HDAC3 inhibitor (BRD3308) modulates microglial pyroptosis and neuroinflammation through PPARγ/NLRP3/GSDMD to improve neurological function after intraventricular hemorrhage in mice

Neuroinflammation plays a vital role in intraventricular hemorrhage (IVH). Excessive neuroinflammation after IVH can activate the inflammasome in the cell and accelerate the occurrence of pyroptosis in cells, produce more inflammatory mediators, increase cell death, and lead to neurological deficits. Previous studies have reported that BRD3308 (BRD), an inhibitor of histone deacetylation by histone deacetylase 3 (HDAC3), suppresses inflammation-induced apoptosis and exhibits anti-inflammatory properties. However, it is unclear how BRD reduces the occurrence of the inflammatory cascade. In this study, we stereotactically punctured the ventricles of male C57BL/6J mice and injected autologous blood via the tail vein to simulate ventricular hemorrhage. Magnetic resonance imaging was used to detect ventricular hemorrhage and enlargement. Our findings demonstrated that BRD treatment significantly improved neurobehavioral performance and decreased neuronal loss, microglial activation, and pyroptosis in the hippocampus after IVH. At the molecular level, this treatment upregulated the expression of peroxisome proliferator-activated receptor γ (PPARγ) and inhibited NLRP3-mediated pyroptosis and inflammatory cytokines. Therefore, we concluded that BRD reduced pyroptosis and neuroinflammation and improve nerve function in part by activating the PPARγ/NLRP3/GSDMD signaling pathway. Our findings suggest a potential preventive role for BRD in IVH. Schematic diagram of the potential molecular mechanism of the neuroinflammatory effect of BRD3308 via the PPARγ/NLRP3/GSDMD pathway after IVH. [Display omitted] •Neuroinflammation and microglia pyroptosis in the periventricular hippocampus contribute to IVH-related neurological impairments.•The results confirm that BRD3308 has the potential to alleviate acute inflammation and pyroptosis in IVH by modulating the PPARγ/NLRP3/GSDMD pathway, enhancing neurofunctional outcomes.