School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, 430070, China.
Illawarra Health and Medical Research Institute and Centre for Translational Neuroscience, School of Medicine, University of Wollongong, Wollongong, NSW, 2522, Australia.
Curr Med Sci. 2021 Aug;41(4):788-802. doi: 10.1007/s11596-021-2401-7. Epub 2021 Aug 17.
Antipsychotics, in particular olanzapine, are first-line medications for schizophrenia. The prefrontal cortex (PFC) is an important region for antipsychotics' therapeutic effects. The PFC inflammatory and immune pathways are associated with schizophrenia pathogenesis. However, the effect of antipsychotics on the inflammatory and immune pathways in the PFC remains unclear. We aimed to examined the time-dependent effect of olanzapine on inflammatory and immune markers in the PFC of rats. Since the inflammatory and immune pathways are related to endoplasmic reticulum (ER) stress, we further investigated whether or not olanzapine-induced inflammation and immune responses were related to ER stress.
Expression of pro-inflammatory markers including IkappaB kinase β (IKKβ), nuclear factor kappa B (NFκB), tumor necrosis factor α (TNF-α), interleukin-6 (IL-6) and IL-1β, and immune-related proteins including inducible nitric oxide synthase (iNOS), toll-like receptor 2 (TLR2) and cluster of differentiation 14 (CD14) were examined by Western blotting.
Olanzapine treatments for 1, 8 and 36 days significantly activated the inflammatory IKKβ/NFκB signaling, and increased the expression of TNF-α, IL-6, IL-1β and immune-related proteins such as iNOS, TLR4 and CD14. Olanzapine treatment for 1 day, 8 and 36 days also induced ER stress in the PFC. Co-treatment with an ER stress inhibitor, 4-phenylbutyrate, inhibited olanzapine-induced inflammation and the immune response in the PFC.
These results suggested olanzapine exposure could be a factor that induces central inflammation and immunological abnormities in schizophrenia subjects. Olanzapine induces PFC inflammation and immune response, possibly via activating ER stress signaling.
抗精神病药，特别是奥氮平，是精神分裂症的一线药物。前额叶皮层（PFC）是抗精神病药治疗效果的重要区域。PFC 的炎症和免疫途径与精神分裂症的发病机制有关。然而，抗精神病药对 PFC 中炎症和免疫途径的影响尚不清楚。我们旨在研究奥氮平对大鼠 PFC 中炎症和免疫标志物的时间依赖性影响。由于炎症和免疫途径与内质网（ER）应激有关，我们进一步研究了奥氮平诱导的炎症和免疫反应是否与 ER 应激有关。
通过 Western blot 检测促炎标志物包括 IkappaB 激酶β（IKKβ）、核因子 kappa B（NFκB）、肿瘤坏死因子α（TNF-α）、白细胞介素 6（IL-6）和白细胞介素 1β（IL-1β）以及免疫相关蛋白，包括诱导型一氧化氮合酶（iNOS）、Toll 样受体 2（TLR2）和 CD14 的表达。
奥氮平治疗 1、8 和 36 天可显著激活炎症 IKKβ/NFκB 信号通路，并增加 TNF-α、IL-6、IL-1β 和免疫相关蛋白（如 iNOS、TLR4 和 CD14）的表达。奥氮平治疗 1 天、8 天和 36 天也诱导了 PFC 中的 ER 应激。内质网应激抑制剂 4-苯丁酸的共同处理抑制了奥氮平诱导的 PFC 炎症和免疫反应。
这些结果表明，奥氮平暴露可能是导致精神分裂症患者中枢炎症和免疫异常的一个因素。奥氮平诱导 PFC 炎症和免疫反应，可能通过激活 ER 应激信号通路。
