A Novel <scp> H ₂ S </scp> Donor Alleviates Neuroinflammation and Seizures by Inhibiting the <scp>C3</scp> ‐ <scp>C3aR</scp> Pathway

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 H₂S 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 H₂S 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 H₂S donor reduced C3 production in astrocytes and regulated the expression of inflammatory cytokines IL-1β and IL-10 in microglia. The H₂S donor also reduced the EEG amplitude of hippocampal epileptic waves and relieved seizures in epileptic mice. These effects of the H₂S 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 H₂S donor. Therefore, the H₂S donor has the potential to be used as a candidate for antiepileptic drugs.