Department of Pharmacology and Toxicology, The Interfaculty Chair of Basic and Clinical Pharmacology and Toxicology, Medical University of Lodz, Łódź, Poland.
Department of Biopharmacy, Medical University of Lodz, Łódź, Poland.
Pharmacol Rep. 2018 Oct;70(5):1032-1039. doi: 10.1016/j.pharep.2018.05.005. Epub 2018 Aug 23.
Recent evidence suggests that the mitogen activated protein kinase (MAPK)-associated signaling pathway in the frontal cortical areas demonstrates abnormal activity in cases of schizophrenia. Moreover, schizophrenia patients often display alterations in the regional cellular energy metabolism and blood flow of the brain; these are shown to parallel changes in angiogenesis primarily mediated by vascular endothelial growth factor (VEGF).
The present study examines the differential effects of time-dependent treatment with haloperidol, olanzapine and amisulpride (20μM) on VEGF and MAPK mRNA expression and VEGF level, using the T98 cell line as an example of nerve cells. For the purposes of comparison, the effect of neuroprotective pituitary adenylate cyclase-activating polypeptide (PACAP) on the expression of VEGF mRNA and secretion were also evaluated in this cell model.
RT-PCR analysis revealed that all the tested neuroleptics increased VEGF mRNA expression after 72-h incubation; however, only haloperidol and olanzapine also increased the level of VEGF detected by ELISA, and they demonstrated significantly stronger effects than PACAP. Haloperidol and olanzapine, but not amisulpride, decreased MAPK14 mRNA expression in T98G cells after 72-h incubation.
The obtained results suggest that haloperidol and olanzapine can trigger the MAPK and VEGF signaling pathway, which may contribute to their neuroprotective mechanism of action.
最近的证据表明，精神分裂症病例中额皮质区域的丝裂原活化蛋白激酶（MAPK）相关信号通路表现出异常活动。此外，精神分裂症患者的大脑区域细胞能量代谢和血流经常发生改变，这些改变与血管内皮生长因子（VEGF）介导的血管生成变化平行。
本研究以 T98 细胞系为例，考察了不同时间依赖性治疗方案对 VEGF 和 MAPK mRNA 表达及 VEGF 水平的影响，所用药物为氟哌啶醇、奥氮平、氨磺必利（20μM）。为了进行比较，还在该细胞模型中评估了神经保护垂体腺苷酸环化酶激活肽（PACAP）对 VEGF mRNA 表达和分泌的影响。
RT-PCR 分析显示，所有测试的神经安定药在孵育 72 小时后均增加了 VEGF mRNA 的表达；然而，只有氟哌啶醇和奥氮平还增加了 ELISA 检测到的 VEGF 水平，其效果明显强于 PACAP。氟哌啶醇和奥氮平，而非氨磺必利，在孵育 72 小时后降低了 T98G 细胞中 MAPK14 mRNA 的表达。
所得结果表明，氟哌啶醇和奥氮平可触发 MAPK 和 VEGF 信号通路，这可能有助于它们的神经保护作用机制。
