PPARα通路介导的N-棕榈酰乙醇胺抗抑郁样作用的大鼠海马神经细胞发生的调控机制

内源性大麻素（eCB）系统有望成为抑郁相关疾病的一个新的治疗靶点，但对其效应机制研究工作的完善尚任重道远。N-棕榈酰乙醇胺（PEA）是eCB样物质，α型过氧化物酶体增殖物激活受体（PPARα）是PEA主要的细胞内分子靶标。我们前期研究发现PEA拮抗慢性应激大鼠抑郁样行为可能与PPARα介导的海马神经发生相关，但其具体作用机制和靶点尚不清楚。据此我们提出假说：PEA通过活化PPARα通路干预海马神经细胞发生，进而拮抗慢性应激诱导的大鼠抑郁样效应。本课题拟从动物、组织、细胞、分子水平等多层次，采用免疫荧光化学、分子生物学等多种技术手段，探讨PEA经PPARα通路对大鼠海马新生细胞/神经干细胞的增殖、分化、迁移、成熟诸环节的影响；明确PPARα介导的PEA拮抗慢性应激诱导的大鼠抑郁样作用与海马神经发生的相关性；揭示eCB样物质PEA抗大鼠抑郁样效应的作用靶点，为抑郁症的临床药物治疗提供新思路。

The endocannabinoid system (eCB) is expected to become a new therapeutic target in depression related disorders, but there is a lot of work to be done to improve this process. N-palmitoylethanolamide (PEA) is an endocannabinoid analogue, peroxisome proliferator-activated receptor-alpha (PPARα) is the major intracellular target of PEA. The applicant’s preliminary study found that PEA can significantly antagonized the depressant-like behavior induced by chronically unpredicted mild stress (CUMS) in rats via PPARα pathway, and our further study suggested that its mechanisms possibly is related to hippocampal neurogenesis. However, the specific mechanisms and targets of the above effect are unclear. Therefore, we propose that PEA can interfere with hippocampal neurogenesis through activation of the PPARα pathway, and then antagonize the depression induced by chronic stress in rats. In the present study, we will use immunofluorescence chemistry, molecular biology and other technical means, at animal, tissue, cell and molecular level, to study the effects of PEA via PPARα pathway on cell proliferation, differentiation, migration and maturation of hippocampal newborn neurons / neural stem cells (NSCs), in hippocampal neurogenesis process. We aim to clarify the possible targets mediated by PPARα channel of PEA on the regulation of hippocampal neurogenesis and the antidepressant-like effect, and provide a new way of medication for clinical depression.