A Non-Peptidic MAS1 Agonist AVE0991 Alleviates Hippocampal Synaptic Degeneration in Rats with Chronic Cerebral Hypoperfusion
A Non-Peptidic MAS1 Agonist AVE0991 Alleviates Hippocampal Synaptic Degeneration in Rats with Chronic Cerebral Hypoperfusion
复制标题
非肽 MAS1 激动剂 AVE0991 可减轻慢性脑灌注不足大鼠的海马突触变性
DOI：
10.2174/1567202618666211012095210
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发表时间：
2021
影响因子：
2.1
通讯作者：
Teng Jiang
中科院分区：
文献类型：
--
作者：
Xiao Xue;Rui Duan;Qiao-Quan Zhang;Si-Yu Wang;Peng-Yu Gong;Yan E;Ying-Dong Zhang;Teng Jiang
背景：慢性脑灌注不足（CCH）是神经退行性疾病的一个促成因素。血管紧张素-（1-7）是新近发现的脑内肾素-血管紧张素系统的七肽，它能激活其受体MAS 1，从而改善慢性脑血管病大鼠的认知功能障碍。由于海马突触变性是认知缺陷的重要病理基础，我们假设激活MAS 1介导的信号传导可能会减轻CCH诱导的海马突触变性.研究方法：在这项研究中，我们验证了这一假设，并揭示了在大鼠模型的CCH诱导双侧颈总动脉结扎手术的潜在机制。在手术后一周，大鼠每天接受腹膜内媒介物注射或非肽类MAS 1激动剂AVE 0991，持续8周。在此过程中，记录脑血流量（CBF）。在治疗期结束时，评估海马中MAS 1、淀粉样蛋白-β（Aβ）、神经炎性细胞因子、胶质细胞标记物和突触素的水平。结果：AVE 0991可明显减轻慢性脑血管病大鼠海马突触变性。这种保护作用可能是通过促进脑血流量恢复、降低海马Aβ水平和抑制神经炎症反应来实现的。结论：这些发现表明MAS 1介导的信号转导可能代表了一个新的治疗靶点CCH相关的神经退行性疾病。
Background: Chronic cerebral hypoperfusion (CCH) is a contributing factor for neurodegenerative diseases. As a recently identified heptapeptide of the brain renin-angiotensin system, angiotensin-(1-7) has been revealed to activate its receptor MAS1 and thus ameliorated cognitive impairments in rats with CCH. Since hippocampal synaptic degeneration represents an important pathological basis of cognitive deficits, we hypothesize that activating MAS1-mediated signaling may alleviate CCH-induced synaptic degeneration in the hippocampus...Methods: In this study, we tested this hypothesis and uncovered the underlying mechanisms in a rat model of CCH induced by bilateral common carotid artery ligation surgery. At one week after the surgery, rats received a daily intraperitoneal vehicle injection or a non-peptidic MAS1 agonist AVE0991 for 8 weeks. During this procedure, Cerebral Blood Flow (CBF) was recorded. The levels of MAS1, amyloid-β (Aβ), neuroinflammatory cytokines, glial cell markers, and synaptophysin in the hippocampus were assessed at the end of the treatment period...Results: We showed that AVE0991 significantly alleviated hippocampal synaptic degeneration in rats with CCH. This protection might be achieved by facilitating CBF recovery, reducing hippocampal Aβ levels, and suppressing neuroinflammatory responses...Conclusion: These findings indicate that MAS1-mediated signaling may represent a novel therapeutic target for CCH-related neurodegenerative diseases.