Alhusban Ahmed, Fouda Abdelrahman Y, Ishrat Tauheed, Soliman Sahar, Fagan Susan C
aCharlie Norwood VA Medical Center, and Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy, and Georgia Regents University, Augusta, Georgia, USA bJordan University of Science and Technology, College of Pharmacy, Irbid, Jordan *Both authors contributed equally to this work.
J Hypertens. 2015 Jan;33(1):170-80. doi: 10.1097/HJH.0000000000000364.
Angiotensin II type 2 receptor (AT2R) stimulation is neuroprotective after experimental stroke. However, the therapeutic utility of AT2R stimulation has been hampered by the lack of a specific agonist with favourable bioavailability. Compound 21 (C21) - the first non-peptide AT2R agonist - offers a potential option to enhance stroke recovery. This study aimed to investigate the effect of C21 administration on early and late stroke outcomes, and the molecular mediators involved.
Rats were subjected to 3 h or 90 min of middle cerebral artery occlusion (MCAO) and randomized to intraperitoneal C21 (0.03 mg/kg) or saline at reperfusion. Animals were sacrificed at 24 h or 7 days and brains were collected for molecular analysis and immunostaining, respectively. Functional outcome at days 1, 4 and 7 was assessed blindly. C21 angiogenic potential was assessed in vitro.
After 3 h of MCAO, C21 treatment reduced infarct size and improved behavioural outcome at 24 h without affecting blood pressure. Co-administration of the AT2R antagonist (PD123319) blocked these effects. On the molecular level, C21 decreased brain haemoglobin content, down-regulated apoptotic and oxidative markers, and increased pro-survival molecules in the brain. After 90 min of MCAO, C21 treatment resulted in sustained functional improvement at 7 days, together with increased vascular density in the ischemic penumbra. In vitro, C21 showed a pro-angiogenic effect that was blocked with brain-derived neurotrophic factor neutralization.
These findings demonstrate that a single dose of C21 is neurovascular-protective and improves stroke outcome possibly through increasing neurotrophin activity, mitigating brain inflammation, and promoting antioxidant and pro-angiogenic effects.
在实验性中风后，血管紧张素II 2型受体（AT2R）刺激具有神经保护作用。然而，由于缺乏具有良好生物利用度的特异性激动剂，AT2R刺激的治疗效用受到了阻碍。化合物21（C21）——首个非肽类AT2R激动剂——为促进中风恢复提供了一种潜在选择。本研究旨在探究给予C21对早期和晚期中风结局的影响以及其中涉及的分子介质。
对大鼠进行3小时或90分钟的大脑中动脉闭塞（MCAO），并在再灌注时随机分为腹腔注射C21（0.03毫克/千克）组或生理盐水组。分别在24小时或7天时处死动物，并收集大脑进行分子分析和免疫染色。在第1、4和7天对功能结局进行盲法评估。在体外评估C21的血管生成潜力。
在MCAO 3小时后，C21治疗可减小梗死体积，并在24小时时改善行为结局，且不影响血压。联合给予AT2R拮抗剂（PD123319）可阻断这些效应。在分子水平上，C21降低了脑血红蛋白含量，下调了凋亡和氧化标志物，并增加了脑中的促生存分子。在MCAO 90分钟后，C21治疗在7天时导致功能持续改善，同时缺血半暗带的血管密度增加。在体外，C21显示出促血管生成作用，该作用可被脑源性神经营养因子中和所阻断。
这些发现表明，单剂量的C21具有神经血管保护作用，并可能通过增加神经营养因子活性、减轻脑炎症以及促进抗氧化和促血管生成作用来改善中风结局。
