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.

Epilepsy; Hydrogen sulfide (H2S); Microglial polarization; Neuroinflammation; Triggering receptor expressed on myeloid cells 2 (TREM2).