Genome-wide analysis of LPS-induced inflammatory response in the rat ventral hippocampus: Modulatory activity of the antidepressant agomelatine

Objectives: Several studies reported that antidepressant drugs have immune-regulatory effects by acting on specific inflammatory mediators. However, considering the highly complex nature of the inflammatory response, we have adopted an unbiased genome-wide strategy to investigate the immune-regulatory activity of the antidepressant agomelatine in modulating the response to an acute inflammatory challenge. Methods: Microarray analysis was used to identify genes modulated in the ventral hippocampus of adult rats chronically treated with agomelatine (40 mg/kg, os) before being challenged with a single injection of lipopolysaccharide (LPS; 250 μg/kg, i.p.). Results: The administration of LPS induced the transcription of 284 genes mainly associated with pathways related to the immune/inflammatory system. Agomelatine modulated pathways not only connected to its antidepressant activity, but was also able to prevent the activation of genes induced by LPS. Further comparisons between gene lists of the diverse experimental groups led to the identification of a few transcripts modulated by LPS on which agomelatine has the larger effect of normalisation. Among them, we found the pro-inflammatory cytokine Il-1β and, interestingly, the metabotropic glutamatergic transporter Grm2. Conclusions: These results are useful to better characterise the association between depression and inflammation, revealing new potential targets for pharmacological intervention for depression associated to inflammation.

研究目的：既往多项研究表明，抗抑郁药物可通过作用于特定炎症介质发挥免疫调节效应。然而鉴于炎症应答的高度复杂性，本研究采用无偏倚全基因组策略，探究抗抑郁药物阿戈美拉汀（agomelatine）在调节急性炎症刺激应答过程中的免疫调节活性。研究方法：本研究采用基因芯片分析（microarray analysis），鉴定成年大鼠在接受单次脂多糖（lipopolysaccharide, LPS）腹腔注射（intraperitoneal, i.p.; 250 μg/kg）刺激前，经阿戈美拉汀（40 mg/kg，口服给药, os）长期处理后，其腹侧海马体（ventral hippocampus）内的差异表达基因。研究结果：脂多糖给药可诱导284个基因的转录，这些基因主要与免疫/炎症系统相关通路有关。阿戈美拉汀不仅可调控与其抗抑郁活性相关的通路，还能够抑制脂多糖诱导的基因激活。通过对不同实验组的基因列表进行进一步比对分析，本研究鉴定出少数受脂多糖调控且阿戈美拉汀可发挥显著正常化作用的转录本。其中包括促炎细胞因子Il-1β，以及值得关注的代谢型谷氨酸转运体Grm2。研究结论：本研究结果有助于更为深入地阐明抑郁症与炎症之间的关联，为炎症相关抑郁症的药理学干预提供了全新的潜在靶点。