Almeida Priscila G C, Nani João Victor, Oses Jean Pierre, Brietzke Elisa, Hayashi Mirian A F
Departamento de Farmacologia, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil.
Programa Multicêntrico de Pós-Graduação em Bioquímica e Biologia Molecular, Instituto de Biociências, Universidade Federal do Mato Grosso do Sul, Campo Grande, MS, Brazil.
Brain Behav Immun Health. 2019 Dec 27;2:100034. doi: 10.1016/j.bbih.2019.100034. eCollection 2020 Feb.
Mental disorders (MDs) are highly prevalent and potentially debilitating complex disorders which causes remain elusive. Looking into deeper aspects of etiology or pathophysiology underlying these diseases would be highly beneficial, as the scarce knowledge in mechanistic and molecular pathways certainly represents an important limitation. Association between MDs and inflammation/neuroinflammation has been widely discussed and accepted by many, as high levels of pro-inflammatory cytokines were reported in patients with several MDs, such as schizophrenia (SCZ), bipolar disorder (BD) and major depression disorder (MDD), among others. Correlation of pro-inflammatory markers with symptoms intensity was also reported. However, the mechanisms underlying the inflammatory dysfunctions observed in MDs are not fully understood yet. In this context, microglial dysfunction has recently emerged as a possible pivotal player, as during the neuroinflammatory response, microglia can be over-activated, and excessive production of pro-inflammatory cytokines, which can modify the kynurenine and glutamate signaling, is reported. Moreover, microglial activation also results in increased astrocyte activity and consequent glutamate release, which are both toxic to the Central Nervous System (CNS). Also, as a result of increased microglial activation in MDs, products of the kynurenine pathway were shown to be changed, influencing then the dopaminergic, serotonergic, and glutamatergic signaling pathways. Therefore, in the present review, we aim to discuss how neuroinflammation impacts on glutamate and kynurenine signaling pathways, and how they can consequently influence the monoaminergic signaling. The consequent association with MDs main symptoms is also discussed. As such, this work aims to contribute to the field by providing insights into these alternative pathways and by shedding light on potential targets that could improve the strategies for pharmacological intervention and/or treatment protocols to combat the main pharmacologically unmatched symptoms of MDs, as the SCZ.
精神障碍（MDs）是高度普遍且可能使人衰弱的复杂疾病，其病因仍然不明。深入研究这些疾病背后的病因学或病理生理学的更深层次方面将非常有益，因为在机制和分子途径方面的知识匮乏无疑是一个重要的限制。MDs与炎症/神经炎症之间的关联已被广泛讨论并为许多人所接受，因为在患有多种MDs的患者中，如精神分裂症（SCZ）、双相情感障碍（BD）和重度抑郁症（MDD）等，报告了促炎细胞因子水平升高。还报告了促炎标志物与症状强度的相关性。然而，MDs中观察到的炎症功能障碍的潜在机制尚未完全了解。在这种背景下，小胶质细胞功能障碍最近已成为一个可能的关键因素，因为在神经炎症反应期间，小胶质细胞可能会过度激活，并且报告了促炎细胞因子的过度产生，这会改变犬尿氨酸和谷氨酸信号传导。此外，小胶质细胞的激活还会导致星形胶质细胞活性增加并随之释放谷氨酸，这两者对中枢神经系统（CNS）都是有毒的。同样，由于MDs中小胶质细胞激活增加，犬尿氨酸途径的产物被证明发生了变化，进而影响多巴胺能、5-羟色胺能和谷氨酸能信号传导途径。因此，在本综述中，我们旨在讨论神经炎症如何影响谷氨酸和犬尿氨酸信号传导途径，以及它们如何进而影响单胺能信号传导。还讨论了随之而来的与MDs主要症状的关联。因此，这项工作旨在通过深入了解这些替代途径并阐明潜在靶点来为该领域做出贡献，这些靶点可以改善药理学干预策略和/或治疗方案，以对抗MDs主要的药理学上无法匹配的症状，如SCZ。
