Exploring depressive behavior using a natural product for novel drug targets

描述（由申请人提供）：抑郁症是最普遍的压力相关的精神状况，对我们的社会造成严重的经济负担。虽然有一些临床上有效的治疗抑郁症和相关的精神疾病，很大一部分患者表现出一线干预治疗的阻力;在目前的抗抑郁药的局限性，需要新的干预措施的基础上抑郁症的病理机制。越来越多的证据表明，在抑郁症患者中观察到免疫和炎症过程的改变，包括促炎和抗炎细胞因子表达的变化，从而高压力环境可能会加剧其紊乱的调节。一致地，啮齿类动物长期暴露于社会失败压力诱导免疫和炎症系统的脑内激活，包括某些细胞因子的升高，这些细胞因子在很大程度上受免疫细胞调节，包括可能导致抑郁动物行为的小胶质细胞。值得注意的是，在传统东方医学中使用的许多天然产物，如Kanpo（传统中药的改编，日本），已被证明具有抗炎因子和抗抑郁剂的功能，并已被经验性地用于治疗和预防炎症相关的人类疾病，包括抑郁症。然而，几乎没有基于机制的证据表明传统草药治疗抑郁症的有效性。茯苓多糖（1，3-葡聚糖）是几种东方药物的主要成分，如Yokukansan。除了Yokukansan的抗抑郁作用的证据外，据报道茯苓多糖具有抗免疫/炎症作用。总之，了解其抗抑郁和抗炎作用之间的机制联系，可能会打开一个新的窗口，识别新的预防和/或治疗抑郁症状的目标。在这个项目中，我们测试的假设，茯苓多糖可以改善应激相关的免疫/炎症变化，导致抗抑郁作用。我们将使用遭受社交失败压力的小鼠来检查茯苓多糖对压力诱导的小胶质细胞免疫变化和抑郁行为的保护和治疗效果（目的1和2）。最后，基于我们的初步研究结果显示茯苓多糖对应激诱导的前额叶皮层小胶质细胞IL 18表达的强烈抑制作用，我们将研究内侧前额叶皮层小胶质细胞特异性敲低IL 18是否可以改善慢性社交失败应激诱导的抑郁行为。明确茯苓多糖的作用机制可能为确定预防和治疗抑郁症及相关精神疾病的新药物靶点提供基础。

DESCRIPTION (provided by applicant): Depression is the most prevalent stress-associated mental condition, imposing a serious economic burden on our society. Although there are a number of clinically effective treatments for depression and associated psychiatric conditions, a large segment of patients exhibit treatment-resistance to first-line interventions; limitations in current antidepressants call for novel interventions based on pathological mechanisms of depression. Accumulating evidence suggests that alterations in immune and inflammation processes, including changes in expression of pro- and anti-inflammatory cytokines are observed in patients with depression, whereby high stress environments may exacerbate their perturbed regulation. Consistently, chronic exposure to social defeat stress in rodents induces intracerebral activation of immune and inflammation systems, including elevation of certain cytokines, that are largely regulated by immune cells, including microglia which may underlie depressive animal behaviors. Notably, many natural products used in traditional Eastern medicine, such as Kanpo (adaptation of traditional Chinese medicine, Japan), have been shown to function as anti-inflammatory factors and antidepressants and have been empirically used for treatment and prevention of inflammation-associated human disease, including depression. Nonetheless, there is almost no mechanism-based evidence for the effectiveness of traditional herbal medicines in treatment of depression. Pachyman (1,3-¿-Glucans) is a main ingredient of several Eastern medicines, such as Yokukansan. In addition to the evidence of the antidepressant effect of Yokukansan, pachyman is reported to have anti-immune/inflammatory effects. Taken together, understanding the mechanistic link between its antidepressant and anti-inflammatory effects may open a new window for identification of novel preventive and/or treatment targets for depressive symptoms. In this project, we test the hypothesis that pachyman may ameliorate stress-associated immune/inflammation changes, leading to antidepressant effects. We will examine the protective and treatment effect of pachyman on stress-induced microglial immune changes and depressive behaviors using mice subjected to social defeat stress (Aims 1 and 2). Finally, based on our preliminary findings showing the strong suppressive effect of pachyman on stress-induced microglial IL18 expression in the prefrontal cortex, we will investigate whether microglia-specific knockdown of IL18 in the medial prefrontal cortex may ameliorate depressive behaviors induced by chronic social defeat stress. Defining the mechanism of action of pachyman may provide a basis for identifying novel drug targets for the prevention and treatment of depression and related mental conditions.