title: Amelioration of diabetes-induced cognitive deficits by GSK-3β inhibition is attributed to modulation of neurotransmitters and neuroinflammation.
abstract: 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.
authors.affiliation: Molecular Neuropharmacology Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, SAS Nagar (Mohali), 160062, Punjab, India.
authors.forename: Ashok Kumar
authors.initials: AK
authors.lastname: Datusalia
authors.forename: Shyam Sunder
authors.initials: SS
authors.lastname: Sharma
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008301:Maleimides / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D007211:Indoles; D008301:Maleimides; D018377:Neurotransmitter Agents; D047428:Protein Kinase Inhibitors; C417521:SB 216763; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3