Multi-Faceted Anti-Obesity Effects of N-Methyl-D-Aspartate (NMDA) Receptor Modulators: Central-Peripheral Crosstalk

Abstract

Abstract Purpose Hypothalamus is central to food intake and satiety. Recent data revealed that N-methyl-D-aspartate receptors (NMDAR) are expressed on the hypothalamic neurons and have interactions with GABAA and serotoninergic neuronal circuits, however exact mechanism in energy homeostasis is not known. The present study aimed to investigate the role of NMDAR modulators on food intake and body fat regulation against progesterone-induced obesity in female Swiss albino mice. Methods Obesity was induced by progesterone administration for 4 weeks and various parameters were recorded like food intake, thermogenesis, lipid profile, organ-to-body weight ratio, white adipose tissue (WAT), adiposity index, and brain serotonin levels. Four NMDAR modulators were selected viz. Dextromethorphan Dxt, minocycline, d-aspartate, and cycloserine. Mice were allocated into 7-groups, groups-1 as vehicle control (arachis oil), group-2 (progesterone + distilled water), and group-3 as positive-control (progesterone + sibutramine), other groups were treated with test drugs + progesterone. Various parameters were recorded like food intake, thermogenesis, serum lipids, insulin, AST and ALT levels, organ: body weight ratio, total body fat, adiposity index, brain serotonin levels, histology of fat tissue, liver, and kidney. Results Dxt treated group has shown a significant downturn in body weight (p < 0.05) by a decline in food-intake (p < 0.01), organ: liver ratio (p < 0.001), adiposity index (p < 0.01), and a rise in body temperature and brain serotonin level (p < 0.001). Conclusion Dxt, demonstrated anti-obesity effects by multiple mechanisms including interaction with hypothalamic GABAA channels, anti-inflammatory and free radical scavenging effects, improving the brain serotonin levels, and increasing insulin release from the pancreatic β-cells.