ORGAN DAMAGE UNDER HYPOXIC STRESS CONDITION AND THEIR THERAPEUTICS APPROACH

Abstract

For the maintenance of cellular homeostasis and energy metabolism, an uninterrupted supply of oxygen (O2) is routinely required in the brain. However, under impaired O2 (Hypoxia) or reduced blood flow (ischemia), the tissues are not sufficiently oxygenated, which triggers disruption of cellular homeostasis in the brain. Further, hypoxia resulting in reduced O2 delivery to brain tissues is supposed to cause neurodegeneration in both in vivo and in vitro models. Similarly, chronic exposure to hypoxia has also been reportedly involved in defective vessels formation. Such vascular abnormalities lead to impaired blood flow, diminished nutrient supply and entry of restricted infiltrates thereby limiting O2 availability to the brain and cause neurological disabilities. Amongst many factors responsible for the brain damage under hypoxia, altered expression of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) have been recently identified as the cause of neuronal cell death. Since there is no disease-modifying therapies have been designed for hypoxia treatment and current medications offer only symptomatic relief with a broad range of side effects. Therefore, the need of the hour is to unravel new and safer therapies which can improve disease symptoms against hypoxic insults. Owing to the limitations of sample availability of hypoxic patients and animal model, the current research scenario is revolved around cellular hypoxic models which are an excellent source of large drug screening and easy to maintain. Prior to in vitro cellular study, we have done in silico analysis of two major proteins including, HIF-1α and VEGF, which are reportedly involved in hypoxia-mediated cellular damage. Consequently, we have targeted these proteins with selected biomolecules in order to regulate their altered expression in the cells. Further, to validate our results we have performed in vitro experiment as well, where we used Cobalt(II) chloride (CoCl2) as a hypoxia mimic compound to induce chemical hypoxia in SH-SY5Y and HEK-293 cell line for exploring molecular mechanistic of hypoxia-induced cellular loss and screening of biomolecules in an attempt to curtail disease symptoms.