Curcumin attenuates NMDA Receptor Phosphorylation on Glutamatergic Terminals and Lowers Blood Pressure in Obese Postmenopausal Mice

Epidemiological reports indicate that nearly 75% of postmenopausal women are hypertensive, and obesity significantly amplifies this risk. Despite available treatments, blood pressure control in postmenopausal women remains markedly pooer compared to age-matched men, and current pharmacological interventions demonstrate limited efficacy in this population. Curcumin, a bioactive compound found in turmeric, possesses antioxidant, anti-inflammatory, and antihypertensive properties. This study investigated whether curcum could lower blood pressure in an obese postmenopausal mouse model, and if so, whether this effect is mediated through modulation of glutamatergic neuronal activity within cardio-regulatory regions of the central nervous system. Our obese postmenopausal mouse model was maintained on a 60% high-fat diet for seventeen weeks. Estrogen deficiency was induced surgically by bilateral ovariectomy during week twelve. Prior to curcumin intervention, these mice exhibited pronounced obesity, hyperglycemia, and significantly elevated systolic blood pressure compared ton controls. Four weeks of daily curcumin administration (300mg) resulted in significantly reductions in body weight, blood glucose, and systolic blood pressure, specific to obese, estrogen-deficient female mice. The physiological responses of curcumin treatment were not observed in lean or obese males and estrogen-replete females. Mechanistically, obesity and estrogen loss were associated with heightened phosphorylation of N-methyl-D-aspartate receptors (pNMDAR) on glutamatergic terminals within key autonomic centers (i.e. paraventricular nucleus and rostral ventrolateral medulla). Curcumin treatment significantly attenuated this receptor phosphorylation, suggesting that under conditions of obesity and estrogen deficiency, curcumin mitigates glutamatergic hyperactivity by inhibiting NMDA receptor signaling, thereby contributing to blood pressure reduction. Background Obesity significantly increases the risk of hypertension in postmenopausal women, presenting a major cardiovascular health challenge in this population. Conventional antihypertensive therapies exhibit diminished efficacy in these women compared to age-matched men, highlighting a critical gap in current treatment strategies. Curcumin, a bioactive compound with documented antihypertensive properties, represents a promising therapeutic candidate. However, its effectiveness and the underlying mechanisms in the context of obesity and estrogen deficiency remains poorly understood. Objective Determine whether curcumin attenuates hypertension progression in an obese postmenopausal model by modulating glutamatergic signaling through suppression of N-methyl-D-aspartate receptor (NMDAR) phosphorylation. Methods 8-week-old male and female C57/BL mice were randomly divided into three groups (n = 24/group) and given ad libitum access to their respective diets [low-fat piperine (10% kcal from fat); high-fat piperine (60% kcal from fat); high-fat curcumin (60% kcal from fat)] for seventeen weeks. Piperine [200uL of a 10% solution of piperine] or curcumin [300mg of curcumin per 200uL + 10% piperine solution] were administered to animals daily, via gavage, during the last four weeks of the study. The female mice were further divided into groups identified as SHAM (ovaries intact – estrogen replete) and OVX (ovaries removed – estrogen depleted). Food and body weight were measured weekly. At the end of the study, glucose, retroperitoneal fat pads, and systolic blood pressure were measured. The hypothalamus was extracted from a subpopulation of mice to conduct western blot analysis. The remaining animals in the study were transcardially perfused for histological analysis. Results Curcumin treatment significantly attenuated the hypertension (p<0.0162) and the weight gain (p<0.0001) observed in ovariectomized mice fed a high-fat diet. Western blot analysis of hypothalamic tissue revealed a marked reduction in NMDA receptor phosphorylation (pNMDAR) following curcumin administration (p=0.001) compared to controls. Consistent with these findings, histological analysis demonstrated decreased pNMDAR expression within the paraventricular nucleus and the rostral ventrolateral medulla, mirroring the biochemical results. Notably, curcumin exerted no effect on NMDA receptor phosphorylation in lean or obese male mice (p=0.3431) and sham-operated females (p=0.2804). Conclusion Collectively, these findings highlight a potential mechanism in which curcumin targets to lower blood pressure specifically under conditions of obesity and estrogen deficiency. However, additional studies are warranted to determine if this mechanism is a direct or indirect effect of curcumin.