CNS Research lab., Pharmacology division, Department of Pharmaceutical Sciences and Drug Research, Faculty of Medicine, Punjabi University, Patiala 147002, Punjab, India.
Pharmacology division, Department of Pharmaceutical Sciences and Drug Research, Faculty of Medicine, Punjabi University, Patiala 147002, Punjab, India.
Vascul Pharmacol. 2021 Apr;137:106827. doi: 10.1016/j.vph.2020.106827. Epub 2020 Dec 17.
The present study investigates the potential of ozagrel, a thromboxane A2 (TXA2) synthase inhibitor, in bilateral common carotid artery occlusion (BCCAo) induced vascular dementia (VaD). Wistar rats were subjected to BCCAo procedure under anesthesia to induce VaD. Morris water maze (MWM) test was employed on 7th day post-surgery to determine learning and memory. Endothelial dysfunction was assessed in isolated aorta by observing endothelial dependent vasorelaxation and levels of serum nitrite. A battery of biochemical and histopathological estimations was performed. Expression analysis of inflammatory cytokines TNF-α and IL-6 was carried out by RT-PCR. BCCAo produced significant impairment in endothelium dependent vasorelaxation and decrease in serum nitrite levels indicating endothelial dysfunction along with poor performance on MWM represents impairment of learning and memory. There was a significant rise in brain oxidative stress level (indicated by increase in brain thiobarbituric acid reactive species and decrease in reduced glutathione levels); increase in brain acetylcholinesterase activity; brain myeloperoxidase activity; brain TNF-α & IL-6 levels, brain TNF-α & IL-6 mRNA expression and brain neutrophil infiltration (as marker of inflammation) were also observed. Treatment of ozagrel (10 & 20 mg/kg, p. o.)/donepezil (0. 5 mg/kg, i.p., serving as standard) ameliorated BCCAo induced endothelial dysfunction; memory deficits; biochemical and histopathological changes in a significant manner. It may be concluded that ozagrel markedly improved endothelial dysfunction; learning and memory; biochemical and histopathological alteration associated with BCCAo induced VaD and that TXA2 can be considered as an important therapeutic target for the treatment of VaD.
本研究探讨了血栓素 A2（TXA2）合酶抑制剂奥扎格雷（ozagrel）在双侧颈总动脉闭塞（BCCAo）诱导血管性痴呆（VaD）中的作用。Wistar 大鼠在麻醉下接受 BCCAo 手术以诱导 VaD。术后第 7 天进行 Morris 水迷宫（MWM）测试以确定学习和记忆能力。通过观察内皮依赖性血管舒张和血清硝酸盐水平来评估离体主动脉的内皮功能障碍。进行了一系列生化和组织病理学评估。通过 RT-PCR 进行炎症细胞因子 TNF-α和 IL-6 的表达分析。BCCAo 导致内皮依赖性血管舒张明显受损，血清硝酸盐水平降低，表明内皮功能障碍，MWM 表现不佳代表学习和记忆受损。大脑氧化应激水平显著升高（表现为大脑硫代巴比妥酸反应性物质增加和还原型谷胱甘肽水平降低）；大脑乙酰胆碱酯酶活性增加；大脑髓过氧化物酶活性；大脑 TNF-α和 IL-6 水平、大脑 TNF-α和 IL-6 mRNA 表达和大脑中性粒细胞浸润（作为炎症标志物）也观察到。奥扎格雷（10 和 20 mg/kg，口服）/多奈哌齐（0.5 mg/kg，腹腔注射，作为标准）治疗显著改善了 BCCAo 诱导的内皮功能障碍；记忆缺陷；生化和组织病理学变化。可以得出结论，奥扎格雷显著改善了 BCCAo 诱导的 VaD 相关的内皮功能障碍；学习和记忆；生化和组织病理学改变，TXA2 可被视为 VaD 治疗的重要治疗靶点。
