The Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Heilongjiang, China.
The Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Heilongjiang, China.
Biomed Pharmacother. 2024 Oct;179:117369. doi: 10.1016/j.biopha.2024.117369. Epub 2024 Aug 30.
Perimenopausal depression is a subtype of depression and is prevalent among perimenopausal women, which has brought a heavy burden to family and society. The pathogenesis of perimenopausal depression is still unclear, which affects the prevention and treatment of perimenopausal depression to a certain extent. Quercetin is a flavonoid compound, and has estrogenic activity and pharmacological effects such as antioxidant, anti-inflammatory, and neuroprotective effects. This study investigated whether quercetin improved perimenopausal depression-like behaviors and potential mechanism. The results demonstrated that quercetin could alleviate the depression-like behaviors in perimenopausal depression rat model, inhibit astrocyte activation, improve ferroptosis-associated mitochondrial damage (such as mitochondrial pyknosis and mitochondrial cristae reduction) in hypothalamus, increase the expressions of histone 3 lysine 9 acetylation (acetyl-H3K9), ferroptosis-associated protein including glutathione peroxidase 4 (GPX4) and Xc- antiporter (SLC7A11), and reduce the expressions of endoplasmic reticulum stress-related proteins including inositol-requiring enzyme 1 (IRE1α), phosphorylated IRE1α (p-IRE1α), X-box binding protein 1 (XBP1) and glucose-regulated protein 78 (GRP78) in hypothalamus of perimenopausal depression rat model. Furtherly, in vitro study indicated that quercetin could restore histone acetylase (HAT)/histone deacetylase (HDAC) homeostasis through binding to estrogen receptors and increase the expression of acetyl-H3K9, inhibiting ferroptosis through IRE1α/XBP1 pathway in astrocytes of hypothalamus. Our findings demonstrated that acetyl-H3K9 is a crucial target in development of perimenopausal depression, and quercetin exhibited antidepressant effects through modulating acetyl-H3K9 mediated ferroptosis in perimenopausal depression. Quercetin might be the prevention and adjuvant treatment strategy of perimenopausal depression.
围绝经期抑郁症是抑郁症的一种亚型，在围绝经期妇女中较为常见，给家庭和社会带来了沉重的负担。围绝经期抑郁症的发病机制尚不清楚，在一定程度上影响了围绝经期抑郁症的防治。槲皮素是一种类黄酮化合物，具有雌激素活性和抗氧化、抗炎、神经保护等药理作用。本研究探讨了槲皮素是否改善围绝经期抑郁症样行为及其潜在机制。结果表明，槲皮素可缓解围绝经期抑郁症大鼠模型的抑郁样行为，抑制星形胶质细胞激活，改善下丘脑铁死亡相关线粒体损伤（如线粒体固缩和线粒体嵴减少），增加组蛋白 3 赖氨酸 9 乙酰化（acetyl-H3K9）、铁死亡相关蛋白包括谷胱甘肽过氧化物酶 4（GPX4）和 Xc-载体（SLC7A11）的表达，并降低下丘脑围绝经期抑郁症大鼠模型中内质网应激相关蛋白包括肌醇需求酶 1（IRE1α）、磷酸化 IRE1α（p-IRE1α）、X 框结合蛋白 1（XBP1）和葡萄糖调节蛋白 78（GRP78）的表达。进一步的体外研究表明，槲皮素通过与雌激素受体结合，可恢复组蛋白乙酰转移酶（HAT）/组蛋白去乙酰化酶（HDAC）的平衡，增加乙酰-H3K9 的表达，通过下丘脑星形胶质细胞的 IRE1α/XBP1 通路抑制铁死亡。我们的研究结果表明，乙酰化组蛋白 3 赖氨酸 9 是围绝经期抑郁症发病的关键靶点，槲皮素通过调节乙酰化组蛋白 3 赖氨酸 9 介导的围绝经期抑郁症铁死亡发挥抗抑郁作用。槲皮素可能是围绝经期抑郁症的预防和辅助治疗策略。
