Delayed Administration of Angiotensin II Type 2 Receptor (AT2R) Agonist Compound 21 Prevents the Development of Post-stroke Cognitive Impairment in Diabetes Through the Modulation of Microglia Polarization
Delayed Administration of Angiotensin II Type 2 Receptor (AT2R) Agonist Compound 21 Prevents the Development of Post-stroke Cognitive Impairment in Diabetes Through the Modulation of Microglia Polarization
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DOI：
10.1007/s12975-019-00752-5
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发表时间：
2019-12-03
影响因子：
6.9
通讯作者：
Ergul, Adviye
中科院分区：
文献类型：
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作者：
Jackson, Ladonya;Dong, Guangkuo;Ergul, Adviye
中风的致残后果是认知障碍，发生在12%-48%的患者中，对此没有治疗。一个关键的障碍是缺乏对中风后认知障碍（PSCI）如何发展的理解。虽然70%的中风患者存在糖尿病和高血压等共病，但临床前研究中共病模型的有限使用进一步导致了这种缺乏进展。为此，我们使用糖尿病的转化模型来研究PSCI的发展。此外，我们评估了化合物21（C21），血管紧张素II 2型受体激动剂，通过对治疗分配设盲、设定严格的纳入标准和实施延迟给药时间点来治疗PSCI的应用。糖尿病是由高脂饮食（HFD）和低剂量链脲佐菌素（STZ）的组合。对照组和糖尿病组大鼠进行1小时大脑中动脉闭塞（MCAO）或假手术。采用去除粘着剂任务（ART）和两次Y迷宫测试大鼠的感觉运动和认知功能。卒中后3天，向符合入选标准的大鼠给予C21或溶剂（溶于饮用水），剂量为0.12 mg/kg/天，持续8周。通过流式细胞术和免疫组织化学（IHC）分析来自新鲜收获的脑的样品。糖尿病加重了PSCI的发展，增加了炎症和脱髓鞘。卒中后3天延迟给予C21可降低死亡率，改善感觉运动和认知缺陷。它还通过调节糖尿病动物中的M1：M2比率来减少炎症和脱髓鞘。
A disabling consequence of stroke is cognitive impairment, occurring in 12%-48% of patients, for which there is no therapy. A critical barrier is the lack of understanding of how post-stroke cognitive impairment (PSCI) develops. While 70% of stroke victims present with comorbid diseases such as diabetes and hypertension, the limited use of comorbid disease models in preclinical research further contributes to this lack of progress. To this end, we used a translational model of diabetes to study the development of PSCI. In addition, we evaluated the application of compound 21 (C21), an angiotensin II Type 2 receptor agonist, for the treatment of PSCI by blinding the treatment assignment, setting strict inclusion criteria, and implementing a delayed administration time point. Diabetes was induced by a high-fat diet (HFD) and low-dose streptozotocin (STZ) combination. Control and diabetic rats were subjected to 1 h middle cerebral artery occlusion (MCAO) or sham surgery. Adhesive removal task (ART) and two-trial Y-maze were utilized to test sensorimotor and cognitive function. Three days post-stroke, rats that met the inclusion criteria were administered C21 or vehicle in drinking water at a dose of 0.12 mg/kg/day for 8 weeks. Samples from freshly harvested brains were analyzed by flow cytometry and immunohistochemistry (IHC). Diabetes exacerbated the development of PSCI and increased inflammation and demyelination. Delayed administration of C21 3 days post-stroke reduced mortality and improved sensorimotor and cognitive deficits. It also reduced inflammation and demyelination through modulation of the M1:M2 ratio in the diabetic animals.