Captopril alleviates epilepsy and cognitive impairment by attenuation of C3-mediated inflammation and synaptic phagocytosis

• Published in: Journal of neuroinflammation 2022-09, Vol.19 (1), p.226-22, Article 226
• Main Authors: Dong, Xinyan, Fan, Jianchen, Lin, Donghui, Wang, Xuehui, Kuang, Haoyu, Gong, Lifen, Chen, Chen, Jiang, Jie, Xia, Ningxiao, He, Dahong, Shen, Weida, Jiang, Peifang, Kuang, Rong, Zeng, Linghui, Xie, Yicheng
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Analysis; Angiotensin; Angiotensin-converting enzyme inhibitors; Animal cognition; Animals; Astrocytes; Brain injury; Brain research; Captopril; Captopril - pharmacology; Captopril - therapeutic use; Care and treatment; Cognition disorders; Cognitive ability; Cognitive deficits; Cognitive Dysfunction - drug therapy; Cognitive Dysfunction - etiology; Complement 3; Complement activation; Complement component C3; Complement component C3a; Complement receptors; Complications and side effects; Convulsions & seizures; Cytokines; Dosage and administration; EEG; Enzyme inhibitors; Enzymes; Epilepsy; Epilepsy - chemically induced; Epilepsy - drug therapy; Glial activation; Health aspects; Inflammation; Inflammation - drug therapy; Kainic acid; Kainic Acid - toxicity; Laboratory animals; Methods; Microglia; Neurodegeneration; Neurological diseases; Neurophysiology; Peptidyl-dipeptidase A; Phagocytosis; Prevention; Proteins; Rats; Rats, Sprague-Dawley; Risk factors; RNA sequencing; Synaptic phagocytosis; Tumor necrosis factor-TNF
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-022-02587-8

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.