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

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 (PPAR _β/δ ), a ligand-activated nuclear receptor, activation upregulates the transcription of CD300a. In this study, we aim to investigate the role of PPAR _β/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 PPAR _β/δ agonist, was administered intranasally at 1 h post-ictus. CD300a small interfering RNA (siRNA) and PPAR _β/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 PPAR _β/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 PPAR _β/δ , CD300a and phosphorylation of SHP1, decreased phosphorylation of Syk, chymase, tryptase, IL-17A and TGF-β1 levels. PPAR _β/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 PPAR _β/δ /CD300a/SHP1 pathway. GW0742 may serve as a potential treatment to reduce brain injury for GMH patients.
Competing Interests: Declaration of Competing Interest None of the authors have any conflicts of interests related to this work.
(Copyright © 2023 Elsevier Inc. All rights reserved.)