Thymoquinone controlled obesity and invigorated cognitive and memory performance in rats consuming a high-fat diet via modulating oxidative stress, inflammation and apoptosis

The current study investigated the mitigating effects of thymoquinone (TQ) against high-fat diet (HFD)-mediated brain injury, cognitive and memory impairment, and the underlying mechanisms. Twenty-four adult male Wistar rats were divided into four groups of six rats each. Rats were fed HFD for 12 weeks to induce obesity. On the 9th week, TQ was administered orally to obese rats for four weeks. The effects of TQ were estimated by neurobehavioral testing, biochemical analysis, DNA damage, molecular docking, and histopathological examination of brains and visceral fat. TQ reduced body weight, body weight gain and adipocyte size, improved hyperlipidemia, and normalized the levels of leptin and adiponectin. TQ significantly attenuated the increase in HbA1c percent and insulin resistance. TQ decreased the accumulation of amyloid-β and tau proteins and improved the levels of neurotransmitters in the brains of obese rats. TQ-treated obese rats showed improved thickening of the pyramidal cell layer in the hippocampus and improved cognitive function and memory impairments. Molecular docking analysis indicated that TQ exhibited a marked affinity for inhibiting binding sites of tau and amyloid-β proteins. Furthermore, TQ controlled oxidative stress and enhanced the Nrf2 expression in the pyramidal cell layer and the activity of HO-1, SOD, and CAT in the brain. The restoration of redox balance by TQ was associated with normalization of inflammatory indicators and alleviation of DNA damage in the brains of HFD-treated animals. These changes contributed to the normalization of mitochondrial apoptotic pathway mediators (p53, Bcl-2, Bax, and caspase-3) and maintained the histological structure of the hippocampus. In conclusion, TQ attenuated brain injury, cognitive impairment, and memory deficit with improvement of body weight gain and metabolic status in obese rats through interrelated biological processes, including regulation of redox balance, inflammatory response, neurotransmitter equilibrium, and regression of DNA injury and apoptosis.