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

Abstract

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. Graphical Abstract

Advances in Epilepsy: Mechanisms, Clinical Trials, and Drug Therapies

“…61 Recent studies have shown that albumin generated by BBB damage can penetrate the intercellular space in the brain, then activate TGF-β signaling pathway changes in astrocytes and destroy the potassium buffering capacity and glutamate metabolism, causing an increase in nerve excitability and lowers the seizure threshold. 62 Studies have suggested that a profound interaction between inflammation and epilepsy, 63 which indicates blocking unwanted inflammatory signals in the brain may provide new strategies for treating epilepsy.…”

Who Dunnit? Angiotensin, Inflammation, or Complement: Unresolved

“…The study by Dong et al interrogated the role of inflammation and immune complement signaling in the generation of epileptic networks in a mouse model of kainic acid (KA)-induced status epilepticus (SE) and acquired temporal lobe epilepsy. 3 …”

“…To address this question, Dong et al utilized captopril as a potential suppressor of C3 signaling, inflammation, and KA-induced epileptogenesis. 3 …”

“… 6 Angiotensin-converting enzymes were found to cleave the C3f fragment, 6 which in turn signals to increase synthesis of the C3 molecule. 3 Based on this observation, the authors hypothesized that captopril would reduce SE-induced increases in neuroinflammation and prevent the subsequent development of epilepsy via modulation of C3 signaling. The experimental design consisted of daily administration of captopril or saline (control) between 3 days and 7 weeks after SE to different groups of mice, and monitoring seizure activity with EEG recordings and measuring cognitive function through a battery of behavioral tests.…”

“…The study by Dong et al interrogated the role of inflammation and immune complement signaling in the generation of epileptic networks in a mouse model of kainic acid (KA)-induced status epilepticus (SE) and acquired temporal lobe epilepsy. 3 In the brain, the immune complement cascade facilitates the generation of different immune signaling molecules needed to "give instructions" for microglial cells, the resident immune cells of the brain, to perform specific functions such as brain patrolling, proliferation, phagocytosis, and/or inflammation. 4 Altered complement signaling is linked to the neuropathology of neurological disorders such as Alzheimer's disease, multiple sclerosis, and stroke, among others.…”