A novel hydrogen sulfide donor reduces neuroinflammation and seizures by activating ATP-sensitive potassium channels.

Epilepsy is a common neurological disorder worldwide. Hydrogen sulfide (H2S) has been found to have anti-seizure effects. However, its mechanism remains to be explored. In the present study, we showed that a novel H2S donor attenuated neuroinflammation by up-regulating ATP-sensitive potassium channel (KATP) expression to reduce seizures. The novel H2S donor significantly reduced the expression of TNF-α and increased the expression of IL-10 in LPS-treated BV2 cells and the hippocampus of pilocarpine-induced epileptic mice. The modulatory effects of the H2S donor on inflammatory cytokines were prevented by glibenclamide, a common KATP channels blocker. The H2S donor promoted the expression of KATP channel subunits SUR2 and Kir6.1 in LPS-treated BV2 cells and the hippocampus of pilocarpine-induced epileptic mice. In addition, the H2S donor reduced the electroencephalography amplitude of hippocampal epileptic waves and reduced seizures in pilocarpine-induced epileptic mice, which were also attenuated by glibenclamide. These results indicated that the novel H2S donor reduced seizures and regulated microglial inflammatory cytokines by activating KATP channels, which may provide a prospective therapeutic strategy for the anti-seizure effects of H2S donor.

A Novel Hydrogen Sulfide Donor Reduces Pilocarpine-Induced Status Epilepticus and Regulates Microglial Inflammatory Profile.

Although epilepsy is one of the most common neurologic disorders, there is still a lack of effective therapeutic drugs for it. Recently, we synthesized a novel hydrogen sulfide (H2S) donor, which is found to reduce seizures in animal models effectively. But it remains to be determined for its mechanism. In the present study, we found that the novel H2S donor could reduce pilocarpine-induced seizures in mice. It alleviated the epileptic behavior, the hippocampal electroencephalography (EEG) activity of seizures, and the damage of hippocampal neurons in status epilepticus mice. In addition, the novel H2S donor could reduce microglial inflammatory response. It not only reduced the upregulation of pro-inflammatory markers [inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2)] in status epilepticus mice, but also increased the levels of microglial anti-inflammatory marker arginase-1 (Arg-1). In lipopolysaccharide-treated microglia BV2 cells, administration of the H2S donor also significantly reduced the lipopolysaccharide-induced upregulation of the expression of the pro-inflammatory markers and increased the expression of the anti-inflammatory markers. Thus, the novel H2S donor regulates microglial inflammatory profile in status epilepticus mice and in vitro. These results suggested that the novel H2S donor can reduce seizures and regulate microglial inflammatory profile, which may be a novel mechanism and potential therapeutic strategy of the H2S donor anti-seizures.

A hydrogen sulfide donor suppresses pentylenetetrazol-induced seizures in rats via PKC signaling.

Epilepsy is a serious neurological disorder. Available antiepileptic drugs are still lacking. Hydrogen sulfide (H2S), a neuron-protective endogenous gasotransmitter, is reported to have effect on epilepsy. But it remains to be determined for its mechanism. In the present study, we found that a novel carbazole-based H2S donor could effectively suppress pentylenetetrazol-induced seizures in rats. The H2S donor could alleviate not only the epileptic behavior of animals but also the hippocampal EEG activity of seizures. The H2S donor down-regulated the expression of aquaporin 4 in the hippocampus of epilepsy rats. The H2S donor also decreased the seizure-induced release of inflammatory cytokines including IL-1ß, IL-6 and TNF-α. In addition, the H2S donor increased protein kinase C (PKC) expression in the hippocampus of epilepsy rats. These effects of the H2S donor on epilepsy rats were attenuated after blockade of PKC signaling by Go6983, suggesting that PKC signaling participated in the antiepileptic process of H2S donor. Taken together, the H2S donor has a beneficial effect on epilepsy control in a PKC-dependent manner.