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
The effects of cinnamaldehyde (CIN), a commonly consumed food flavor, against high-cholesterol diet (HCD)-induced vascular damage in rabbits were evaluated. Male New Zealand rabbits (n = 24) were allo Show more
The effects of cinnamaldehyde (CIN), a commonly consumed food flavor, against high-cholesterol diet (HCD)-induced vascular damage in rabbits were evaluated. Male New Zealand rabbits (n = 24) were allocated to four groups at random: control, fed with standard rabbit chow; CIN, fed with standard diet and administered CIN; HCD, fed with 1% cholesterol-enriched diet; and HCD-CIN, fed with HCD and treated with CIN. CIN was orally given at a dose of (10 mg/kg/day) concomitantly with each diet type from day 1 until the termination of the experimental protocol (4 weeks). HCD elicited significant elevations in serum levels of total cholesterol (TC), triglycerides (TGs), and high- and low-density lipoprotein cholesterol (HDL-C and LDL-C, respectively) compared with control rabbits. Moreover, aortic levels of nitric oxide metabolites (NOx) and antioxidant enzyme activities were significantly lower, while aortic levels of malondialdehyde (MDA) and myeloperoxidase (MPO) activity were significantly higher, in HCD-fed rabbits relative to control animals. CIN administration mitigated or completely reversed HCD-induced metabolic alterations, vascular oxidative stress, and inflammation. Moreover, CIN ameliorated HCD-induced vascular functional and structural irregularities. Aortic rings from HCD-CIN group showed improved relaxation to acetylcholine compared to aortas from HCD group. Moreover, CIN decreased atherosclerotic lipid deposition and intima/media (I/M) ratio of HCD aortas. CIN-mediated effects might be related to its ability to attenuate the elevated aortic mRNA expression of cholesteryl ester transfer protein (CETP) and MPO in HCD group. Interestingly, the vasculoprotective effects of CIN treatment in the current study do not seem to be mediated via Nrf2-dependent mechanisms. In conclusion, CIN may mitigate the development of atherosclerosis in hypercholestrolemic rabbits via cholesterol-lowering, antiinflammatory and antioxidant activities. Show less