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

Exp Neurol. 2024 Feb:372:114615. doi: 10.1016/j.expneurol.2023.114615. Epub 2023 Nov 22.

Abstract

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.

Keywords: CD300a; Germinal matrix hemorrhage; Inflammation; Mast cell; PPAR(β/δ).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Newborn
  • Cerebral Hemorrhage
  • Chymases
  • Humans
  • Inflammation
  • Interleukin-17
  • Mast Cells / metabolism
  • PPAR delta* / genetics
  • PPAR delta* / metabolism
  • PPAR-beta* / genetics
  • PPAR-beta* / metabolism
  • RNA, Small Interfering
  • Rats
  • Rats, Sprague-Dawley
  • Thiazoles / pharmacology
  • Transforming Growth Factor beta1
  • Tryptases

Substances

  • PPAR delta
  • PPAR-beta
  • Chymases
  • Interleukin-17
  • Transforming Growth Factor beta1
  • Tryptases
  • Thiazoles
  • RNA, Small Interfering