The Experts below are selected from a list of 303 Experts worldwide ranked by ideXlab platform

John H. Zhang - One of the best experts on this subject based on the ideXlab platform.

  • rh relaxin 2 attenuates degranulation of mast cells by inhibiting nf κb through pi3k akt tnfaip3 pathway in an experimental Germinal Matrix Hemorrhage rat model
    Journal of Neuroinflammation, 2020
    Co-Authors: Yan Ding, Jerry Flores, Tongyu Zhang, Shengpeng Liu, Tianyi Wang, Gang Zhao, Fanfan Chen, Umut Ocak, John H. Zhang
    Abstract:

    Mast cells play an important role in early immune reactions in the brain by degranulation and the consequent inflammatory response. Our aim of the study is to investigate the effects of rh-relaxin-2 on mast cells and the underlying mechanisms in a Germinal Matrix Hemorrhage (GMH) rat model. One hundred seventy-three P7 rat pups were subjected to GMH by an intraparenchymal injection of bacterial collagenase. Clodronate liposome was administered through intracerebroventricular (i.c.v.) injections 24 h prior to GMH to inhibit microglia. Rh-relaxin-2 was administered intraperitoneally at 1 h and 13 h after GMH. Small interfering RNA of RXFP1 and PI3K inhibitor LY294002 were given by i.c.v. injection. Post-GMH evaluation included neurobehavioral function, Western blot analysis, immunofluorescence, Nissl staining, and toluidine blue staining. Our results demonstrated that endogenous relaxin-2 was downregulated and that RXFP1 level peaked on the first day after GMH. Administration of rh-relaxin-2 improved neurological functions, attenuated degranulation of mast cells and neuroinflammation, and ameliorated post-hemorrhagic hydrocephalus (PHH) after GMH. These effects were associated with RXFP1 activation, increased expression of PI3K, phosphorylated AKT and TNFAIP3, and decreased levels of phosphorylated NF-κB, tryptase, chymase, IL-6, and TNF-α. However, knockdown of RXFP1 and PI3K inhibition abolished the protective effects of rh-relaxin-2. Our findings showed that rh-relaxin-2 attenuated degranulation of mast cells and neuroinflammation, improved neurological outcomes, and ameliorated hydrocephalus after GMH through RXFP1/PI3K-AKT/TNFAIP3/NF-κB signaling pathway.

  • NT-4 attenuates neuroinflammation via TrkB/PI3K/FoxO1 pathway after Germinal Matrix Hemorrhage in neonatal rats
    Journal of neuroinflammation, 2020
    Co-Authors: Tianyi Wang, Yan Ding, Jiping Tang, Junyi Zhang, Gang Chen, John H. Zhang
    Abstract:

    Neuroinflammation plays an important role in pathogenesis of Germinal Matrix Hemorrhage (GMH). Neurotrophin-4 (NT-4) is a member of the neurotrophin family and interacts with the tropomyosin receptor kinase B (TrkB). NT-4 has been shown to confer neuroprotective effects following cerebral ischemia. We aimed to investigate the neuroprotective function of NT-4-TrkB signaling, as well as its downstream signaling cascade phosphatidylinositol-3-kinases (PI3K)/protein kinase B (Akt)/forkhead box protein O1 (FoxO1), following GMH in neonatal rats. GMH was induced by intraparenchymal injection of bacterial collagenase (0.3 U) in P7 rat pups. A total of 163 pups were used in this study. Recombinant human NT-4 was administered intranasally at 1 h after the collagenase injection. The selective TrkB antagonist ANA-12, selective PI3K inhibitor LY294002, and FoxO1 activating CRISPR were administered intracerebroventricularly at 24 h prior to NT-4 treatment to investigate the underlying mechanism. Short-term and long-term neurobehavioral assessments, immunofluorescence staining, Nissl’s staining, and Western blot were performed. Expression of phosphorylated TrkB increased after GMH, reaching the peak level at day 3 after Hemorrhage. TrkB receptors were observed on neurons, microglia, and astrocytes. The administration of rh-NT-4 induced phosphorylation of TrkB, expression of PI3K, and phosphorylation of Akt. Meanwhile, it decreased FoxO1 and IL-6 levels. Selective inhibition of TrkB/PI3K/Akt signaling in microglia increased the expression levels of FoxO1 and pro-inflammatory cytokines. FoxO1 activating CRISPR increased the expression of IL-6, suggesting that FoxO1 might be a potential inducer of pro-inflammatory factors. These results suggested that PI3K/Akt/FoxO1 signaling may be the downstream pathway of activation of TrkB. The rat pups treated with rh-NT-4 performed better than vehicle-treated animals in both short-term and long-term behavioral tests. These data showed that rh-NT-4 reduced the expression levels of pro-inflammatory cytokines, improved neurological function, attenuated neuroinflammation, and thereby mitigated post-hemorrhagic hydrocephalus after GMH by TrkB/PI3K/Akt/FoxO1 pathway. These results indicated that rh-NT-4 could be a promising therapeutic strategy to ameliorate neuroinflammation and hydrocephalus after GMH or other similar brain injuries.

