Obuchowicz Ewa, Bielecka-Wajdman Anna M, Paul-Samojedny Monika, Nowacka Marta
Department of Pharmacology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland.
Department of Pharmacology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland.
Cytokine. 2017 Jun;94:37-44. doi: 10.1016/j.cyto.2017.04.004. Epub 2017 Apr 11.
The microglial hypothesis of schizophrenia suggests that its neuropathology is closely associated with neuroinflammation manifested, inter alia, by an increased expression of cytokines. However, clinical investigations imply that schizophrenia is a heterogeneous disease and in some groups of patients the activated inflammatory process does not contribute to the disease-associated impairment of brain function. Clinical studies revealed also an equivocal impact of antipsychotics on peripheral and CSF cytokines, whereas experimental research performed on the stimulated glia cultures showed their inhibitory effect on pro-inflammatory cytokine levels. In the present study, the effect of chlorpromazine, haloperidol and risperidone (0.5, 5 or 10μM) on production of pro-inflammatory cytokines IL-1β and TNF-α and anti-inflammatory IL-10 was investigated in the unstimulated and lipopolysaccharide-stimulated primary rat mixed glial cell cultures. In the unstimulated cultures, haloperidol at all applied concentrations, risperidone at 5, 10μM and chlorpromazine at 10μM increased IL-10 levels in the culture supernatants without a significant influence on IL-1β or TNF-α levels, and all drugs applied at 10μM induced a robust increase in IL-10 mRNA expression. Under strong inflammatory activation, haloperidol and risperidone at all concentrations reduced production of both pro-inflammatory cytokines, without adverse effects on IL-10 expression when used at 10μM. Chlorpromazine at all concentrations diminished the production of three cytokines and did not induce anti-inflammatory effect. These results suggest that dependently on glia activation antipsychotics via different mechanisms may induce anti-inflammatory effect and that this activity is not common for all drugs under conditions of strong glia activation.
精神分裂症的小胶质细胞假说表明，其神经病理学与神经炎症密切相关，尤其是细胞因子表达增加所表现出的神经炎症。然而，临床研究表明精神分裂症是一种异质性疾病，在某些患者群体中，激活的炎症过程对与疾病相关的脑功能损害并无作用。临床研究还揭示了抗精神病药物对周围和脑脊液细胞因子的影响不明确，而对受刺激的神经胶质细胞培养物进行的实验研究表明它们对促炎细胞因子水平有抑制作用。在本研究中，研究了氯丙嗪、氟哌啶醇和利培酮（0.5、5或10μM）对未受刺激和脂多糖刺激的原代大鼠混合神经胶质细胞培养物中促炎细胞因子白细胞介素-1β和肿瘤坏死因子-α以及抗炎细胞因子白细胞介素-10产生的影响。在未受刺激的培养物中，所有应用浓度的氟哌啶醇、5和10μM的利培酮以及10μM的氯丙嗪均增加了培养上清液中的白细胞介素-10水平，而对白细胞介素-1β或肿瘤坏死因子-α水平无显著影响，并且所有10μM的药物均诱导白细胞介素-10 mRNA表达显著增加。在强烈的炎症激活下，所有浓度的氟哌啶醇和利培酮均降低了两种促炎细胞因子的产生，在10μM使用时对白细胞介素-10表达无不良影响。所有浓度的氯丙嗪均减少了三种细胞因子的产生，且未诱导抗炎作用。这些结果表明，抗精神病药物可能通过不同机制依赖于神经胶质细胞激活而诱导抗炎作用，并且在强烈的神经胶质细胞激活条件下，这种活性并非所有药物都具备。
