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A Novel H2S Donor Alleviates Neuroinflammation and Seizures by Inhibiting the C3-C3aR Pathway
Yaru Yang1, Xutao Wang1, Tiantian Wang1
1Department of Physiology, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China.
Insights
A novel hydrogen sulfide (H₂S) donor reduces seizures by inhibiting astrocyte and microglia activation via the complement 3 (C3)-C3a receptor (C3aR) pathway, offering potential as an antiepileptic drug.
Area of Science:
- Neuroscience
- Neuroinflammation
- Pharmacology
Background:
- Astrocytes and microglia are activated in epilepsy, interacting via the C3-C3aR pathway, which exacerbates seizures.
- A novel hydrogen sulfide (H₂S) donor exhibits anti-seizure properties, but its underlying mechanism requires elucidation.
Purpose of the Study:
- To investigate the mechanism by which a novel H₂S donor exerts anti-seizure effects.
- To determine if the H₂S donor modulates astrocyte-microglia interaction through the C3-C3aR pathway.
Main Methods:
- Utilized LPS-treated astrocytes and pilocarpine-induced epileptic mice models.
- Assessed C3 production in astrocytes and inflammatory cytokine expression (IL-1β, IL-10) in microglia.
- Measured EEG amplitude of hippocampal epileptic waves and seizure severity.
- Investigated the effects of C3 administration and C3aR antagonist treatment.
Main Results:
- The H₂S donor inhibited astrocyte and microglia activation and their interaction via the C3-C3aR pathway.
- H₂S donor treatment reduced C3 production, neuroinflammation, and regulated inflammatory cytokines.
- The H₂S donor decreased seizure activity and hippocampal epileptic wave amplitude.
- Reversal of H₂S donor effects by C3 and mimicry by C3aR antagonist confirmed the pathway's involvement.
Conclusions:
- The novel H₂S donor alleviates seizures by suppressing C3-C3aR-mediated neuroinflammation and astrocyte-microglia crosstalk.
- This study reveals a novel mechanism for the anti-seizure effects of the H₂S donor.
- The H₂S donor demonstrates potential as a therapeutic candidate for epilepsy treatment.
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 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.
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