5,7,4′-Trimethoxyflavone attenuates cognitive impairment in diabetic mice via inhibition of NLRP3 inflammasome activation

Diabetic encephalopathy, a severe consequence of diabetes mellitus, is marked by cognitive deterioration. Neuroinflammation is pivotal in the pathophysiology of this illness. This study examined the efficacy of 5,7,4′-trimethoxyflavone (TMF) in mitigating cognitive deficits in streptozotocin (STZ)-induced diabetic mice through the modulation of neuroinflammation. Male mice were administered STZ to induce diabetes before treatment with TMF. Cognitive function was evaluated using the Morris water maze and Y-maze tests. Brain tissue was examined for oxidative stress indicators, including SOD, CAT, and MDA. The expression levels of critical neuroinflammatory components, including the NLRP3 inflammasome and its adaptor protein ASC, together with the downstream cytokines IL-1β and IL-18, were assessed. In addition, the concentrations of BDNF, cleaved caspase-1, GFAP, and NeuN were measured. Our findings indicated that TMF treatment markedly boosted cognitive function in diabetic mice, as reflected by improved spatial learning and memory in the Morris water maze and superior working memory in the Y-maze. Moreover, TMF treatment diminished oxidative stress, as evidenced by elevated SOD and CAT activity and decreased MDA levels. TMF markedly inhibited the activation of the NLRP3 inflammasome by diminishing the expression of NLRP3 and ASC, hence reducing the levels of IL-1β and IL-18. Furthermore, TMF therapy elevated BDNF levels and decreased cleaved caspase-1 expression, indicating neuroprotective properties. An immunohistochemical study demonstrated that TMF therapy reduced GFAP expression and elevated NeuN expression in the hippocampus. The results collectively indicate that TMF provides neuroprotection and mitigates cognitive deficits in STZ-induced diabetic mice by effectively suppressing neuroinflammation and oxidative stress pathways in a dose-dependent manner. Consequently, TMF presents potential as a treatment drug for diabetic encephalopathy.