A Novel H2S Donor Suppresses Pilocarpine-Induced Seizures Through TREM2 Signaling.

Triggering receptor expressed on myeloid cells 2 (TREM2) located on microglial membranes and its downstream PI3K/PKB signaling pathway are involved in epilepsy. We have synthesized a novel carbazole-based H2S donor (HS-D2023) which was synthesized from N-Ethyl-3-carbazolecarboxaldehyde and has ideal safety with stable release of H2S. The H2S donor has been demonstrated to suppress seizures in pilocarpine-induced status epilepticus model in mice. However, its mechanism remains to be explored. The aim of the current study is to investigate whether the antiepileptic effects of the novel H2S donor involve TREM2 and PI3K/PKB signaling. We found that the H2S donor pretreatment prevented the down-regulation of TREM2 expression levels in the hippocampus in pilocarpine-induced epileptic mice. The effects of the H2S donor on latent period, duration and severity of seizures and EEG epileptic waves were significantly attenuated in TREM2-KO epileptic mice compared to WT epileptic mice, suggesting that the H2S donor exerted antiepileptic effects through TREM2-dependent signaling. The effects of the H2S donor on epileptic seizures and EEG epileptic waves were prevented by the PI3K inhibitor LY294002. The H2S donor could significantly rescue the attenuated expression levels of p-PI3K and p-PKB in WT, but not TREM2-KO epileptic mice. The H2S donor also failed to restore the balance between pro- and anti-inflammatory factors in TREM2-KO epileptic mice. These results suggested that the H2S donor could upregulate TREM2 expression and subsequent activate the PI3K/PKB signaling pathway to suppress seizures. The finding may provide a prospective target for the treatment of epilepsy.