6-Gingerol ameliorates high-fat, high-sucrose diet-induced metabolic dysfunction and depressive-like behaviors by attenuating neuroinflammation and oxidative stress

High-calorie diets cause metabolic syndrome, obesity, and emotional disturbances, with neurological consequences. These prevalent conditions impair both peripheral and central nervous system function, elevating depression risk. These complications represent prevalent chronic conditions in modern society. The bioactive compound 6-gingerol demonstrates antioxidant and anti-inflammatory properties. This study investigated 6-gingerol’s protective effects against depression-like behavior and metabolic syndrome induced by a high-fat, high-sucrose diet (HFHS) in rats. Male Sprague-Dawley rats were randomly divided into six groups (n = 8/group): normal control (balanced diet; 4.12 kcal/g), HFHS-fed (5.57 kcal/g + 0.8 kcal/mL), low-dose (100 mg/kg/day, oral 6-gingerol), high-dose (200 mg/kg/day, oral 6-gingerol), and HFHS-fed groups receiving low-dose (100 mg/kg/day) or high-dose (200 mg/kg/day) oral 6-gingerol for ten weeks. Behavioral tests (forced swim, tail suspension) were conducted. Measured parameters included fasting blood glucose, serum lipids, insulin, leptin, hs-CRP, neurochemical markers (BDNF, GABA, AChE), neurotransmitters (serotonin, dopamine), oxidative stress markers, and inflammatory cytokines. Brain tissues were analyzed histopathologically and immunohistochemically. Both 6-gingerol doses significantly (p < 0.05) improved hyperglycemia, insulin resistance, dyslipidemia, hs-CRP, and leptin levels. Glutathione and glutathione peroxidase increased, while malondialdehyde, protein carbonyl, nitric oxide, TNF-α, and IL-6 significantly decreased. Immobility time in forced swim and tail suspension tests was significantly reduced. Neurochemical and neurotransmitter markers in brain tissue improved significantly (p < 0.05). GFAP and iNOS expression was reduced (p < 0.05), showing dose dependency. Histopathological and histochemical analyses confirmed 6-gingerol’s neuroprotection. 6-Gingerol, especially at high dose, effectively alleviated HFHS-induced metabolic syndrome, and depression-like behavior. These findings underscore its potential as a prophylactic against neurobehavioral deficits, and diet-associated depression.