-Oryzanol Ameliorates Depressive Behavior in Ovariectomized Mice by Regulating Hippocampal Nitric Oxide Synthase: A Potential Therapy for Menopausal Depression

ScopeDepression is a severe mental condition, common among menopausal women. gamma-Oryzanol (ORY) has various biological properties; however, the effect of ORY on menopausal depression and its underlying mechanisms have not been investigated.Methods and resultsORY is orally administered to ovariectomized (OVX) mice for 20 weeks. ORY administration results in lower immobility time in the tail suspension and forced swim test and increases locomotor activity in the open field test. In the primary hippocampal neurons and hippocampi of OVX mice, ORY treatment increases nitric oxide (NO) production and neuronal NO synthase (nNOS) expression. Further, the phosphorylation of extracellular signal-regulated kinase (ERK), cAMP response element-binding protein (CREB), and tropomyosin receptor kinase B, along with the expression of brain-derived neurotrophic factior (BDNF), is upregulated. These stimulatory effects of ORY are diminished by treatment with estrogen receptor beta (ER beta) antagonist. ORY similarly interacts with ER beta in the molecular docking analysis. Moreover, intracerebroventricular injection of 7-nitroindazole, a nNOS inhibitor, abolishes the antidepressant effects of ORY.ConclusionsThe results indicate that ORY attenuates depressive behavior in OVX mice by upregulating ER beta-mediated hippocampal nNOS expression and activating the ERK-CREB-BDNF signaling networks. The findings suggest that ORY is a potential therapeutic agent for attenuating menopausal depression. gamma-Oryzanol (ORY) has neurological effects such as cognitive function and sleep-promoting function. Estrogen-deficiency contributes to the higher incidence of depression. ORY exerts its antidepressant-like effects by targeting hippocampal nNOS expression in ovariectomized mice. ORY increases ER beta-mediated nNOS expression and activates ERK-CREB-BDNF signaling pathways. ORY may be used as a therapeutic agent for attenuating menopausal depression. image