Withaferin-A attenuates T2DM-induced male reproductive dysfunction mediated by ERα in brain and testes of Swiss albino mice

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease, characterized by persistence hyperglycemia resulting from diminished response to insulin secretion or resistance. The present study evaluated the ameliorative effects of Withaferin-A on T2DM-induced reproductive dysfunction in mice. For the same, mice were intraperitoneally injected with Streptozotocin (STZ), (40 mg/kg/day) for 5 consecutive days to induce T2DM. Mice were then treated with WA (8 mg/kg/day) both in normal and diabetic conditions (STZ+WA). Next, blood glucose levels, OGTT, IPTT, oxidative stress and reproductive parameters were estimated. For reproductive performance, immunofluorescent localization of GnRH-I and ERα in POA and PVN region of hypothalamus and ERα in testes was performed. STZ-induced diabetes triggered reproductive dysfunctions as mediated by low ir-GnRH-I and ERα in the brain and ERα in the testes along with declined testosterone and estradiol levels. Interestingly, treatment with WA significantly reduced the blood glucose levels and enhanced glucose clearance including oxidative stress in the brain, pancreas and testes as indicated by low levels of H 2 O 2 and MDA in STZ+WA. This study report for the first time that WA can efficiently combat T2DM induced reproductive dysfunction via enhancing endogenous testosterone, estrogen and increased ir-GnRH-I and ERα in the brain and ERα in the testes of T2DM mice.