Fatty acid amide hydrolase inhibitor URB597 shows antidepressant effects through reduction of neuroinflammation and restoration of BDNF levels in mPFC of chronically stressed rats

Abstract

Modulating the endocannabinoid system is emerging as a promising approach for treating various inflammatory, neurodegenerative, and psychiatric disorders. Major depressive disorder is a prevalent cause of disability worldwide, affecting up to 6% of the population and posing significant health and economic challenges. Since the existing antidepressant treatments are often insufficient, the endocannabinoid system presents an attractive target for potential therapies. To explore this possibility, two-month-old Wistar rats of both sexes were subjected to chronic unpredictable stress (CUS) for six weeks. During the last two weeks of stress protocol rats were injected with either a fatty acid amide hydrolase inhibitor, URB597 (i.p. 0.3 mg/kg), or a vehicle. At the end of the sixth week sucrose intake test was used to assess depressive-like behavior. After sacrificing the animals, Western blot analysis was used to determine the levels of brain-derived neurotrophic factor (BDNF) protein and levels of pro-inflammatory cytokine IL-1β in medial prefrontal cortex. The CUS exposure induced anhedonia in both female and male rats, and URB597 treatment alleviated these symptoms. Moreover, CUS increased the levels of IL1-β in the mPFC of both sexes. Stressed animals that have received URB597 had decreased levels of IL1-β structures compared to the animals receiving only vehicle. CUSexposed male and female rats also had lower levels of BDNF in the mPFC, but URB597 restored BDNF levels in female rats to those observed in control animals. Taken together, these findings suggest that URB597 may have antidepressant effects through reducing neuroinflammation and restoring BDNF levels in mPFC.