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GW0742 reduces mast cells degranulation and attenuates neurological impairments via PPAR β/δ /CD300a/SHP1 pathway after GMH in neonatal rats.
- Source :
-
Experimental neurology [Exp Neurol] 2024 Feb; Vol. 372, pp. 114615. Date of Electronic Publication: 2023 Nov 22. - Publication Year :
- 2024
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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 (PPAR <subscript>β/δ</subscript> ), a ligand-activated nuclear receptor, activation upregulates the transcription of CD300a. In this study, we aim to investigate the role of PPAR <subscript>β/δ</subscript> in the attenuation of germinal matrix hemorrhage (GMH)-induced mast cell activation via CD300a/SHP1 pathway.<br />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 <subscript>β/δ</subscript> agonist, was administered intranasally at 1 h post-ictus. CD300a small interfering RNA (siRNA) and PPAR <subscript>β/δ</subscript> 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.<br />Results: Results demonstrated that endogenous protein levels of PPAR <subscript>β/δ</subscript> 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 <subscript>β/δ</subscript> , CD300a and phosphorylation of SHP1, decreased phosphorylation of Syk, chymase, tryptase, IL-17A and TGF-β1 levels. PPAR <subscript>β/δ</subscript> siRNA and CD300a siRNA abolished the beneficial effects of GW0742.<br />Conclusions: GW0742 inhibited mast cell-induced inflammation and improved neurobehavior after GMH, which is mediated by PPAR <subscript>β/δ</subscript> /CD300a/SHP1 pathway. GW0742 may serve as a potential treatment to reduce brain injury for GMH patients.<br />Competing Interests: Declaration of Competing Interest None of the authors have any conflicts of interests related to this work.<br /> (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Subjects :
- Humans
Rats
Animals
Animals, Newborn
Mast Cells metabolism
Chymases
Interleukin-17
Rats, Sprague-Dawley
Transforming Growth Factor beta1
Tryptases
Cerebral Hemorrhage
Thiazoles pharmacology
Inflammation
RNA, Small Interfering
PPAR delta genetics
PPAR delta metabolism
PPAR-beta genetics
PPAR-beta metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2430
- Volume :
- 372
- Database :
- MEDLINE
- Journal :
- Experimental neurology
- Publication Type :
- Academic Journal
- Accession number :
- 37995951
- Full Text :
- https://doi.org/10.1016/j.expneurol.2023.114615