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

作者全名："Lu, Weitian; Huang, Juan; Flores, Jerry; Li, Peng; Wang, Wenna; Liu, Shengpeng; Zhang, John H.; Tang, Jiping"

作者地址："[Lu, Weitian; Huang, Juan] Chongqing Med Univ, Inst Neurosci, Basic Med Coll, Chongqing 400016, Peoples R China; [Flores, Jerry; Li, Peng; Wang, Wenna; Liu, Shengpeng; Tang, Jiping] Loma Linda Univ, Dept Physiol & Pharmacol, Sch Med, Loma Linda, CA 92350 USA; [Zhang, John H.] Loma Linda Univ, Dept Neurosurg, Sch Med, Loma Linda, CA 92350 USA; [Zhang, John H.] Loma Linda Univ, Dept Anesthesiol, Sch Med, Loma Linda, CA 92350 USA; [Tang, Jiping] Risley Hall,11041 Campus St, Loma Linda, CA 92350 USA"

通信作者："Tang, JP (通讯作者)，Risley Hall,11041 Campus St, Loma Linda, CA 92350 USA."

来源：EXPERIMENTAL NEUROLOGY

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:001129800100001

JCR分区：Q1

影响因子：5.3

年份：2024

卷号：372

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Germinal matrix hemorrhage; Mast cell; CD300a; PPAR beta/delta; Inflammation

摘要："<bold>Background: </bold>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 beta/delta (PPAR(beta/delta)), a ligand-activated nuclear receptor, activation upregulates the transcription of CD300a. In this study, we aim to investigate the role of PPAR(beta/delta) in the attenuation of germinal matrix hemorrhage (GMH)-induced mast cell activation via CD300a/SHP1 pathway.<bold>Methods: </bold>GMH model was induced by intraparenchymal injection of bacterial collagenase into the right hemispheric ganglionic eminence in P7 Sprague Dawley rats. GW0742, a PPAR(beta/delta) agonist, was administered intranasally at 1 h post-ictus. CD300a small interfering RNA (siRNA) and PPAR(beta/delta) 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.<bold>Results: </bold>Results demonstrated that endogenous protein levels of PPAR(beta/delta) and CD300a were decreased, whereas chymase, tryptase, IL-17A and transforming growth factor beta 1 (TGF-beta 1) 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(beta/delta), CD300a and phosphorylation of SHP1, decreased phosphorylation of Syk, chymase, tryptase, IL-17A and TGF-beta 1 levels. PPAR(beta/delta) siRNA and CD300a siRNA abolished the beneficial effects of GW0742.<bold>Conclusions: </bold>GW0742 inhibited mast cell-induced inflammation and improved neurobehavior after GMH, which is mediated by PPAR(beta/delta)/CD300a/SHP1 pathway. GW0742 may serve as a potential treatment to reduce brain injury for GMH patients."

基金机构："Foundation for the National In-stitutes of Health [NS101284, NS103822]"

基金资助正文：This study was supported by the Foundation for the National In-stitutes of Health to Jiping Tang (NS101284) and to John H. Zhang (NS103822) .