Methanimine derivative (BN3) alleviates obesity-associated neurobehavior alteration by influencing metabolic and neuroinflammatory gene pathways in in-vivo zebrafish model.
📄 Abstract
Obesity is a chronic disease caused by the accumulation of cholesterol, which often requires long-term management strategies, such as dietary changes, increased physical activity, and psychological support. Obesity associated neurobehavioral disorders are a growing global health concern, emphasizing the need for innovative therapeutic strategies. Our study evaluates the therapeutic efficacy of (Z)-1-(furan-2-yl)-N-(4-(2-nitrophenyl)-6-(p-tolyl)pyrimidin-2-yl)methanimine referred as BN3 derivative, in treating high-fat diet-induced metabolic and behavioral dysfunctions in a zebrafish model. The research focused on reducing oxidative stress, lipid accumulation, and neurobehavioral deficits, which are closely linked to obesity-related metabolic stress. In this study, zebrafish were divided into five separate experimental groups: control group, model of obesity caused by high-fat diets, BN3 (50 µM and 100 µM), and Positive Control (PC) Group treated with Lovastatin 100 µM. Initially, fish were fed a high-fat diet for 14 days and followed by 30 days of exercise and simultaneously administering BN3 treatments via oral gavage. Assessment of biochemical, histopathology, gene expression, and behavioral were carried out. The results indicated that BN3 treatment significantly decreased oxidative stress levels by enhancing the activity of four antioxidant enzymes (Superoxide Dismutase, Catalase, Glutathione Transferase and Glutathione Peroxidase). BN3 also decreased lipid accumulation as evidenced through histological staining analysis, and total cholesterol estimation. BN3 enhanced locomotion, social interaction, and exploratory behaviors, and reduced anxiety, with the 100 µM treatment group exhibiting the same results as the PC. Gene expression analysis indicates that BN3 is modulating pparγ, fas, pik3cd, src-3, and bdnf pathways (metabolic and neuroinflammation pathways). BN3 impacted these multiple metabolic and neurobehavioral impairments associated with obesity through a multisite treatment approach. BN3 demonstrates significant therapeutic potential, assuring further studies to explore its long-term safety, pharmacokinetics, and translational application in managing obesity and related disorders.