Cognitive enhancing effect of Canagliflozin in aluminum-induced rat model of Alzheimer's-like disease: Cross-talk between Amyloid-Β and BDNF/GSK-3β signaling.

The strong relationship between Alzheimer's Disease (AD) and diabetes mellitus (DM) is described by the term "type 3 diabetes". Canagliflozin (CAN), a sodium-glucose co-transporter 2 inhibitor (SGLT2i), is an antidiabetic agent under investigation as a potential new treatment for AD due to its acetylcholinesterase (AChE) inhibitory properties. We aimed to examine the effect of CAN on the efficacy of the anti-acetylcholinesterase, rivastigmine (RIV), against aluminum chloride (AlCl3)-induced AD rat model. The efficacy of CAN, RIV, and CAN plus RIV against abnormal behavioral, biochemical, and histological changes in AlCl3-induced AD in rats was examined. Three weeks of treatment with CAN partially reversed the AlCl3-induced behavioral dysfunction, along with significantly elevated levels of brain-derived neurotrophic factor (BDNF) and decreased levels of AChE, glycogen synthase kinase-3β (GSK3β), amyloid beta (Aβ) deposits, and inducible nitric oxide synthase (iNOS) expression. Histological examination revealed that CAN administration significantly increased RIV's efficacy by protecting neurons in rats' hippocampal tissues from AlCl3-induced damage. Interestingly, the RIV + CAN combination exhibited a more pronounced inhibitory effect on Aβ plaque formation, iNOS activity, and neurodegeneration compared to either RIV or CAN alone. However, this combination did not show any additive benefits for behavior, AChE activity, BDNF, or GSK3β concentrations compared with RIV alone. Our research indicates that CAN has potential benefits for AD, as evidenced by improvements in cognitive abilities, cholinergic activity, and neurogenesis in rats with AD. This is attributed to the upregulation of BDNF/GSK3β signaling, reduced neuroinflammation, and Aβ deposition.