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.

 

Comments:

The study you described investigates the potential therapeutic effects of BRD3308 (BRD), an inhibitor of histone deacetylase 3 (HDAC3), in the context of intraventricular hemorrhage (IVH) in a mouse model. IVH is associated with excessive neuroinflammation, which can lead to various detrimental outcomes, including pyroptosis (a type of programmed cell death) and neuronal loss, ultimately resulting in neurological deficits.

In this study, the researchers used a mouse model to simulate IVH and administered BRD treatment. The results demonstrated several significant findings:

1. **Improved Neurobehavioral Performance:** Mice treated with BRD showed enhanced neurobehavioral performance, indicating a positive effect on their neurological function.

2. **Reduced Neuronal Loss:** BRD treatment decreased neuronal loss in the hippocampus, suggesting a potential neuroprotective effect.

3. **Suppressed Microglial Activation:** Microglia are immune cells in the central nervous system, and their activation can contribute to neuroinflammation. BRD treatment led to a reduction in microglial activation, indicating a decrease in neuroinflammation.

4. **Inhibition of Pyroptosis:** Pyroptosis is a form of cell death associated with inflammation. BRD treatment inhibited pyroptosis in the hippocampus, indicating a potential mechanism for its neuroprotective effects.

5. **Modulation of Molecular Pathways:** At the molecular level, BRD treatment upregulated the expression of peroxisome proliferator-activated receptor γ (PPARγ) and inhibited NLRP3-mediated pyroptosis and inflammatory cytokines. PPARγ is a nuclear receptor that plays a role in regulating inflammation and metabolism. NLRP3 is a component of the inflammasome, a multiprotein complex involved in the activation of inflammatory responses.

6. **Activation of PPARγ/NLRP3/GSDMD Signaling Pathway:** BRD was found to reduce pyroptosis and neuroinflammation, at least in part, by activating the PPARγ/NLRP3/GSDMD signaling pathway. This pathway likely plays a crucial role in mediating the observed effects of BRD in reducing neuroinflammation and pyroptosis.

In summary, the study suggests that BRD treatment has therapeutic potential in mitigating the detrimental effects of IVH. By targeting the PPARγ/NLRP3/GSDMD signaling pathway, BRD reduces neuroinflammation, inhibits pyroptosis, and improves neurobehavioral outcomes. These findings provide valuable insights into the molecular mechanisms underlying the neuroprotective effects of BRD in the context of IVH and highlight its potential as a preventive or therapeutic intervention for this condition.

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