Indirubin-3′-monoxime prevents aberrant activation of GSK-3β/NF-κB and alleviates high fat-high fructose induced An-aggregation, gliosis and apoptosis in mice brain

Deciphering the molecular mechanisms of amyloid pathology and glial cell-mediated neuroinflammation, offers a novel avenue for therapeutic intervention against neurodegeneration. Recent findings demonstrate a crucial link between activation of glycogen synthase kinase-3 beta (GSK-3 beta), amyloid deposition and a neuroinflammatory state. However, studies demonstrating the pharmacological effects of GSK-3 beta inhibition and the interlinked molecular mechanisms still remain elusive. The present study explores whether high fat-high fructose diet (HFFD)-induced neuropathological changes could be alleviated by indirubin-3'-monoxime (IMX), a GSK-3 beta inhibitor. Male Swiss albino mice (8 weeks old) were fed with normal pellet or HFFD for 60 days. HFFD mice were treated with IMX once daily for last 7 days of the experimental period. HFFD fed-mice had significant amyloid deposits in cerebral cortex and hippocampus, and protein expression analyses showed activation of GSK-3 beta, nuclear translocation of NF-kappa B p65 and upregulation of inflammatory (TNF-alpha, IL-6, COX-2), astrocytic (GFAP), glial surface (CD-68) and pro-apoptotic markers (Bax and caspase-3). IMX treatment promotes the inhibitory phosphorylation of GSK-3 beta at Ser(9) and moreover, a marked reduction in the phosphorylation of IKK-beta, which prevents translocation and activation of NF-kappa B. Protein expression studies in IMX-treated brain tissues positively correlate with the anti-neuroinflammatory effects of GSK-3 beta inhibition. Taken together, our results provide substantial evidence that IMX could potentially attenuate neuroinflammation in coordination with the master transcription factor-NF-kappa B.