A Novel H2S Donor Alleviates Neuroinflammation and Seizures by Inhibiting the C3‐C3aR Pathway

ABSTRACT Both astrocytes and microglia are activated in the epileptic brain. There is an interaction between them through the complement 3 (C3)‐C3a receptor (C3aR) pathway, which plays a detrimental role in seizures. Our self‐developed novel H 2 S donor has been found to have anti‐seizure effects. However, its mechanism remains to be explored. In the present study, we showed that the novel H 2 S donor can inhibit the activation of astrocytes and microglia and their interaction through C3‐C3aR signaling, which contributed to alleviating microglial neuroinflammation and seizures. In LPS‐treated astrocytes and pilocarpine‐induced epileptic mice, the H 2 S donor reduced C3 production in astrocytes and regulated the expression of inflammatory cytokines IL‐1β and IL‐10 in microglia. The H 2 S donor also reduced the EEG amplitude of hippocampal epileptic waves and relieved seizures in epileptic mice. These effects of the H 2 S donor can be reversed by intranasal C3 treatment and mimicked by a C3aR antagonist. These findings provide a novel mechanism underlying the anti‐seizure effects of the H 2 S donor. Therefore, the H 2 S donor has the potential to be used as a candidate for antiepileptic drugs.