism; D002908:Chronic Disease; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004965:Estrogen Antagonists / Q000494:pharmacology; D044950:Flavanones / Q000494:pharmacology*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D002534:Hypoxia, Brain / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D051379:Mice; D009410:Nerve Degeneration / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011794:Quercetin / Q000494:pharmacology*; D011897:Random Allocation; D025801:Ubiquitin / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000975:Antioxidants; D004965:Estrogen Antagonists; D044950:Flavanones; D018840:HSP70 Heat-Shock Proteins; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018696:Neuroprotective Agents; D025801:Ubiquitin; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D011794:Quercetin; C505409:Casp3 protein, mouse; D053148:Caspase 3; C005273:naringenin