  • nt 4 attenuates neuroinflammation via trkb pi3k foxo1 pathway after Germinal Matrix Hemorrhage in neonatal rats
    Journal of Neuroinflammation, 2020
    Co-Authors: Yan Ding, Jiping Tang, Tianyi Wang, Junyi Zhang, Gang Chen, John H. Zhang
    Abstract:

    Neuroinflammation plays an important role in pathogenesis of Germinal Matrix Hemorrhage (GMH). Neurotrophin-4 (NT-4) is a member of the neurotrophin family and interacts with the tropomyosin receptor kinase B (TrkB). NT-4 has been shown to confer neuroprotective effects following cerebral ischemia. We aimed to investigate the neuroprotective function of NT-4-TrkB signaling, as well as its downstream signaling cascade phosphatidylinositol-3-kinases (PI3K)/protein kinase B (Akt)/forkhead box protein O1 (FoxO1), following GMH in neonatal rats. GMH was induced by intraparenchymal injection of bacterial collagenase (0.3 U) in P7 rat pups. A total of 163 pups were used in this study. Recombinant human NT-4 was administered intranasally at 1 h after the collagenase injection. The selective TrkB antagonist ANA-12, selective PI3K inhibitor LY294002, and FoxO1 activating CRISPR were administered intracerebroventricularly at 24 h prior to NT-4 treatment to investigate the underlying mechanism. Short-term and long-term neurobehavioral assessments, immunofluorescence staining, Nissl’s staining, and Western blot were performed. Expression of phosphorylated TrkB increased after GMH, reaching the peak level at day 3 after Hemorrhage. TrkB receptors were observed on neurons, microglia, and astrocytes. The administration of rh-NT-4 induced phosphorylation of TrkB, expression of PI3K, and phosphorylation of Akt. Meanwhile, it decreased FoxO1 and IL-6 levels. Selective inhibition of TrkB/PI3K/Akt signaling in microglia increased the expression levels of FoxO1 and pro-inflammatory cytokines. FoxO1 activating CRISPR increased the expression of IL-6, suggesting that FoxO1 might be a potential inducer of pro-inflammatory factors. These results suggested that PI3K/Akt/FoxO1 signaling may be the downstream pathway of activation of TrkB. The rat pups treated with rh-NT-4 performed better than vehicle-treated animals in both short-term and long-term behavioral tests. These data showed that rh-NT-4 reduced the expression levels of pro-inflammatory cytokines, improved neurological function, attenuated neuroinflammation, and thereby mitigated post-hemorrhagic hydrocephalus after GMH by TrkB/PI3K/Akt/FoxO1 pathway. These results indicated that rh-NT-4 could be a promising therapeutic strategy to ameliorate neuroinflammation and hydrocephalus after GMH or other similar brain injuries.

