Glibenclamide alleviates hydrocephalus after intraventricular hemorrhage by targeting metabolic reprogramming of border-associated macrophages.

BACKGROUND

Post-hemorrhagic hydrocephalus (PHH) following intraventricular hemorrhage (IVH) is a devastating complication associated with poor prognosis, primarily characterized by cerebrospinal fluid (CSF) absorption impairment due to meningeal fibrosis. Currently, effective pharmacological interventions targeting this fibrotic process are lacking.

METHODS

In this study, utilizing a mouse model of IVH and a combination of immunofluorescence, flow cytometry, transcriptomic sequencing, and metabolic assays, we investigated the crosstalk between border-associated macrophages (BAMs) and meningeal fibroblasts during fibrosis.

RESULTS

Our results demonstrated that IVH induces extensive activation of meningeal fibroblasts and pathological deposition of extracellular matrix (ECM). Specific depletion of BAMs significantly attenuated meningeal fibrosis, identifying them as critical drivers of this pathology. Mechanistically, IVH triggered distinct metabolic reprogramming in CD206+ BAMs, characterized by enhanced glycolysis and accumulation of mitochondrial reactive oxygen species (ROS). This metabolic stress drove BAMs to secrete profibrotic TGF-beta1, which subsequently activated downstream fibroblasts via paracrine signaling. Notably, we found that glibenclamide effectively targeted and inhibited the metabolic abnormalities and ROS production in BAMs, blocking TGF-beta1 release and consequently suppressing fibroblast activation, thereby ameliorating hydrocephalus.

CONCLUSIONS

Collectively, our findings uncover the "BAM metabolic reprogramming-fibroblast activation" axis as a key pathophysiological driver of meningeal fibrosis and establish a novel mechanism for glibenclamide in preventing PHH through immunometabolic modulation, offering a promising therapeutic target for clinical intervention.