MTOR Inhibitor rapamycin can reverses the combination antiretroviral therapy induced central nervous system disorder

Abstract

BackgroundAccumulating evidences indicate that the combined antiretroviral therapy (cART) has dramatically increased the life expectancy of HIV infected individuals. However, existing HIV population on cART show several complications including liver or pancreas damage, cardiovascular diseases and central nervous system disorders. Unexpectedly the prevalence of HIV+ associated neurotoxicity is on the rise. Hence, the current study is undertaken to determining the potential therapeutic effects of rapamycin against anti‐retroviral therapy induced neuronal dysfunction.ObjectiveThis study is aimed at exploring the therapeutic potential of rapamycin on cART induced central nervous system disorder.MethodologyPrimary midbrain neuronal cells (PMNC) were treated with antiretroviral drugs like Ritonavir (protease inhibitor) and Abacavir (reverse transcriptase inhibitor) in the combined form.ResultsAfter 24 hours treatment, immunoblot analysis shows that there is upregulation of autophagy marker proteins LC3 II, P62 levels in cART treated primary midbrain neuronal cells compared to control cells. Similarly, cART treated cells shows upregulation of endoplasmic reticulum (ER) resident proteins expression with mitochondrial dysfunction. These results are suggesting that neuronal cells treated with cART have dysregulated autophagy, higher ER stress and mitochondrial dysfunction. The beneficial effects of rapamycin are well described; though, it is unknown whether rapamycin ameliorates the harmful effects of cART‐induced toxicity in neuronal cells. Hence, in this study, we intend to investigate the effects of rapamycin on PMNC treated with cART. Our results indicate that rapamycin treatment ameliorates the autophagy dysfunction as well as, it normalizes the mitochondrial function and reduces the ER stress.ConclusionThis study shows that rapamycin have a good potential in reversing cART‐induced autophagy and mitochondrial dysfunction in primary midbrain neuronal cells.Schematic representation of therapetic effects of rapamycinFigure 1