Division of Experimental Vascular Research, Department of Clinical Sciences, Lund University, Lund, Sweden.
Trinity College Institute of Neuroscience, University of Dublin, Dublin, Ireland.
Acta Physiol (Oxf). 2018 May;223(1):e12985. doi: 10.1111/apha.12985. Epub 2017 Nov 12.
The aim was to evaluate the beneficial effect of early mitogen-activated protein kinase (MEK)1/2 inhibition administered at a clinical relevant time-point using the transient middle cerebral artery occlusion model and a dedicated rodent magnetic resonance imaging system (9.4T) to monitor cerebrovascular changes non-invasively for 2 weeks.
Transient middle cerebral artery occlusion was induced in male rats for two hours followed by reperfusion. The specific MEK1/2 inhibitor U0126 was administered ip at 6 and 24 hours post-reperfusion. Neurological functions were evaluated by 6- and 28-point tests. 9.4 T magnetic resonance imaging was used to monitor morphological infarct changes at day 2, 8 and 14 after stroke and to evaluate cerebral perfusion at day 14. Immunohistochemistry evaluation of Ki67 was performed 14 days post-stroke.
U0126 improved long-term behavioural outcome and significantly reduced infarct size. In addition, cerebral perfusion in U0126-treated animals was improved compared to the vehicle group. Immunohistochemistry showed a significant increase in Ki67 cells in U0126-treated animals compared to the vehicle group.
Early MEK1/2 inhibition improves long-term functional outcome, promotes recovery processes after stroke and most importantly provides a realistic time window for therapy.
本研究旨在评估在短暂性大脑中动脉闭塞模型和专用啮齿动物磁共振成像系统（9.4T）中，于临床相关时间点给予早期丝裂原活化蛋白激酶（MEK）1/2 抑制剂的有益效果，以非侵入性方式监测脑血管变化 2 周。
雄性大鼠短暂性大脑中动脉闭塞 2 小时后再灌注。在再灌注后 6 小时和 24 小时，通过腹腔内给药给予特定的 MEK1/2 抑制剂 U0126。采用 6 点和 28 点测试评估神经功能。9.4T 磁共振成像用于监测中风后第 2、8 和 14 天的形态学梗塞变化，并评估第 14 天的脑灌注。中风后 14 天进行 Ki67 的免疫组织化学评估。
U0126 改善了长期行为结局，显著减少了梗塞面积。此外，与对照组相比，U0126 治疗动物的脑灌注得到改善。免疫组织化学显示，与对照组相比，U0126 治疗动物的 Ki67 细胞显著增加。
早期 MEK1/2 抑制可改善长期功能结局，促进中风后的恢复过程，最重要的是为治疗提供了一个现实的时间窗口。
