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Background <p>Status epilepticus (SE) is a life-threatening neurological emergency with high mortality, often leading to acute cerebral edema and chronic cognitive impairment. Its pathology involves both immune and vascular dysfunction. The complement C3/C3a receptor (C3/C3aR) signaling pathway has recently emerged as a key regulator of immune activation and blood-brain barrier (BBB) permeability. This study investigates whether bindarit, a potent anti-inflammatory drug, mitigates SE-induced brain injury through modulation of the C3/C3aR pathway.</p> Methods <p>SE modeling mice were randomized to receive daily bindarit or vehicle. To explore underlying mechanisms, C3aR antagonist (C3aRA) and recombinant C3a were used in additional groups. Post-SE brain injuries were assessed, including survival, memory performance, histopathology, brain edema, BBB integrity, neurovascular inflammation, microglia-astrocyte interactions, and microglial synaptic engulfment.</p> Results <p>We found that bindarit treatment improved survival and memory, reduced histological damage, alleviated brain edema, preserved BBB integrity, and attenuated endothelial inflammation in SE mice. It promoted a shift in microglia from a pro-inflammatory to an anti-inflammatory-associated features, reversed pathological microglia-astrocyte crosstalk, limited synaptic elimination, and restored microglial morphology. Mechanistically, bindarit inhibited neurotoxic astrocyte-derived C3 production and reduced C3aR expression in both microglia and endothelial cells. C3aRA produced comparable protective effects, whereas co-administration of C3a partially negated bindarit’s benefits.</p> Conclusions <p>Bindarit confers robust neuroprotection in SE by preserving BBB integrity, attenuating neurovascular inflammation, reducing synaptic loss, and improving cognitive outcomes. These effects are mediated predominantly through inhibition of the C3/C3aR pathway, highlighting bindarit as a promising therapeutic candidate for SE.</p>

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Bindarit attenuates brain injury and neuroinflammation in status epilepticus by disrupting C3/C3aR signaling and modulating microglia-astrocyte interactions

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月13日

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  • Jiancong Chen,
  • Yanhong Hu,
  • Jiaxin Xie,
  • Haiping Zhou,
  • Tingting Yang,
  • Mingjia Yu,
  • Jingwen Wu,
  • Suyue Pan,
  • Kaibin Huang

摘要

Background

Status epilepticus (SE) is a life-threatening neurological emergency with high mortality, often leading to acute cerebral edema and chronic cognitive impairment. Its pathology involves both immune and vascular dysfunction. The complement C3/C3a receptor (C3/C3aR) signaling pathway has recently emerged as a key regulator of immune activation and blood-brain barrier (BBB) permeability. This study investigates whether bindarit, a potent anti-inflammatory drug, mitigates SE-induced brain injury through modulation of the C3/C3aR pathway.

Methods

SE modeling mice were randomized to receive daily bindarit or vehicle. To explore underlying mechanisms, C3aR antagonist (C3aRA) and recombinant C3a were used in additional groups. Post-SE brain injuries were assessed, including survival, memory performance, histopathology, brain edema, BBB integrity, neurovascular inflammation, microglia-astrocyte interactions, and microglial synaptic engulfment.

Results

We found that bindarit treatment improved survival and memory, reduced histological damage, alleviated brain edema, preserved BBB integrity, and attenuated endothelial inflammation in SE mice. It promoted a shift in microglia from a pro-inflammatory to an anti-inflammatory-associated features, reversed pathological microglia-astrocyte crosstalk, limited synaptic elimination, and restored microglial morphology. Mechanistically, bindarit inhibited neurotoxic astrocyte-derived C3 production and reduced C3aR expression in both microglia and endothelial cells. C3aRA produced comparable protective effects, whereas co-administration of C3a partially negated bindarit’s benefits.

Conclusions

Bindarit confers robust neuroprotection in SE by preserving BBB integrity, attenuating neurovascular inflammation, reducing synaptic loss, and improving cognitive outcomes. These effects are mediated predominantly through inhibition of the C3/C3aR pathway, highlighting bindarit as a promising therapeutic candidate for SE.