ABSTRACT
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.
Subject(s)
AMP-Activated Protein Kinases , Isothiocyanates , Polycystic Ovary Syndrome , Sulfoxides , Humans , Female , Rats , Animals , AMP-Activated Protein Kinases/metabolism , Kelch-Like ECH-Associated Protein 1/metabolism , Depression/drug therapy , Sirtuin 1/metabolism , Polycystic Ovary Syndrome/complications , Polycystic Ovary Syndrome/drug therapy , NF-E2-Related Factor 2/metabolism , Protein Serine-Threonine Kinases/metabolism , Antidepressive Agents/pharmacology , Antidepressive Agents/therapeutic use , Autophagy , Sucrose/pharmacologyABSTRACT
OBJECTIVES: As one of the most frequent worldwide neurological disorders, epilepsy is an alteration of the central nervous system (CNS) characterized by abnormal increases in neuronal electrical activity. The mammalian target of rapamycin (mTOR) signalling pathway has been investigated as an interesting objective in epilepsy research. Vinpocetine (VNP), a synthesized derivative of the apovincamine alkaloid, has been used in different cerebrovascular disorders. This study aimed to examine the modulatory effects of VNP on neurobehavioral comorbidities via the mTOR signalling pathway in a lithium-pilocarpine (Li-Pil) rat model of seizures. METHODS: In male Wistar rats, seizures were induced with a single administration of pilocarpine (60 mg/kg; i.p.) 20 hours after the delivery of a single dose of lithium (3 mEq/kg; i.p.). VNP (10 mg/kg; i.p.) was administered daily for 14 consecutive days before Li-Pil administration. KEY FINDINGS: VNP had a protective effect against Li-Pil-induced seizures. VNP improved both the locomotor and cognitive abilities, moreover, VNP exerted a neuroprotective action, as verified histologically and by its inhibitory effects on hippocampal glutamate excitotoxicity, mTOR pathway, and inflammatory and apoptotic parameters. CONCLUSIONS: VNP is a valuable candidate for epilepsy therapy via its modulation of the mechanisms underlying epileptogenesis with emphasis on its modulatory effect on mTOR signalling pathway.
