Hypoxian osuudesta, HIF1

Research Report 

Naringenin and quercetin reverse the effect of hypobarichypoxia and elicit neuroprotective response in the murine model

 Aditi Sarkar

, M. Sonia Angeline

, Kushi Anand

, Rashmi K Ambasta

, Pravir Kumar

Functional genomics and Cancer biology laboratory, Center for Medical Engineering, Vellore Institute of Technology, Vellore,TN 632014, India

Department of Biotechnology, Delhi Technological University, Delhi 110042, India

Department of Neurology, Adjunct faculty, Tufts University School of Medicine, Boston, MA, USA

Accepted 21 August 2012Available online 6 September 2012

Keywords:

Hypobaric-hypoxiaHIF1

Flavonoids Neuroprotection Caspase Ubiquitin

a b s t r a c t

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 (10 mg/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 1a (HIF1a), vascular endothelialgrowth 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 immunofluor-escence results, where we confirmed the down regulation of caspase 3 and ubiquitinated       proteins
.To  conclude, treatment 
with  NGEN andQUR alonesubstantially amelioratedhypoxiainduced brain dysfunction and acts like a neuroprotectant.

.http://dx.doi.org/10.1016/j.brainres.2012.08.036Abbreviations: HIF1

a

, Hypoxia inducible factor 1a

; VEGF, Vascular endothelial growth factor; HSPs, Heat shock proteins;CHIP, C-terminus Hsp70 interacting protein; NGEN, Naringenin; UPS, Ubiquitin proteasome system; QUR, Quercetin;Ub, Ubiquitin; FITC, Fluorescein isothiocyanate; HRP, Horse radish peroxidase

n

Correspondence to: Delhi Technological University (Formerly Delhi Colleg