NADPH oxidase-induced activation of transforming growth factor-beta-1 causes neuropathy by suppressing antioxidant signaling pathways in alcohol use disorder
ArticleOther Scholarly Work
Bhowmick, Saurav, Alikunju, Saleena, Muneer, PM Abdul. (2022). NADPH oxidase-induced activation of transforming growth factor-beta-1 causes neuropathy by suppressing antioxidant signaling pathways in alcohol use disorder
. Neuropharmacology, 213 109136. 10.1016/j.neuropharm.2022.109136
Oxidative signaling and inflammatory cascades are the central mechanism in alcohol-induced brain injury, which result in glial activation, neuronal and myelin loss, neuronal apoptosis, and ultimately long-term neurological deficits. While transforming growth factor-beta1 (TGF-β1) has a significant role in inflammation and apoptosis in myriads of other pathophysiological conditions, the precise function of increased TGF-β1 in alcohol use disorder (AUD)-induced brain damage is unknown. In this study, our objective is to study ethanol-induced activation of TGF-β1 and associated mechanisms of neuroinflammation and apoptosis. Using a mouse model feeding with ethanol diet and an in vitro model in mouse cortical neuronal cultures, we explored the significance of TGF-β1 activation in the pathophysiology of AUD. Our study demonstrated that the activation of TGF-β1 in ethanol ingestion correlated with the induction of free radical generating enzyme NADPH oxidase (NOX). Further, using TGF-β type I receptor (TGF-βRI) inhibitor SB431542 and TGF-β antagonist Smad7, we established that the alcohol-induced activation of TGF-β1 impairs antioxidant signaling pathways and leads to neuroinflammation and apoptosis. Blocking of TGF-βRI or inhibition of TGF-β1 diminished TGF-β1-induced inflammation and apoptosis. Further, TGF-β1 activation increased the phosphorylation of R-Smads including Smad2 and Smad3 proteins. Using various biochemical analyses and genetic approaches, we demonstrated the up-regulation of pro-inflammatory cytokines IL-1β and TNF-α and apoptotic cell death in neurons. In conclusion, this study significantly extends our understanding of the pathophysiology of AUD and provides a unique insight for developing various therapeutic interventions by activating antioxidant signaling pathways for the treatment of AUD-induced neurological complications.
