URB597 modulates neuroplasticity, neuroinflammatory, and Nrf2/HO-1 signaling pathways in the hippocampus and prefrontal cortex of male and female rats in a stress-induced model of depression

Major depressive disorder is often associated with cognitive impairments, and neuroinflammation is considered a key contributor to the onset of depression. Pharmacological inhibition of fatty acid amide hydrolase (FAAH), which augments endocannabinoid signaling, has emerged as a promising approach to treating depression. The main purpose of this study is to asses the influence of FAAH inhibitor URB597 on inflammatory response and oxidative stress in chronic unpredictable stress (CUS)-induced depressive female and male rats and to explore the underlying molecular mechanisms. Chronically stressed animals showed long-term memory deficits, while URB597 improved memory only in stressed males. URB597 treatment enhanced levels of brain-derived neurotrophic factor (BDNF) in the hippocampus and mPFC of stressed female and male rats and increased phosphorylated calcium/calmodulin-dependent protein kinase II (pCaMKII) levels in the hippocampus and mPFC of CUS males. Additionally, increased phosphorylation of JAK2 and STAT3 in the hippocampus and mPFC of CUS male and female rats, was reduced following URB597 treatment. URB597 decreased the CUS-enhanced iNOS protein expression in the hippocampus and mPFC of both sexes. Furthermore, URB597 normalized CUS-induced reductions in Nrf2 and HO-1 levels in the mPFC of both sexes, with no changes in the hippocampus. Our findings suggest that URB597 may inhibit the CUS-induced neuroinflammatory response by suppressing the pro-inflammatory mediators and the activation of the JAK2/STAT3 signaling in the hippocampus and mPFC of both sexes. URB597 treatment contributed to synaptic plasticity in a sex-specific manner by upregulating brain CaMKII signaling in males. URB597 also exerts neuroprotective effects through region-specific antioxidant properties. These results have implications for sex-specific treatment strategies in stress-related neuropsychiatric disorders.