A mechanistic exploration of the metabolome of African mango seeds and its potential to alleviate cognitive impairment induced by high-fat/high-carbohydrate diets: Involvement of PI3K/AKT/GSK-3β/CREB, PERK/CHOP/Bcl-2, and AMPK/SIRT-1/mTOR Axes.

Irvingia gabonensis (Aubry-Lecomte ex O'Rorke) Baill., also known as "African mango" or "bush mango", belonging to family Irvingiaceae, has been mostly used as food and traditional medicine for weight loss and to enhance the health.The overconsumption of high-fat and high-carbohydrate (HFHC) food induces oxidative stress, leading to neurological and cognitive dysfunction. Consequently, there is an immediate need for effective treatment. Hence, this study explored the efficacy of orlistat, metformin, and I. gabonensis seeds' total aqueous extract (IG SAE) in addressing HFHC-induced cognitive impairment by mitigating oxidative stress and their underlying mechanistic pathways.Initially, the secondary metabolite profile of IG SAE is determined using high-performance liquid chromatography coupled with a mass detector (UHPLC/MS). The in vivo study involves two phases: an established model phase with control (10 rats on a standard diet) and HFHC diet group (50 rats) for 3 months. In the study phase, HFHC is divided into 5 groups. The first subgroup receives HFHC diet only, while the remaining groups each receive HFHC diet with either Orlistat, metformin, or IG SAE at doses of 100 mg/kg and 200 mg/kg, respectively, for 28 days.More than 150 phytoconstituents were characterized for the first holistic approach onto IG metabolome. Characterization of IG SAE revealed that tannins dominate metabolites in the plant. Total phenolics and flavonoids were estimated to standardize our extract (77.12 ± 7.09 μg Gallic acid equivalent/mg extract and 8.039 ± 0.53 μg Rutin equivalent/mg extract, respectively). Orlistat, metformin, and IG SAE successfully reduced the body weight, blood glucose level, lipid profile, oxidative stress and neurotransmitters levels leading to improved behavioral functions as well as histological alternation. Also, IG SAE halted inflammation, apoptosis, and endoplasmic reticulum stress, together with promoting autophagy, via modulation of PI3K/AKT/GSK-3β/CREB, PERK/CHOP/Bcl-2 and AMPK/SIRT-1/m-TOR pathways.Metformin, orlistat, and IG SAE offer a promising multi-target therapy to mitigate HFHC diet-induced oxidative stress, addressing cognitive function. This involves diverse molecular mechanisms, particularly the modulation of inflammation, ER stress, and both PI3K/AKT/GSK-3β/CREB and AMPK/SIRT-1/m-TOR pathways. Furthermore, the higher dose of IG SAE demonstrated effects comparable to orlistat and metformin across most studied parameters.