Captopril alleviates epilepsy and cognitive impairment by attenuation of C3-mediated inflammation and synaptic phagocytosis.
Captopril alleviates epilepsy and cognitive impairment by attenuation of C3-mediated inflammation and synaptic phagocytosis.
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DOI：
10.1186/s12974-022-02587-8
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发表时间：
2022-09-14
影响因子：
9.3
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中科院分区：
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来自实验和临床研究的证据表明，免疫炎症反应在癫痫引起的脑损伤中发挥着重要作用。卡托普利是一种血管紧张素转换酶抑制剂(ACEI)，此前已被证明可抑制多种神经疾病的免疫炎症反应。然而，卡托普利对癫痫的治疗潜力仍不清楚。本研究采用SD大鼠腹腔注射海人酸(KA)建立癫痫状态。卡托普利(50 mg/kg，ip)在KA给药后每天给药，从第3天到第49天。脑电图法显示，卡托普利能有效抑制KA诱发的癫痫。此外，卡托普利改善了癫痫诱发的认知障碍，在Morris水迷宫、Y迷宫和新颖的客观测试中的表现有所改善。RNA测序(RNA-seq)分析表明，卡托普利逆转了癫痫相关的广泛生物学过程，特别是胶质细胞激活、补体系统介导的吞噬作用和炎症因子的产生。有趣的是，卡托普利抑制癫痫诱导的激活和星形胶质细胞与小胶质细胞之间的异常接触。免疫组织化学实验表明，卡托普利可能通过C3-C3ar介导的海马区吞噬作用减轻小胶质细胞依赖的突触重构。最后，鼻腔应用重组C3a(1.3μg/kg/d)可部分阻断卡托普利的上述作用。我们的研究结果表明，卡托普利通过减轻炎症和C3介导的突触吞噬作用，减少癫痫和认知损害的发生。这种方法很容易适应临床实践中的长期疗效和安全性。
Evidence from experimental and clinical studies implicates immuno-inflammatory responses as playing an important role in epilepsy-induced brain injury. Captopril, an angiotensin-converting enzyme inhibitor (ACEi), has previously been shown to suppress immuno-inflammatory responses in a variety of neurological diseases. However, the therapeutic potential of captopril on epilepsy remains unclear. In the present study, Sprague Dawley (SD) rats were intraperitoneally subjected to kainic acid (KA) to establish a status epilepticus. Captopril (50 mg/kg, i.p.) was administered daily following the KA administration from day 3 to 49. We found that captopril efficiently suppressed the KA-induced epilepsy, as measured by electroencephalography. Moreover, captopril ameliorated the epilepsy-induced cognitive deficits, with improved performance in the Morris water maze, Y-maze and novel objective test. RNA sequencing (RNA-seq) analysis indicated that captopril reversed a wide range of epilepsy-related biological processes, particularly the glial activation, complement system-mediated phagocytosis and the production of inflammatory factors. Interestingly, captopril suppressed the epilepsy-induced activation and abnormal contact between astrocytes and microglia. Immunohistochemical experiments demonstrated that captopril attenuated microglia-dependent synaptic remodeling presumably through C3–C3ar-mediated phagocytosis in the hippocampus. Finally, the above effects of captopril were partially blocked by an intranasal application of recombinant C3a (1.3 μg/kg/day). Our findings demonstrated that captopril reduced the occurrence of epilepsy and cognitive impairment by attenuation of inflammation and C3-mediated synaptic phagocytosis. This approach can easily be adapted to long-term efficacy and safety in clinical practice.
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影响因子：
4
作者：
Benicky, Julius;Sanchez-Lemus, Enrique;Pavel, Jaroslav;Saavedra, Juan M.
通讯作者：
Saavedra, Juan M.
影响因子：
5.8
作者：
Boskabadi, Javad;Askari, Vahid Reza;Boskabady, Mohammad Hossein
通讯作者：
Boskabady, Mohammad Hossein
影响因子：
4.6
作者：
Bronisz E;Kurkowska-Jastrzębska I
通讯作者：
Kurkowska-Jastrzębska I
影响因子：
2.6
作者：
Ivanova, Natasha M.;Atanasova, Dimitrina;Tchekalarova, Jana D.
通讯作者：
Tchekalarova, Jana D.
影响因子：
82.9
作者：
Maroso, Mattia;Balosso, Silvia;Vezzani, Annamaria
通讯作者：
Vezzani, Annamaria