Amelioration of diabetes-induced cognitive deficits by GSK-3β inhibition is attributed to modulation of neurotransmitters and neuroinflammation.

Chronic type 2 diabetes (T2D) causes cognitive deficits which are debilitating to the young as well as the older population. Glycogen synthase kinase-3β (GSK-3β) signaling has been reported to be impaired in insulin-resistant and T2D animal models. In this study, we have investigated the involvement of GSK-3β in cognitive deficits associated with T2D using SB216763, a GSK-3 β inhibitor. In high-fat diet-streptozotocin (HFD-STZ) model of T2D in rats, cognitive deficits appeared on the 15th week after induction of diabetes. Treatment with GSK-3β inhibitor SB216763 (i.p. daily for 3 weeks) reversed impaired cognitive performance in the Morris water maze, Y-maze, and passive avoidance tests. Administration of SB216763 also significantly improved acetylcholine esterase activity, GABA, and glutamate levels in the hippocampus and cortex of diabetic rats. Importantly, GSK-3β inhibition showed an increase in pGSK-3β and pCREB expression and reduction in pNF-κB-p65 expression in both hippocampus and cortex. Neuroinflammation was reduced by SB216763 in diabetic rats as evident from reduction in IL-6, TNF-α, COX-2, and inducible nitric oxide synthase levels. This study suggests that cognitive deficits associated with diabetes involved intricate compartmental interaction between transcription factors and neurotransmitter homeostasis/energy metabolism, and GSK-β might play a central role in diabetes-induced cognitive impairment.