Exendin-4 抑制基质金属蛋白酶-9 的激活，并减少高血糖小鼠局灶性脑缺血后的梗死生长。
Exendin-4 Inhibits Matrix Metalloproteinase-9 Activation and Reduces Infarct Growth After Focal Cerebral Ischemia in Hyperglycemic Mice.
机构信息
From the Department of Neurology, Juntendo University, Tokyo, Japan (T.K., R.T., K.Y., Y.U., N.H.); and Department of Neurology, Juntendo University Urayasu Hospital, Chiba, Japan (Y.S., H.S., T.U.).
出版信息
Stroke. 2016 May;47(5):1328-35. doi: 10.1161/STROKEAHA.116.012934. Epub 2016 Mar 15.
BACKGROUND AND PURPOSE
Admission hyperglycemia is an independent risk factor for poor outcome of ischemic stroke. Amelioration of hyperglycemia by insulin has not been shown to improve the poststroke outcome. Glucagon-like peptide 1 receptor agonists, which modulate glucose levels by stimulating insulin secretion, have been shown to exert cytoprotective effects by inhibiting inflammation and oxidative stress. This study aimed to evaluate whether the glucagon-like peptide 1 receptor agonist exendin-4 could reduce glucose levels and exert protective effects after acute focal ischemia in hyperglycemic mice.
METHODS
Hyperglycemia was induced by intraperitoneal injection of dextrose 15 minutes before transient middle cerebral artery occlusion was performed for 60 minutes using an intraluminal thread. We assessed 4 groups: (1) normal glucose (vehicle control), (2) induced hyperglycemia, (3) induced hyperglycemia with insulin treatment, and (4) induced hyperglycemia with exendin-4 treatment. Neurovascular injuries in brains from each group were evaluated 24 hours and 7 days post ischemia.
RESULTS
Hyperglycemia significantly increased infarct volume (36.3±1.20 versus 26.9±1.28; P<0.001), brain edema (P<0.05), and hemorrhagic transformation compared with control (P<0.001). This increase in infarct volume was associated with increased blood-brain barrier disruption and matrix metalloproteinase-9 activation. Exendin-4, but not insulin, attenuated matrix metalloproteinase-9 activation, proinflammatory cytokine (tumor necrosis factor-α) release, and biomarkers of oxidative stress and showed significant inhibition of infarct growth at 24 hours (23.6±0.97 versus 36.3±1.20; P<0.001) and at 7 days after ischemia (21.0±0.92 versus 29.3±1.41; P<0.001).
CONCLUSIONS
Treatment with exendin-4 could be a potentially useful therapeutic option for treatment of acute ischemic stroke with transient hyperglycemia.
背景与目的
入院时的高血糖是缺血性脑卒中不良预后的独立危险因素。胰岛素降低高血糖的作用并未显示能改善脑卒中后的转归。胰高血糖素样肽 1 受体激动剂通过刺激胰岛素分泌来调节血糖水平，已被证明通过抑制炎症和氧化应激发挥细胞保护作用。本研究旨在评估胰高血糖素样肽 1 受体激动剂 exendin-4 是否能降低高血糖小鼠急性局灶性缺血后的血糖水平并发挥保护作用。
方法
在通过管内线进行 60 分钟短暂性大脑中动脉闭塞前 15 分钟，通过腹腔内注射葡萄糖诱导高血糖。我们评估了 4 组：（1）正常血糖（载体对照），（2）诱导高血糖，（3）诱导高血糖用胰岛素治疗，（4）诱导高血糖用 exendin-4 治疗。在缺血后 24 小时和 7 天，评估每组大脑的神经血管损伤。
结果
与对照组相比，高血糖显著增加梗死体积（36.3±1.20 比 26.9±1.28；P<0.001）、脑水肿（P<0.05）和出血性转化（P<0.001）。梗死体积的增加与血脑屏障破坏和基质金属蛋白酶-9 激活增加有关。Exendin-4 但不是胰岛素，可减轻基质金属蛋白酶-9 激活、促炎细胞因子（肿瘤坏死因子-α）释放和氧化应激生物标志物，并在 24 小时（23.6±0.97 比 36.3±1.20；P<0.001）和缺血后 7 天（21.0±0.92 比 29.3±1.41；P<0.001）显著抑制梗死生长。
结论
用 exendin-4 治疗可能是治疗伴有短暂性高血糖的急性缺血性脑卒中的一种潜在有效治疗选择。
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