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Background: Diabetes is a metabolic chronic disorder affecting the central nervous system. A growing body of evidence have depicted that high glucose level leads to the activation of the transient receptor potential melastatin 2 (TRPM2) channels. However, there are no studies targeting TRPM2 channels in diabetes-induced cognitive decline using a pharmacological approach. Objective: The intent of the present study was to investigate the effects of 2- aminoethoxydiphenyl borate (2-APB), a TRPM2 inhibitor, in diabetes-induced cognitive impairment. Method:: Streptozotocin (STZ, 50 mg/kg, i.p.) was used to induce diabetes in rats. Animals were randomly divided into the treatment group, model group and age-matched control and pre se group. 2-APB treatment was given for three weeks to the animals. After 10-days of treatment behavioural parameters were performed. Animals were sacrificed at 10th-week of diabetic induction and the hippocampus and cortex were isolated. After that, protein and mRNA expression study was performed in the hippocampus. Acetylcholinesterase (AchE) activity was done in the cortex. Results: : Our study showed the 10th-week diabetic animals developed cognitive impairment which was evident from the behavioural parameters. Diabetic animals depicted an increase in the TRPM2 mRNA and protein expression in the hippocampus as well as increased AchE activity in the cortex. However, memory associated proteins were down-regulated namely Ca2+/calmodulin-dependent protein kinase II (CaMKII-Thr286), glycogen synthase kinase 3 beta (GSK-3β-Ser9), cAMP response element-binding protein (CREB-Ser133), and postsynaptic density protein 95 (PSD-95). Gene expression of parvalbumin, calsequestrin and brain-derived neurotrophic factor (BDNF) were down-regulated while mRNA level of calcineurin A/ protein phosphatase 3 catalytic subunit alpha (PPP3CA) was upregulated in the hippocampus of diabetic animals. After three-week treatment with 2-APB significantly ameliorated the alteration in behavioural cognitive parameters in diabetic rats. Moreover, 2- APB also down-regulated the expression of TRPM2 mRNA and protein in the hippocampus as well as AchE activity in the cortex of diabetic animals as compared to diabetic animals. Moreover, 2-APB treatment also upregulated the CaMKII (Thr-286), GSK-3β (Ser9), CREB (Ser133), and PSD-95 expression and mRNA levels of parvalbumin, calsequestrin, and BDNF while mRNA level of calcineurin A was down-regulated in the hippocampus of diabetic animals. Conclusion: : This study confirms the ameliorative effect of TRPM2 channel inhibitor in the diabetes-induced cognitive deficits. Inhibition of TRPM2 channels reduces the calcium associated downstream signaling and showed a neuroprotective effect of TRPM2 channels in diabetes-induced cognitive impairment.

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