Sun Xiaohui, Wang Tian, Zhou Lin, Zhang Ce, Fu Fenghua
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong, China.
Front Pharmacol. 2023 Apr 21;14:1073099. doi: 10.3389/fphar.2023.1073099. eCollection 2023.
The aim is to investigate the effect of toludesvenlafaxine (Tdv), a reuptake inhibitor of serotonin, norepinephrine, and dopamine, on the neurological function in cerebral ischemic rats and the underlying mechanisms. Middle cerebral artery occlusion/reperfusion (MCAO/R) model was induced in rats and the neuroprotective effects of Tdv were evaluated by infarct size, Garcia test, and beam walking test. Neuronal apoptosis in the peri-infarct area was observed by TUNEL staining. And the apoptosis-related proteins were evaluated with Western blotting. The role of CREB pathway in effect of Tdv was also investigated using Western blotting and immunofluorescence. In the MCAO/R model, administration of Tdv reduced the infarct size, promoted neural functional recovery, decreased the expression of Bax and Caspase-3, and increased the expression of Bcl-2 and BDNF. In addition, Tdv reduced neuronal apoptosis in the peri-infarct area. Tdv increased the expression of phosphorylated CREB. The application of the specific CREB inhibitor, compound 666-15, could reverse the anti-ischemic cerebral injury of Tdv in MCAO/R rats. Tdv ameliorated cerebral ischemic injury through reducing neuronal apoptosis and increasing the expression of BDNF via the activation of CREB pathway.
目的是研究5-羟色胺、去甲肾上腺素和多巴胺再摄取抑制剂托度文拉法辛（Tdv）对脑缺血大鼠神经功能的影响及其潜在机制。在大鼠中诱导大脑中动脉闭塞/再灌注（MCAO/R）模型，并通过梗死面积、加西亚试验和横梁行走试验评估Tdv的神经保护作用。通过TUNEL染色观察梗死周边区域的神经元凋亡。并用蛋白质免疫印迹法评估凋亡相关蛋白。还使用蛋白质免疫印迹法和免疫荧光法研究了CREB通路在Tdv作用中的作用。在MCAO/R模型中，给予Tdv可减小梗死面积，促进神经功能恢复，降低Bax和Caspase-3的表达，并增加Bcl-2和BDNF的表达。此外，Tdv减少了梗死周边区域的神经元凋亡。Tdv增加了磷酸化CREB的表达。应用特异性CREB抑制剂化合物666-15可逆转Tdv对MCAO/R大鼠的抗缺血性脑损伤作用。Tdv通过减少神经元凋亡并通过激活CREB通路增加BDNF的表达来改善脑缺血损伤。
