Protective Role of Acetate Against Depressive-Like Behaviour Associated with Letrozole-Induced PCOS Rat Model: Involvement of HDAC2 and DNA Methylation.

Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder amongst women of reproductive age. PCOS has been demonstrated to induce depressive-like behaviour. Epigenetic alterations such as histone deacetylation (HDAC) and DNA methylation have been suggested in major depression. However, their effects with respect to neuroinflammation are not clear. This study therefore investigated the pathogenic involvement of epigenetic changes in PCOS-associated depression and the protective role of HDACi, especially acetate. Virgin female Wistar rats (140 ± 10 g) were assigned into four groups: the groups received vehicle (control), acetate (200 mg/kg), letrozole (1 mg/kg) and letrozole plus acetate, respectively. The administrations were done concomitantly by oral gavage for 21 days. Treatment with letrozole caused hyperandrogenism, hypoestrogenism, hyperinsulinemia and multiple ovarian cysts/degenerated follicles. In addition, these animals showed depressive-like behaviours and increased expression of HDAC2 and DNA methyltransferase in PFC and hippocampal tissues. Biochemical analyses showed elevated levels of NF-κB, malondialdehyde and acetylcholine (ACH) with glutathione depletion in PFC and hippocampus as well as elevated plasma malondialdehyde and impaired anti-oxidant system in letrozole-treated animals. Histological analysis of PFC and hippocampus showed neurodegeneration in letrozole-treated animals compared with control. However, these alterations were attenuated when treated with acetate. The study demonstrates that PCOS-associated depression is characterised by neuroinflammation and elevated ACH levels, accompanied by increased expression of HDAC2/DNA methyltransferase in PFC and hippocampus. Besides, the study suggests that acetate protects against PCOS-associated depression through suppression of prefrontal and hippocampal DNA methylation and prefrontal but not hippocampal HDAC2 expression.