Carnosic Acid Mitigates Depression-Like Behavior in Ovariectomized Mice via Activation of Nrf2/HO-1 Pathway

The peri- and post-menopausal periods have been described as the "window of vulnerability" for the development of depressive symptoms that impair women activities and quality of life. The etiopathogenesis of these symptoms is multifactorial and may confer resistance to traditional antidepressants. Attention is now directed toward phytochemicals for their pleiotropic functions and safer profiles. This study investigated the possible perturbation of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways as an underlying mechanism of post-ovariectomy depression and highlighted the potential benefits of carnosic acid (CA) on the associated behavioral, biochemical, and histopathological alterations. Female Balb/c mice were randomly assigned to be sham-operated or ovariectomized (OVX). After 3 weeks, OVX mice received either a vehicle, CA (20 mg/kg/day), or tin protoporphyrin IX (SnPP-IX; a heme oxygenase-1 (HO-1) inhibitor; 50 μmol/kg/day) for 3 weeks. Our findings revealed that OVX mice had depressive but not anxiety-like behavior. Suppressed Nrf2 and its downstream signaling, and augmented proinflammatory markers were observed in both the hippocampus and prefrontal cortex. CA treatment alleviated depressive behavior, induced the expression of Nrf2, HO-1, thioredoxin-1, and brain-derived neurotrophic factor, and enhanced serotonin levels. CA also suppressed oxidative stress, reduced TNF-α, IL-1β, and iNOS mRNA expression, and ameliorated OVX-induced histopathological changes. SnPP-IX aggravated post-OVX behavioral, neurobiochemical, and histological deteriorations, and reduced CA-protective effects. In conclusion, Nrf2/HO-1 signaling suppression and the associated proinflammatory state are key mechanisms in post-OVX depression. CA exerts multifaceted neuroprotection in OVX mice and represents a promising candidate for clinical evaluation as an antidepressant.