Exploring depressive behavior using a natural product for novel drug targets

描述（由申请人提供）：抑郁症是最普遍的与压力相关的精神疾病，给我们的社会带来了严重的经济负担。尽管有许多临床有效的治疗抑郁症和相关精神疾病的方法，但很大一部分患者对一线干预措施表现出治疗抗性；当前抗抑郁药物的局限性呼唤基于抑郁病理机制的新干预措施。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，包括促炎性和抗炎性细胞因子的表达变化，因此高压力环境可能会加剧它们的失调调节。一直以来，啮齿动物长期暴露于社会失败压力下，会引起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是由免疫细胞调节的，包括可能是抑郁动物行为基础的小胶质细胞。值得注意的是，传统东方医学中使用的许多天然产品，如Kanpo（日本对传统中医的改编），已被证明具有抗炎因素和抗抑郁剂的作用，并已被经验用于治疗和预防与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在治疗抑郁症方面的有效性。Pachyman（1,3-葡聚糖）是一些东药的主要成分，如Yokukansan。除了Yokukansan具有抗抑郁作用的证据外，据报道pachyman还具有抗免疫/炎症作用。综上所述，了解其抗抑郁和抗炎作用之间的机制联系可能为识别新的抑郁症状预防和/或治疗靶点打开一扇新的窗口。在这个项目中，我们检验了pachyman可能改善应激相关的免疫/炎症变化，从而导致抗抑郁作用的假设。我们将研究pachyman对应激诱导的小胶质细胞免疫变化和抑郁行为的保护和治疗作用（目的1和2）。最后，基于我们的初步发现，pachyman对应激诱导的前额皮质小胶质细胞il - 18表达有很强的抑制作用，我们将研究内侧前额皮质小胶质特异性敲低il - 18是否可以改善慢性社会失败应激诱导的抑郁行为。明确pachyman的作用机制可能为发现新的药物靶点，预防和治疗抑郁症及相关精神疾病提供基础。

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.