Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor, cognitive, and metabolic dysfunction, largely driven by mitochondrial impairment and defective energy meta Show more
Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor, cognitive, and metabolic dysfunction, largely driven by mitochondrial impairment and defective energy metabolism. Altered signaling through hypoxia-inducible factor-1α (HIF-1α) and PI3K/AKT cascades contributes to neuronal vulnerability. Canagliflozin (Cana), a sodium-glucose cotransporter-2 inhibitor, has shown cognitive benefits in experimental studies. Here, we evaluated whether Cana mitigates 3-nitropropionic acid (3NP, 10 mg/kg, i.p., 14 days)-induced HD-like neurotoxicity in rats. Animals received Cana (5 or 10 mg/kg, p.o.) daily for 14 days, followed by behavioral assessments (open-field, Morris water maze, novel object recognition), histopathology, immunohistochemistry, and biochemical assays. Cana treatment significantly improved locomotor and memory performance, reduced striatal histopathological alterations, and attenuated GFAP immunoreactivity. Mechanistically, Cana upregulated HIF-1α and downstream GLUT1/GLUT3/HKII, restored PI3K/AKT/CREB/BDNF signaling, and enhanced SIRT1/PGC-1α/Nrf2 antioxidant responses, while suppressing inflammatory mediators and caspase-3 activation. These findings highlight Cana as a promising disease-modifying strategy for HD by targeting both energy metabolism and pro-survival pathways. Show less