**Background:** Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, amyloid-β (Aβ) plaques, neurofibrillary tangles, oxidative stress, and brain glucose hypometabolism. Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor (SGLT2i) used for diabetes, has shown neuroprotective potential in previous studies. This study aimed to evaluate the protective effects of dapagliflozin against aluminum chloride (AlCl3)-induced AD in rats, focusing on the cholinergic system, glucose metabolism, AMPK/mTOR signaling, and oxidative stress.
**Methods:** Forty male albino Swiss rats were divided into four groups (n=6 per group for most analyses): (1) untreated control, (2) AlCl3 (70 mg/kg IP daily for 9 weeks), (3) AlCl3 + dapagliflozin (1 mg/kg PO for the last 4 weeks), and (4) AlCl3 + dapagliflozin (5 mg/kg PO for the last 4 weeks). Cognitive function was assessed using the Morris Water Maze (MWM) and Y-maze spontaneous alternation tests. Brain tissue was analyzed for acetylcholinesterase (AChE), Aβ levels, oxidative stress markers (MDA, SOD, GSH, CAT), brain glucose levels, glucose transporters (GLUT-1, GLUT-3), glycolytic enzymes (LDH-A, PDK-1), and signaling proteins (p-AMPK, p-mTOR, HO-1) using ELISA, PCR, and western blot. Histopathological examination of the cerebral cortex and hippocampus was performed.
**Key Results:** AlCl3 administration significantly impaired cognitive performance, as shown by increased escape latency in the MWM and reduced spontaneous alternation in the Y-maze. Dapagliflozin treatment significantly improved these behavioral deficits (p < 0.05). Biochemically, AlCl3 increased brain AChE activity and Aβ levels, while dapagliflozin dose-dependently reduced both (p < 0.05). Oxidative stress markers showed that AlCl3 increased MDA to 20.6 ± 1.9 ng/g (vs. control 3.1 ± 0.2) and decreased SOD (8 ± 1 vs. 41.2 ± 3.4 u/g), GSH (8.6 ± 1.1 vs. 52.7 ± 2.4 pg/g), and CAT (7.1 ± 0.8 vs. 37.5 ± 2.3 u/g). Dapagliflozin (5 mg/kg) significantly reversed these changes: MDA 5.6 ± 0.6, SOD 27.1 ± 0.5, GSH 39.3 ± 0.8, CAT 24.9 ± 1.4 (all p < 0.05 vs. AlCl3). Brain glucose levels were elevated in the AlCl3 group (23.54 ± 1 mg/dL vs. control 13.7 ± 0.1) and reduced by dapagliflozin (5 mg/kg: 15.5 ± 0.2). Dapagliflozin upregulated GLUT-1, GLUT-3, LDH-A, and PDK-1 gene expression and increased p-AMPK, p-mTOR, and HO-1 protein levels compared to the AlCl3 group (p < 0.05). Histopathological examination confirmed that AlCl3 caused neuronal degeneration, amyloid plaques, and neurofibrillary tangles in the cortex and hippocampus, which were markedly ameliorated by dapagliflozin treatment, with the 5 mg/kg dose showing near-normal histology.
**Clinical Implications:** This preclinical study provides evidence that dapagliflozin may have therapeutic potential for Alzheimer's disease through multiple mechanisms: reducing cholinergic dysfunction, decreasing Aβ accumulation, attenuating oxidative stress, improving brain glucose metabolism via upregulation of glucose transporters and glycolytic enzymes, and activating the AMPK/mTOR/HO-1 signaling pathway. The findings support the repurposing of SGLT2 inhibitors for neurodegenerative diseases. However, the study used a chemically induced AD model in rats, and the biochemical analyses were performed on whole brain homogenate rather than specific regions like the hippocampus. Human clinical trials are needed to confirm these neuroprotective effects in AD patients.