Li Lei, Kan Weijing, Zhang Yi, Wang Tianyi, Yang Feng, Ji Tengfei, Wang Gang, Du Jing
The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital & Advanced Innovation Center for Human Brain Protection, Capital Medical University, 100088, Beijing, China.
Basic and Translational Medicine Center, China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital & Advanced Innovation Center for Human Brain Protection, Capital Medical University, 100070, Beijing, China.
Transl Psychiatry. 2024 Oct 2;14(1):400. doi: 10.1038/s41398-024-03127-z.
Major depressive disorder (MDD) is a common disease affecting 300 million people worldwide. The existing drugs are ineffective for approximately 30% of patients, so it is urgent to develop new antidepressant drugs with novel mechanisms. Here, we found that norisoboldine (NOR) showed an antidepressant efficacy in the chronic social defeat stress (CSDS) depression model in the tail suspension, forced swimming, and sucrose consumption tests. We then utilized the drug-treated CSDS mice paradigm to segregate and gain differential protein groups of CSDS versus CON (CSDS), imipramine (IMI)-treated versus CSDS (IMI), and NOR-treated versus CSDS (NOR) from the prefrontal cortex. These protein expression alterations were first analyzed by ANOVA with p < 0.05. The protein cluster 1 and cluster 3, in which the pattern of protein levels similar to the mood pattern, showed enrichment in functions and localizations related to mitochondrion, ribosome and synapses. Further GO analysis of the common proteins for NOR groups and NOR groups supported the findings from ANOVA analysis. We employed Protein-Protein interaction (PPI) analysis to examine the proteins of NOR and NOR revealing an enrichment of the proteins associated with the mitochondrial ribosomal and synaptic functions. Further independent analysis using parallel reaction monitoring (PRM) revealed that Cox7c, Mrp142, Naa30, Ighm, Apoa4, Ssu72, Mrps30, Apoh, Acbd5, and Cdv3, exhibited regulation in the NOR-treated group to support the homeostasis of mitochondrial functions. Additionally, Dcx, Arid1b, Rnf112, and Fam3c, were also observed to undergo modulation in the NOR-treated groups to support the synaptic formation and functions. These findings suggest that the proteins involved in depression treatment exert effects in strengthen the mitochondrial and synaptic functions in the mice PFC. Western blot analysis supported the data that the levels of Mrpl42, Cox7c, Naa30, Rnf112, Dcx Apoa4, Apoh and Fam3c were altered in the CSDS mice, and rescued by NOR treatment, supporting the PRM data. NOR treatment also rescued the NLRP3 inflammasome activation in CSDS mice. In summary, the current proteomic research conducted on the prefrontal cortex has provided valuable insights into the specific and shared molecular mechanisms underlying pathophysiology and treatment to CSDS-induced depression, shedding light on the therapeutic effects of Norisoboldine.
重度抑郁症（MDD）是一种常见疾病，全球约有3亿人受其影响。现有药物对约30%的患者无效，因此迫切需要研发具有新作用机制的新型抗抑郁药物。在此，我们发现去甲异波尔定（NOR）在慢性社会挫败应激（CSDS）抑郁模型的悬尾、强迫游泳和蔗糖消耗试验中显示出抗抑郁功效。然后，我们利用药物处理的CSDS小鼠模型，从前额叶皮质中分离并获得CSDS组与对照组（CSDS）、丙咪嗪（IMI）处理组与CSDS组（IMI）以及NOR处理组与CSDS组（NOR）的差异蛋白组。这些蛋白表达变化首先通过方差分析进行分析，p<0.05。蛋白簇1和簇3中，蛋白水平模式与情绪模式相似，显示在线粒体、核糖体和突触相关的功能和定位上富集。对NOR组和NOR组的共同蛋白进行进一步的基因本体（GO）分析支持了方差分析的结果。我们采用蛋白质-蛋白质相互作用（PPI）分析来研究NOR组和NOR组的蛋白质，揭示了与线粒体核糖体和突触功能相关的蛋白质的富集。使用平行反应监测（PRM）进行的进一步独立分析表明，Cox7c、Mrp142、Naa30、Ighm、Apoa4、Ssu72、Mrps30、Apoh、Acbd5和Cdv3在NOR处理组中表现出调节作用，以支持线粒体功能的稳态。此外，还观察到Dcx、Arid1b、Rnf112和Fam3c在NOR处理组中也发生了调节，以支持突触的形成和功能。这些发现表明，参与抑郁症治疗的蛋白质在增强小鼠前额叶皮质的线粒体和突触功能方面发挥作用。蛋白质免疫印迹分析支持了以下数据：CSDS小鼠中Mrpl42、Cox7c、Naa30、Rnf112、Dcx、Apoa4、Apoh和Fam3c的水平发生了改变，而NOR处理可使其恢复，这支持了PRM数据。NOR处理还可挽救CSDS小鼠中NLRP3炎性小体的激活。总之，目前在前额叶皮质上进行的蛋白质组学研究为CSDS诱导的抑郁症的病理生理学和治疗的特定和共同分子机制提供了有价值的见解，揭示了去甲异波尔定的治疗效果。
