GW0742 reduces mast cells degranulation and attenuates neurological impairments via PPARβ/δ/CD300a/SHP1 pathway after GMH in neonatal rats

by Selleckchem | Jan 13 2024

Background: Activation of mast cells plays an important role in brain inflammation. CD300a, an inhibitory receptor located on mast cell surfaces, has been reported to reduce the production of pro-inflammatory cytokines and exert protective effects in inflammation-related diseases. Peroxisome proliferator-activated receptor β/δ (PPARβ/δ), a ligand-activated nuclear receptor, activation upregulates the transcription of CD300a. In this study, we aim to investigate the role of PPARβ/δ in the attenuation of germinal matrix hemorrhage (GMH)-induced mast cell activation via CD300a/SHP1 pathway.

Methods: GMH model was induced by intraparenchymal injection of bacterial collagenase into the right hemispheric ganglionic eminence in P7 Sprague Dawley rats. GW0742, a PPARβ/δ agonist, was administered intranasally at 1 h post-ictus. CD300a small interfering RNA (siRNA) and PPARβ/δ siRNA were injected intracerebroventricularly 5 days and 2 days before GMH induction. Behavioral tests, Western blot, immunofluorescence, Toluidine Blue staining, and Nissl staining were applied to assess post-GMH evaluation.

Results: Results demonstrated that endogenous protein levels of PPARβ/δ and CD300a were decreased, whereas chymase, tryptase, IL-17A and transforming growth factor β1 (TGF-β1) were elevated after GMH. GMH induced significant short- and long-term neurobehavioral deficits in rat pups. GW0742 decreased mast cell degranulation, improved neurological outcomes, and attenuated ventriculomegaly after GMH. Additionally, GW0742 increased expression of PPARβ/δ, CD300a and phosphorylation of SHP1, decreased phosphorylation of Syk, chymase, tryptase, IL-17A and TGF-β1 levels. PPARβ/δ siRNA and CD300a siRNA abolished the beneficial effects of GW0742.

Conclusions: GW0742 inhibited mast cell-induced inflammation and improved neurobehavior after GMH, which is mediated by PPARβ/δ/CD300a/SHP1 pathway. GW0742 may serve as a potential treatment to reduce brain injury for GMH patients.

Comments:

This study seems to delve into the intricate relationship between PPARβ/δ activation, mast cell behavior post-GMH, and the subsequent impact on brain inflammation. The findings suggest that GW0742, a PPARβ/δ agonist, could potentially mitigate the effects of GMH by suppressing mast cell activation through the CD300a/SHP1 pathway.

The methods utilized—such as the GMH model induction in rats, intranasal administration of GW0742, and siRNA injections targeting PPARβ/δ and CD300a—seem comprehensive. Behavioral tests, Western blot analysis, immunofluorescence, and staining techniques have been employed to assess various aspects post-GMH.

The observed decrease in PPARβ/δ and CD300a alongside the elevation of mast cell-related factors and pro-inflammatory cytokines after GMH supports the premise of this study. Notably, the positive impact of GW0742 on reducing mast cell degranulation, improving neurological outcomes, and mitigating ventriculomegaly post-GMH is intriguing. Additionally, the molecular mechanisms involving the modulation of PPARβ/δ, CD300a, SHP1 phosphorylation, and the subsequent reduction in pro-inflammatory markers paint a promising picture for potential therapeutic interventions.

However, some aspects could benefit from further exploration or clarification. For instance, detailed insights into the specific mechanisms linking PPARβ/δ activation to CD300a upregulation and subsequent SHP1 phosphorylation would enhance the understanding of this pathway. Further studies validating these findings in different models or clinical settings could strengthen the translational potential of GW0742 as a treatment for GMH-related brain injuries.

Overall, this research underscores the intricate interplay between molecular pathways and the potential therapeutic implications for treating GMH-induced brain injuries.