  • a comprehensive review of therapeutic targets that induce microglia macrophage mediated hematoma resolution after Germinal Matrix Hemorrhage
    Journal of Neuroscience Research, 2020
    Co-Authors: Jerry Flores, Damon Klebe, Jiping Tang, John H. Zhang
    Abstract:

    Currently, there is no effective treatment for Germinal Matrix Hemorrhage and intraventricular Hemorrhage (GMH-IVH), a common and often fatal stroke subtype in premature infants. Secondary brain injury after GMH-IVH is known to involve blood clots that contribute to inflammation and neurological deficits. Furthermore, the subsequent blood clots disrupt normal cerebrospinal fluid circulation and absorption after GMH-IVH, contributing to posthemorrhagic hydrocephalus (PHH). Clinically, GMH-IVH severity is graded on a I to IV scale: Grade I is confined to the Germinal Matrix, grade II includes intraventricular Hemorrhage, grade III includes intraventricular Hemorrhage with extension into dilated ventricles, and grade IV includes intraventricular Hemorrhage with extension into dilated ventricles as well as parenchymal hemorrhaging. GMH-IVH hematoma volume is the best prognostic indicator, where patients with higher grades have worsened outcomes. Various preclinical studies have shown that rapid hematoma resolution quickly ameliorates inflammation and improves neurological outcomes. Current experimental evidence identifies alternatively activated microglia as playing a pivotal role in hematoma clearance. In this review, we discuss the pathophysiology of GMH-IVH in the development of PHH, microglia/macrophage's role in the neonatal CNS, and established/potential therapeutic targets that enhance M2 microglia/macrophage phagocytosis of blood clots after GMH-IVH.

  • posthemorrhagic hydrocephalus development after Germinal Matrix Hemorrhage established mechanisms and proposed pathways
    Journal of Neuroscience Research, 2020
    Co-Authors: Damon Klebe, Jerry Flores, Jiping Tang, Devin W. Mcbride, Paul R. Krafft, John H. Zhang
    Abstract:

    In addition to being the leading cause of morbidity and mortality in premature infants, Germinal Matrix Hemorrhage (GMH) is also the leading cause of acquired infantile hydrocephalus. The pathophysiology of posthemorrhagic hydrocephalus (PHH) development after GMH is complex and vaguely understood, although evidence suggests fibrosis and gliosis in the periventricular and subarachnoid spaces disrupts normal cerebrospinal fluid (CSF) dynamics. Theories explaining general hydrocephalus etiology have substantially evolved from the original bulk flow theory developed by Dr. Dandy over a century ago. Current clinical and experimental evidence supports a new hydrodynamic theory for hydrocephalus development involving redistribution of vascular pulsations and disruption of Starling forces in the brain microcirculation. In this review, we discuss CSF flow dynamics, history and development of theoretical hydrocephalus pathophysiology, and GMH epidemiology and etiology as it relates to PHH development. We highlight known mechanisms and propose new avenues that will further elucidate GMH pathophysiology, specifically related to hydrocephalus.

Yan Ding - One of the best experts on this subject based on the ideXlab platform.

  • rh relaxin 2 attenuates degranulation of mast cells by inhibiting nf κb through pi3k akt tnfaip3 pathway in an experimental Germinal Matrix Hemorrhage rat model
    Journal of Neuroinflammation, 2020
    Co-Authors: Yan Ding, Jerry Flores, Tongyu Zhang, Shengpeng Liu, Tianyi Wang, Gang Zhao, Fanfan Chen, Umut Ocak, John H. Zhang
    Abstract:

