基于电压门控钙通道所维持钙稳态探究淫羊藿苷抗抑郁机制

Depression is a complex disorder that involves biological, psychological and environmental factors in its aetiology. That the hypothalamic–pituitary–adrenal axis is dysregulated is evidenced by studies examining glucocorticoids hypersecretion. Glucocorticoids-induced neurotoxicity of hippocampus has been implicated in the pathophysiology of depression, although the exact mechanism remains uncertain. Our previous studies demonstrated that icariin, showing antidepressant-like activity, has a protective effect against corticosterone-induced apoptosis in primary cultured rat hippocampal neurons. The rise in intracellular Ca2+ plays key role in the glucocorticoids-induced neurotoxicity of hippocampus. There exists mounting data on glucocorticoids-induced alterations of intracellular calcium homeostasis by targeting voltage-gated Ca2+ (Cav) channels. The present project is designed to identify the molecular mechanism of icariin as an antidepressant, which may be related to modulation of Cav1.2 channel trafficking to and from the plasma membrane. A better understanding of neurobiological mechanisms of depression will help open up new avenues for therapeutic strategies.

抑郁症是生物、心理与社会环境等多种因素交互作用的结果，已知下丘脑-垂体-肾上腺轴功能持续亢进以及糖皮质激素（GC）过度分泌是抑郁症发生的重要病理基础，过量GC诱导的海马神经元损伤是抑郁症的关键病理环节，但确切机制尚未完全阐明。本课题组前期工作发现中药淫羊藿单体淫羊藿苷（ICA）具有保护海马神经元的作用，已知胞内Ca2+超载是GC诱导海马神经元损伤的重要因素，而介导Ca2+内流的电压门控Ca2+（Cav）通道恰恰是GC主要靶点之一，因此本课题拟从膜转运经典途径：COPII转运复合体、Arf1-dependent蛋白转运途径、dynamin1介导的内吞以及Cav1.2通道蛋白降解环节入手，研究ICA对于Cav1.2通道膜表达和膜转运的调控作用以及可能机制，从而深入探索ICA抗抑郁机理，为ICA在抑郁症的进一步临床应用提供理论基础和应用依据，为以Cav通道为靶点的抗抑郁干预手段提供思路和方向。

抑郁症作为全球关注的重要精神心理疾病，深入研究其发病机制并寻找有效防治方法和手段具有十分重要的意义。已知下丘脑-垂体-肾上腺轴功能持续亢进以及糖皮质激素（GC）过度分泌是抑郁症发生的重要病理基础，过量GC诱导的海马神经元损伤是抑郁症的关键病理环节，但确切机制尚未完全阐明。本课题组前期工作发现淫羊藿单体淫羊藿苷（ICA）具有海马神经元保护作用，而胞内Ca2+超载是GC诱导海马神经元损伤的重要因素，介导Ca2+内流的电压门控Ca2+（Cav）通道又恰恰是GC主要靶点之一，因此本课题从膜转运经典途径：COPII转运复合体、Arf1-dependent蛋白转运途径、dynamin1介导的内吞以及Cav1.2通道蛋白降解环节入手，探究ICA能否调控Cav1.2通道膜表达和膜转运以及可能机制，研究结果表明ICA对皮质酮所致Cav1.2通道功能及膜表达水平改变具有调控作用，此调控效应通过影响CopII转运复合体、Arf1-dependent蛋白转运途径以及dynamin1介导的内吞这些细胞物质运输环节来发挥作用，从而从膜转运角度阐释ICA抗抑郁机理，为ICA在抑郁症的进一步临床应用提供理论基础和应用依据，为以Cav通道为靶点的抗抑郁干预手段、拓展抗抑郁药物领域提供思路和方向。