Sulforaphane's role in Redefining autophagic Responses in depression associated with polycystic ovarian syndrome: Unveiling the SIRT1/AMPK/LKB1 pathway connection

Polycystic ovarian syndrome (PCOS) has been associated with depression and suicidal ideations in females. Studies have highlighted the role of autophagic deficiency in depression pathogenesis. Sulforaphane (SFN) is a natural product that improved autophagic deficiency and showed antidepressant activity in depressed patients. Herein, the study aimed to evaluate the impact of using SFN on depression-associated with PCOS via hippocampal energy sensors and cellular bioenergetics. PCOS was induced by administering letrozole (1 mg/kg, p. o.) for 21 days, followed by SFN treatment (0.5 mg/kg, i. p.) for one week. Two days before euthanasia, PCOS rats showed anhedonic behavior in the sucrose preference test and increased immobility time in the forced swimming test. Depressed rats showed a reduction in nuclear SIRT1 and an elevated cytoplasmic one. This was associated with a reduction in phosphorylation of energy sensors, liver kinase B1 (LKB1), and adenosine monophosphate kinase (AMPK), along with an imbalance of autophagic markers such as Beclin-1, microtubule-associated protein I/II light chain 3, autophagy enzyme 7 and selective autophagy receptor P62. Additionally, Nrf2 and KEAP1 levels were decreased. These abnormalities were alleviated by SFN treatment, as evidenced by the nuclear translocation of SIRT1 and the repression of downstream proteins, including FOXO1, NF-κB, and TNF-α production. These changes were reflected in improved behavioral performance in the sucrose preference test (SPT) and forced swimming test (FST). The antidepressant effects of SFN were counteracted by an autophagic inhibitor, 3-methyladenine. Eventually, SFN, as a nutraceutical, has a promising antidepressant effect via restoring autophagic-related depression in the PCOS rat model.