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

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.