    Mast cells play an important role in early immune reactions in the brain by degranulation and the consequent inflammatory response. Our aim of the study is to investigate the effects of rh-relaxin-2 on mast cells and the underlying mechanisms in a Germinal Matrix Hemorrhage (GMH) rat model. One hundred seventy-three P7 rat pups were subjected to GMH by an intraparenchymal injection of bacterial collagenase. Clodronate liposome was administered through intracerebroventricular (i.c.v.) injections 24 h prior to GMH to inhibit microglia. Rh-relaxin-2 was administered intraperitoneally at 1 h and 13 h after GMH. Small interfering RNA of RXFP1 and PI3K inhibitor LY294002 were given by i.c.v. injection. Post-GMH evaluation included neurobehavioral function, Western blot analysis, immunofluorescence, Nissl staining, and toluidine blue staining. Our results demonstrated that endogenous relaxin-2 was downregulated and that RXFP1 level peaked on the first day after GMH. Administration of rh-relaxin-2 improved neurological functions, attenuated degranulation of mast cells and neuroinflammation, and ameliorated post-hemorrhagic hydrocephalus (PHH) after GMH. These effects were associated with RXFP1 activation, increased expression of PI3K, phosphorylated AKT and TNFAIP3, and decreased levels of phosphorylated NF-κB, tryptase, chymase, IL-6, and TNF-α. However, knockdown of RXFP1 and PI3K inhibition abolished the protective effects of rh-relaxin-2. Our findings showed that rh-relaxin-2 attenuated degranulation of mast cells and neuroinflammation, improved neurological outcomes, and ameliorated hydrocephalus after GMH through RXFP1/PI3K-AKT/TNFAIP3/NF-κB signaling pathway.

  • Rh-relaxin-2 attenuates degranulation of mast cells by inhibiting NF-κB through PI3K-AKT/TNFAIP3 pathway in an experimental Germinal Matrix Hemorrhage rat model.
    Journal of neuroinflammation, 2020
    Co-Authors: Gang Zhao, Yan Ding, Jerry Flores, Shengpeng Liu, Tianyi Wang, Fanfan Chen, Umut Ocak
    Abstract:

    Mast cells play an important role in early immune reactions in the brain by degranulation and the consequent inflammatory response. Our aim of the study is to investigate the effects of rh-relaxin-2 on mast cells and the underlying mechanisms in a Germinal Matrix Hemorrhage (GMH) rat model. One hundred seventy-three P7 rat pups were subjected to GMH by an intraparenchymal injection of bacterial collagenase. Clodronate liposome was administered through intracerebroventricular (i.c.v.) injections 24 h prior to GMH to inhibit microglia. Rh-relaxin-2 was administered intraperitoneally at 1 h and 13 h after GMH. Small interfering RNA of RXFP1 and PI3K inhibitor LY294002 were given by i.c.v. injection. Post-GMH evaluation included neurobehavioral function, Western blot analysis, immunofluorescence, Nissl staining, and toluidine blue staining. Our results demonstrated that endogenous relaxin-2 was downregulated and that RXFP1 level peaked on the first day after GMH. Administration of rh-relaxin-2 improved neurological functions, attenuated degranulation of mast cells and neuroinflammation, and ameliorated post-hemorrhagic hydrocephalus (PHH) after GMH. These effects were associated with RXFP1 activation, increased expression of PI3K, phosphorylated AKT and TNFAIP3, and decreased levels of phosphorylated NF-κB, tryptase, chymase, IL-6, and TNF-α. However, knockdown of RXFP1 and PI3K inhibition abolished the protective effects of rh-relaxin-2. Our findings showed that rh-relaxin-2 attenuated degranulation of mast cells and neuroinflammation, improved neurological outcomes, and ameliorated hydrocephalus after GMH through RXFP1/PI3K-AKT/TNFAIP3/NF-κB signaling pathway.

  • nt 4 attenuates neuroinflammation via trkb pi3k foxo1 pathway after Germinal Matrix Hemorrhage in neonatal rats
    Journal of Neuroinflammation, 2020
    Co-Authors: Yan Ding, Jiping Tang, Tianyi Wang, Junyi Zhang, Gang Chen, John H. Zhang
    Abstract:

