Jawharji_2026_Nutr.Neurosci__1

BACKGROUND AND OBJECTIVE: This study evaluated the effects of a high, low, and low-carbohydrate ketogenic diet (HCD, LCD, and LCKD) on hippocampal damage and memory impairment in high-fat diet (HFD) rats. METHODS: Male rats were allocated into five groups. A control group received normal chow for 16 weeks, whereas the remaining groups were fed an HFD for 8 weeks and were then switched to normal chow, HCD, LCD, or LCKD for a further 8 weeks. RESULTS AND CONCLUSION: Final body weight, homeostasis model assessment of insulin resistance, fasting glucose and insulin, and serum free fatty acids, triglycerides, and total cholesterol were increased in the high-fat diet and high-fat diet plus high-carbohydrate diet groups. These rats also showed increased hippocampal tumor necrosis factor-alpha, interleukin-6, malondialdehyde, acetylcholinesterase, and nuclear factor kappa B messenger RNA and nuclear levels, together with reduced acetylcholine, reduced glutathione, superoxide dismutase, and nuclear factor erythroid 2-related factor 2 messenger RNA and nuclear levels. Severe dentate gyrus degeneration was also observed, with generally greater changes after the high-carbohydrate diet. Low-carbohydrate and low-carbohydrate ketogenic diets attenuated these metabolic, oxidative, inflammatory, structural, and memory abnormalities. However, increased hippocampal nuclear factor erythroid 2-related factor 2 messenger RNA and nuclear levels occurred only with the low-carbohydrate ketogenic diet. Thus, both diets alleviated high-fat diet-induced hippocampal damage and memory deficits, whereas the ketogenic diet additionally activated the nuclear factor erythroid 2-related factor 2 antioxidant and anti-inflammatory axis.