N-palmitoylethanolamine modulates hippocampal neuroplasticity in rats with stress-induced depressive behavior phenotype
N-palmitoylethanolamine modulates hippocampal neuroplasticity in rats with stress-induced depressive behavior phenotype
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DOI：
10.1016/j.ejphar.2023.176041
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发表时间：
2023-09-07
影响因子：
5
通讯作者：
Yu，Hailing
中科院分区：
文献类型：
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作者：
Zhang，Luwen;Tang，Wenjuan;Yu，Hailing
生物活性脂质介质N-棕榈酰乙醇酰胺（PEA）是一种内源性大麻素样分子。本研究在前期研究的基础上，进一步探讨PEA通过过氧化物酶体增殖物激活受体α（peroxisome proliferator-activated receptor alpha，PPARα）通路的抗抑郁作用，重点探讨PEA对海马神经可塑性的干预作用。在实验的最后一周对不可预知的慢性轻度应激（uCMS）诱导的大鼠进行行为学测试，然后保留脑组织样品用于随后的免疫组织化学检测和Western印迹分析。在体外培养条件下，分别采用Hoechst染色法和Western blot法检测CORT诱导的HT 22细胞凋亡及凋亡相关蛋白的表达。结果表明，PEA可改善uCMS诱导的大鼠抑郁样表型，阻止uCMS诱导的海马BrdU阳性细胞数量减少，增加BrdU/NeuN共定位，上调海马突触相关蛋白NCAM、MAP 2、SYN和PSD 95的表达。Hoechst染色结果显示，PEA明显增加CORT诱导的海马神经元数目减少。Western blot分析显示，PEA可降低CORT诱导的HT 22细胞caspase-3和c-caspase-3的表达，增加Bcl-2/Bax的比值。MK 886（一种PPARα拮抗剂）可部分或完全逆转上述作用。结论：PEA治疗抑郁性心境障碍的作用可能是通过靶向海马神经可塑性，包括增加成年神经发生和突触可塑性，下调神经元凋亡，重塑功能整合后的海马回路，而PPARα通路可能参与了这一过程。
Bioactive lipid mediator N-palmitoylethanolamide (PEA) is an endocannabinoid-like molecule. Based on our previous data, this study aimed to further investigate the antidepressant property of PEA via the peroxisome proliferator-activated receptor alpha (PPARα) pathway, focusing on the intervention of PEA on hippocampal neuroplasticity. Behavioral tests were performed in rats induced by unpredictable chronic mild stress (uCMS) in the last week of the experiment, and then the brain tissue samples were retained for subsequent immunohistochemical detection and Western blot analysis. In vitro, the apoptosis of HT22 cells induced by CORT and apoptosis-related proteins were detected by Hoechst staining and Western blot, respectively. The results showed that PEA ameliorated the depression-like phenotype in rats induced by uCMS, prevented the uCMS-induced reduction in the number of BrdU-positive cells, and increased BrdU/NeuN co-localization in the hippocampus, and upregulated the levels of synapse associated protein NCAM, MAP2, SYN and PSD95 in the hippocampus. Hoechst staining results showed that PEA significantly increased the CORT-induced reduction in the number of hippocampal neurons. Western blot analysis showed that PEA decreased the expression of caspase-3 and c-caspase-3, and increased the ratio of Bcl-2/Bax in CORT-induced HT22 cells. MK886, a PPARα antagonist, partially or completely reversed these effects. In conclusion, the therapeutic potential of PEA for depressive mood disorders may be through targeting the hippocampal neuroplasticity, including increasing adult neurogenesis and synaptic plasticity, as well as down-regulated neuronal apoptosis, to remodel hippocampal circuitries upon functional integration and PPARα pathway may be involved in this process.