盐酸氟西汀对高原脑水肿大鼠脑组织的保护作用

The protective effect of fluoxetine hydrochloride on brain tissues of rats with high altitude cerebral edema

目的研究盐酸氟西汀对模拟高原脑水肿大鼠脑组织的保护作用及其作用机制。方法通过小鼠常压密闭缺氧耐受力实验确定盐酸氟西汀最佳给药剂量及给药时间;采用大型低压氧舱进行高原脑水肿大鼠造模;HE染色观察大鼠脑组织病理学结构变化;酶标仪法检测丙二醛(MDA)水平和超氧化物歧化酶(SOD)活性;Western blot法检测缺氧相关蛋白HIF-1α、VEGF、MMP-9以及AQP4、SERT的表达。结果与缺氧模型组相比,给予盐酸氟西汀干预后:小鼠存活时间延长,盐酸氟西汀中剂量组(14 mg·kg^(-1))效果最佳,延长率为17.78%;脑组织病理损伤有所改善,脑含水量减少,血脑屏障渗透性减小;大鼠脑组织内MDA含量减少,SOD活性增强。Western blot结果表明,HIF-1α、VEGF、MMP-9、AQP4、SERT蛋白均明显下调。结论盐酸氟西汀对高原脑水肿大鼠具有保护作用,其机制可能与改善氧化应激、激活HIF-1α/VEGF/MMP-9信号通路并且影响SERT蛋白表达有关,SERT可能为治疗高原脑水肿的潜在靶点。

Aim To study the protective effect of fluoxetine hydrochloride on brain tissues of rats with simulated high altitude cerebral edema(HACE)and its mechanism.Methods The optimal dosage and time of fluoxetine hydrochloride were determined by the hypoxia tolerance test of mice under normal pressure.The rat model of brain edema at high altitude was established by large-scale low-pressure oxygen chamber.HE staining was used to observe the pathological changes of brain tissues in rats.Microplate reader was used to detect the corresponding indexes of oxidative stress such as malondialdehyde(MDA)level and superoxide dismutase(SOD)activity.The expressions of hypoxia-related proteins HIF-1α,VEGF,MMP-9,AQP4 and SERT were detected by Western blot.Results Compared with the hypoxia model group,after the intervention of fluoxetine hydrochloride,the survival time of mice was prolonged,and the middle dose of fluoxetine(14 mg·kg^(-1)) had the best effect,with an extension rate of 17.78%.The pathological damage of brain was improved,the water content of brain decreased,and the permeability of blood-brain barrier decreased.MDA content in rat brain decreased and SOD activity increased.Western blot results showed that HIF-1α,VEGF,MMP-9,AQP4,SERT protein were significantly down-regulated.Conclusions Fluoxetine has protective effect on rats with brain edema at high altitude,and its mechanism may be related to improving oxidative stress,activating HIF-1α/VEGF/MMP-9 signaling pathway and affecting the expression of SERT protein.SERT may be a potential target for treating brain edema at high altitude.