Role of HSP90 Inhibitor In Treatment Of Metabolic Disorder

Abstract

newlineDiabetes is a disease of complex aetiology with hyperglycaemia and oxidative stress as major perpetrators of adverse complications. A great leap in the pathophysiological understanding of the disease in the last decade leads to identification of multiple therapeutic targets, opening new avenues in treatment. However, combinatorial therapy is too complicated and many times vain. A search for compounds that can modulate multiple targets is therefore gaining momentum in the pharmaceutical circle. Against this background molecular chaperone modulators are logically attractive therapeutic leads as chaperones have a huge known protein clientele and many diabetic targets are clients of the chaperone Hsp90. newlineIn the present study we investigated the antidiabetic potential of Gedunin (a limonoid from Neem plant, Azadirachta indica) and a known Hsp90 inhibitor. In silico inquiry and analysis show promising interaction and modulation of important diabetic targets by Gedunin. In vitro studies on hyperglycaemia revealed that gedunin inhibited alpha amylase and reduced glucose uptake by yeast cells. Gedunin restored activity of cellular antioxidant enzymes, inhibited pro-oxidants, glycosylation and lipid peroxidation causing distinct amelioration of oxidative stress thereby exhibiting anti-oxidant potential. In in vivo studies at the tested dose of Gedunin there was no acute or sub-acute toxicity observed as tested through haematological and histological markers. Here results point towards restoration of blood glucose and protective influence on hepatic, renal and pancreatic histology. Modulation and restoration of other blood indices acting as hyperglycaemic markers was also observed. newlineIn the search for effective therapy against diabetes, safety and modulation of multiple targets are the key filters that need to be applied. Use of the pure HPLC grade compound in the present study, rules out unaccounted effects of plant extract components.Our study shows that Gedunin exhibits antidiabetic potential as predicted.