Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
Int Immunopharmacol. 2021 Jun;95:107582. doi: 10.1016/j.intimp.2021.107582. Epub 2021 Mar 25.
It is well known that females are more vulnerable than males to stress-related psychiatric disorders, particularly during perimenopausal and postmenopausal periods. Hormone replacement therapy (HRT) has been widely used for the management of postmenopausal depression. However, HRT could be associated with severe adverse effects, including increased risk for coronary heart disease, breast cancer and endometrial cancer. Thus, there is a pressing demand for novel therapeutic options for postmenopausal depression without sacrificing uterine health. Simvastatin (SIM) was proven to have neuroprotective activities besides its hypocholesterolemic effect, the former can be attributed to its, antioxidant, anti-apoptotic and anti-inflammatory activities. Moreover, many reports highlighted that SIM has estrogenic activity and was able to induce the expression of estrogen receptors in rats. The present study showed that SIM (20 mg/kg, p.o.) markedly attenuated depressive-like behavior in ovariectomized (OVX) rats. Moreover, SIM prohibited hippocampal microglial activation, abrogated P2X7 receptor, TLR2 and TLR4 expression, inhibited NLRP3 inflammasome activation, with subsequent reduction in the levels of pro-inflammatory mediators; IL-1β and IL-18. Furthermore, a marked elevation in hippocampal expression of ERα and ERβ was noted in SIM-treated animals, without any significant effect on uterine relative weight or ERα expression. Taken together, SIM could provide a safer alternative for HRT for the management of postmenopausal depression, without any hyperplastic effect on the uterus.
众所周知，女性比男性更容易受到与压力相关的精神疾病的影响，尤其是在围绝经期和绝经后期间。激素替代疗法（HRT）已广泛用于治疗绝经后抑郁症。然而，HRT 可能会引起严重的不良反应，包括增加患冠心病、乳腺癌和子宫内膜癌的风险。因此，迫切需要新的治疗选择来治疗绝经后抑郁症，同时又不牺牲子宫健康。辛伐他汀（SIM）除了具有降胆固醇作用外，还被证明具有神经保护活性，前者可归因于其抗氧化、抗凋亡和抗炎活性。此外，许多报道强调 SIM 具有雌激素活性，并能够在大鼠中诱导雌激素受体的表达。本研究表明，SIM（20mg/kg，po）可显著减轻去卵巢（OVX）大鼠的抑郁样行为。此外，SIM 抑制了海马小胶质细胞的激活，阻断了 P2X7 受体、TLR2 和 TLR4 的表达，抑制了 NLRP3 炎性小体的激活，随后降低了促炎介质的水平；IL-1β 和 IL-18。此外，在 SIM 治疗的动物中，海马 ERα 和 ERβ 的表达明显升高，但对子宫相对重量或 ERα 的表达没有任何显著影响。总之，SIM 可以为 HRT 提供一种更安全的替代方案，用于治疗绝经后抑郁症，而对子宫没有任何增生作用。
