PDF(Pubmed)
Abstract：
Microglia are the primary innate immune cells of the central nervous system and extensively contribute to brain homeostasis. Dysfunctional or excessive activity of microglia may be associated with several neuropsychiatric disorders, including schizophrenia. Therefore, we examined whether aripiprazole and risperidone could influence the expression of the Cd200-Cd200r and Cx3cl1-Cx3cr1 axes, which are crucial for the regulation of microglial activity and interactions of these cells with neurons. Additionally, we evaluated the impact of these drugs on microglial pro- and anti-inflammatory markers (Cd40, Il-1β, Il-6, Cebpb, Cd206, Arg1, Il-10 and Tgf-β) and cytokine release (IL-6, IL-10). The research was executed in organotypic cortical cultures (OCCs) prepared from the offspring of control rats (control OCCs) or those exposed to maternal immune activation (MIA OCCs), which allows for the exploration of schizophrenia-like disturbances in animals. All experiments were performed under basal conditions and after additional stimulation with lipopolysaccharide (LPS), following the \"two-hit\" hypothesis of schizophrenia. We found that MIA diminished the mRNA level of Cd200r and affected the OCCs\' response to additional LPS exposure in terms of this parameter. LPS downregulated the Cx3cr1 expression and profoundly changed the mRNA levels of pro- and anti-inflammatory microglial markers in both types of OCCs. Risperidone increased Cd200 expression in MIA OCCs, while aripiprazole treatment elevated the gene levels of the Cx3cl1-Cx3cr1 dyad in control OCCs. The antipsychotics limited the LPS-generated increase in the expression of proinflammatory factors (Il-1β and Il-6) and enhanced the mRNA levels of anti-inflammatory components (Cd206 and Tgf-β) of microglial polarization, mostly in the absence of the MIA procedure. Finally, we observed a more pronounced modulating impact of aripiprazole on the expression of pro- and anti-inflammatory cytokines when compared to risperidone in MIA OCCs. In conclusion, our data suggest that MIA might influence microglial activation and crosstalk of microglial cells with neurons, whereas aripiprazole and risperidone could beneficially affect these changes in OCCs.
摘要：
小胶质细胞是中枢神经系统的主要先天性免疫细胞，广泛有助于脑稳态。小胶质细胞的功能失调或过度活动可能与几种神经精神疾病有关。包括精神分裂症.因此,我们研究了阿立哌唑和利培酮是否可以影响Cd200-Cd200r和Cx3cl1-Cx3cr1轴的表达，这对于调节小胶质细胞活性和这些细胞与神经元的相互作用至关重要。此外,我们评估了这些药物对小胶质细胞促炎和抗炎标志物（Cd40，IL-1β，Il-6,Cebpb,Cd206，Arg1，Il-10和Tgf-β）和细胞因子释放（IL-6，IL-10）。这项研究是在由对照大鼠（对照OCC）或暴露于母体免疫激活（MIAOCC）的后代制备的器官型皮质培养物（OCC）中进行的，这可以探索动物中精神分裂症样的紊乱。所有实验都是在基础条件下和额外用脂多糖（LPS）刺激后进行的，遵循精神分裂症的“两次打击”假设。我们发现MIA降低了Cd200r的mRNA水平，并根据此参数影响了OCC对额外LPS暴露的反应。LPS下调了Cx3cr1的表达，并深刻地改变了两种OCC中促炎和抗炎小胶质细胞标志物的mRNA水平。利培酮增加MIAOCC中Cd200的表达，而阿立哌唑治疗提高了对照OCC中Cx3cl1-Cx3cr1dyad的基因水平。抗精神病药限制了LPS产生的促炎因子（IL-1β和IL-6）表达的增加，并增强了小胶质细胞极化的抗炎成分（Cd206和Tgf-β）的mRNA水平，主要是在没有MIA程序的情况下。最后,在MIAOCC中,与利培酮相比,我们观察到阿立哌唑对促炎和抗炎细胞因子表达的调节作用更为显著.总之,我们的数据表明，MIA可能会影响小胶质细胞的激活和小胶质细胞与神经元的串扰，而阿立哌唑和利培酮可以有益地影响OCC的这些变化。