    Neuroinflammation plays an important role in pathogenesis of Germinal Matrix Hemorrhage (GMH). Neurotrophin-4 (NT-4) is a member of the neurotrophin family and interacts with the tropomyosin receptor kinase B (TrkB). NT-4 has been shown to confer neuroprotective effects following cerebral ischemia. We aimed to investigate the neuroprotective function of NT-4-TrkB signaling, as well as its downstream signaling cascade phosphatidylinositol-3-kinases (PI3K)/protein kinase B (Akt)/forkhead box protein O1 (FoxO1), following GMH in neonatal rats. GMH was induced by intraparenchymal injection of bacterial collagenase (0.3 U) in P7 rat pups. A total of 163 pups were used in this study. Recombinant human NT-4 was administered intranasally at 1 h after the collagenase injection. The selective TrkB antagonist ANA-12, selective PI3K inhibitor LY294002, and FoxO1 activating CRISPR were administered intracerebroventricularly at 24 h prior to NT-4 treatment to investigate the underlying mechanism. Short-term and long-term neurobehavioral assessments, immunofluorescence staining, Nissl’s staining, and Western blot were performed. Expression of phosphorylated TrkB increased after GMH, reaching the peak level at day 3 after Hemorrhage. TrkB receptors were observed on neurons, microglia, and astrocytes. The administration of rh-NT-4 induced phosphorylation of TrkB, expression of PI3K, and phosphorylation of Akt. Meanwhile, it decreased FoxO1 and IL-6 levels. Selective inhibition of TrkB/PI3K/Akt signaling in microglia increased the expression levels of FoxO1 and pro-inflammatory cytokines. FoxO1 activating CRISPR increased the expression of IL-6, suggesting that FoxO1 might be a potential inducer of pro-inflammatory factors. These results suggested that PI3K/Akt/FoxO1 signaling may be the downstream pathway of activation of TrkB. The rat pups treated with rh-NT-4 performed better than vehicle-treated animals in both short-term and long-term behavioral tests. These data showed that rh-NT-4 reduced the expression levels of pro-inflammatory cytokines, improved neurological function, attenuated neuroinflammation, and thereby mitigated post-hemorrhagic hydrocephalus after GMH by TrkB/PI3K/Akt/FoxO1 pathway. These results indicated that rh-NT-4 could be a promising therapeutic strategy to ameliorate neuroinflammation and hydrocephalus after GMH or other similar brain injuries.

  • NT-4 attenuates neuroinflammation via TrkB/PI3K/FoxO1 pathway after Germinal Matrix Hemorrhage in neonatal rats
    Journal of neuroinflammation, 2020
    Co-Authors: Tianyi Wang, Yan Ding, Jiping Tang, Junyi Zhang, Gang Chen, John H. Zhang
    Abstract:

    Neuroinflammation plays an important role in pathogenesis of Germinal Matrix Hemorrhage (GMH). Neurotrophin-4 (NT-4) is a member of the neurotrophin family and interacts with the tropomyosin receptor kinase B (TrkB). NT-4 has been shown to confer neuroprotective effects following cerebral ischemia. We aimed to investigate the neuroprotective function of NT-4-TrkB signaling, as well as its downstream signaling cascade phosphatidylinositol-3-kinases (PI3K)/protein kinase B (Akt)/forkhead box protein O1 (FoxO1), following GMH in neonatal rats. GMH was induced by intraparenchymal injection of bacterial collagenase (0.3 U) in P7 rat pups. A total of 163 pups were used in this study. Recombinant human NT-4 was administered intranasally at 1 h after the collagenase injection. The selective TrkB antagonist ANA-12, selective PI3K inhibitor LY294002, and FoxO1 activating CRISPR were administered intracerebroventricularly at 24 h prior to NT-4 treatment to investigate the underlying mechanism. Short-term and long-term neurobehavioral assessments, immunofluorescence staining, Nissl’s staining, and Western blot were performed. Expression of phosphorylated TrkB increased after GMH, reaching the peak level at day 3 after Hemorrhage. TrkB receptors were observed on neurons, microglia, and astrocytes. The administration of rh-NT-4 induced phosphorylation of TrkB, expression of PI3K, and phosphorylation of Akt. Meanwhile, it decreased FoxO1 and IL-6 levels. Selective inhibition of TrkB/PI3K/Akt signaling in microglia increased the expression levels of FoxO1 and pro-inflammatory cytokines. FoxO1 activating CRISPR increased the expression of IL-6, suggesting that FoxO1 might be a potential inducer of pro-inflammatory factors. These results suggested that PI3K/Akt/FoxO1 signaling may be the downstream pathway of activation of TrkB. The rat pups treated with rh-NT-4 performed better than vehicle-treated animals in both short-term and long-term behavioral tests. These data showed that rh-NT-4 reduced the expression levels of pro-inflammatory cytokines, improved neurological function, attenuated neuroinflammation, and thereby mitigated post-hemorrhagic hydrocephalus after GMH by TrkB/PI3K/Akt/FoxO1 pathway. These results indicated that rh-NT-4 could be a promising therapeutic strategy to ameliorate neuroinflammation and hydrocephalus after GMH or other similar brain injuries.

  • Rh-relaxin-2 Attenuates Degranulation of mast cells by Inhibiting NF-κB through PI3K-AKT/TNFAIP3 Pathway in an Experimental Germinal Matrix Hemorrhage Rat Model
    2020
    Co-Authors: Gang Zhao, Yan Ding, Jerry Flores, Shengpeng Liu, Tianyi Wang, Fanfan Chen, Umut Ocak
    Abstract:

    Abstract Background: Mast cells play an important role in early immune reactions in the brain by inducing degranulation and releasing inflammatory mediators. Our aim of the study is to investigate the effects of rh-relaxin-2 on mast cells and the underlying mechanisms in a GMH rat model. Methods: One hundred and sixty-four P7 rat pups were subjected to Germinal Matrix Hemorrhage (GMH) by an intraparenchymal injection of bacterial collagenase. Clodronate liposome was administered through intracerebroventricular (i.c.v.) injections 24 hours prior to GMH to inhibit microglia. Rh-relaxin-2 was administered intraperitoneally at 1 hour and 12 hours after GMH. Small interfering RNA of RXFP1 and PI3K inhibitor LY294002 were given by i.c.v. injections. Post-GMH evaluation included neurobehavioral function, Western blot analysis, immunofluorescence, Nissl staining, and Toluidine staining. Results: Our results demonstrated that endogenous relaxin-2 was downregulated and that RXFP1 level peaked on the first day after GMH. Administration of rh-relaxin-2 improved neurological functions, attenuated degranulation of mast cells and neuroinflammation, and ameliorated post-hemorrhagic hydrocephalus after GMH. These effects were associated with RXFP1 activation, increased expression of PI3K, phosphorylated AKT and TNFAIP3, and decreased levels of phosphorylated NF-κB, tryptase, chymase, IL-6 and TNF-α. However, knockdown of RXFP1 and PI3K abolished the protective effects of rh-relaxin-2. Conclusions: Our findings showed that rh-relaxin-2 attenuated degranulation of mast cells and neuroinflammation, improved neurological outcomes and ameliorated hydrocephalus after GMH through RXFP1/PI3K-AKT/TNFAIP3/NF-κB signaling pathway.

Jiping Tang - One of the best experts on this subject based on the ideXlab platform.

  • NT-4 attenuates neuroinflammation via TrkB/PI3K/FoxO1 pathway after Germinal Matrix Hemorrhage in neonatal rats
    Journal of neuroinflammation, 2020
    Co-Authors: Tianyi Wang, Yan Ding, Jiping Tang, Junyi Zhang, Gang Chen, John H. Zhang
    Abstract:

    Neuroinflammation plays an important role in pathogenesis of Germinal Matrix Hemorrhage (GMH). Neurotrophin-4 (NT-4) is a member of the neurotrophin family and interacts with the tropomyosin receptor kinase B (TrkB). NT-4 has been shown to confer neuroprotective effects following cerebral ischemia. We aimed to investigate the neuroprotective function of NT-4-TrkB signaling, as well as its downstream signaling cascade phosphatidylinositol-3-kinases (PI3K)/protein kinase B (Akt)/forkhead box protein O1 (FoxO1), following GMH in neonatal rats. GMH was induced by intraparenchymal injection of bacterial collagenase (0.3 U) in P7 rat pups. A total of 163 pups were used in this study. Recombinant human NT-4 was administered intranasally at 1 h after the collagenase injection. The selective TrkB antagonist ANA-12, selective PI3K inhibitor LY294002, and FoxO1 activating CRISPR were administered intracerebroventricularly at 24 h prior to NT-4 treatment to investigate the underlying mechanism. Short-term and long-term neurobehavioral assessments, immunofluorescence staining, Nissl’s staining, and Western blot were performed. Expression of phosphorylated TrkB increased after GMH, reaching the peak level at day 3 after Hemorrhage. TrkB receptors were observed on neurons, microglia, and astrocytes. The administration of rh-NT-4 induced phosphorylation of TrkB, expression of PI3K, and phosphorylation of Akt. Meanwhile, it decreased FoxO1 and IL-6 levels. Selective inhibition of TrkB/PI3K/Akt signaling in microglia increased the expression levels of FoxO1 and pro-inflammatory cytokines. FoxO1 activating CRISPR increased the expression of IL-6, suggesting that FoxO1 might be a potential inducer of pro-inflammatory factors. These results suggested that PI3K/Akt/FoxO1 signaling may be the downstream pathway of activation of TrkB. The rat pups treated with rh-NT-4 performed better than vehicle-treated animals in both short-term and long-term behavioral tests. These data showed that rh-NT-4 reduced the expression levels of pro-inflammatory cytokines, improved neurological function, attenuated neuroinflammation, and thereby mitigated post-hemorrhagic hydrocephalus after GMH by TrkB/PI3K/Akt/FoxO1 pathway. These results indicated that rh-NT-4 could be a promising therapeutic strategy to ameliorate neuroinflammation and hydrocephalus after GMH or other similar brain injuries.

  • nt 4 attenuates neuroinflammation via trkb pi3k foxo1 pathway after Germinal Matrix Hemorrhage in neonatal rats
    Journal of Neuroinflammation, 2020
    Co-Authors: Yan Ding, Jiping Tang, Tianyi Wang, Junyi Zhang, Gang Chen, John H. Zhang
    Abstract:

    Neuroinflammation plays an important role in pathogenesis of Germinal Matrix Hemorrhage (GMH). Neurotrophin-4 (NT-4) is a member of the neurotrophin family and interacts with the tropomyosin receptor kinase B (TrkB). NT-4 has been shown to confer neuroprotective effects following cerebral ischemia. We aimed to investigate the neuroprotective function of NT-4-TrkB signaling, as well as its downstream signaling cascade phosphatidylinositol-3-kinases (PI3K)/protein kinase B (Akt)/forkhead box protein O1 (FoxO1), following GMH in neonatal rats. GMH was induced by intraparenchymal injection of bacterial collagenase (0.3 U) in P7 rat pups. A total of 163 pups were used in this study. Recombinant human NT-4 was administered intranasally at 1 h after the collagenase injection. The selective TrkB antagonist ANA-12, selective PI3K inhibitor LY294002, and FoxO1 activating CRISPR were administered intracerebroventricularly at 24 h prior to NT-4 treatment to investigate the underlying mechanism. Short-term and long-term neurobehavioral assessments, immunofluorescence staining, Nissl’s staining, and Western blot were performed. Expression of phosphorylated TrkB increased after GMH, reaching the peak level at day 3 after Hemorrhage. TrkB receptors were observed on neurons, microglia, and astrocytes. The administration of rh-NT-4 induced phosphorylation of TrkB, expression of PI3K, and phosphorylation of Akt. Meanwhile, it decreased FoxO1 and IL-6 levels. Selective inhibition of TrkB/PI3K/Akt signaling in microglia increased the expression levels of FoxO1 and pro-inflammatory cytokines. FoxO1 activating CRISPR increased the expression of IL-6, suggesting that FoxO1 might be a potential inducer of pro-inflammatory factors. These results suggested that PI3K/Akt/FoxO1 signaling may be the downstream pathway of activation of TrkB. The rat pups treated with rh-NT-4 performed better than vehicle-treated animals in both short-term and long-term behavioral tests. These data showed that rh-NT-4 reduced the expression levels of pro-inflammatory cytokines, improved neurological function, attenuated neuroinflammation, and thereby mitigated post-hemorrhagic hydrocephalus after GMH by TrkB/PI3K/Akt/FoxO1 pathway. These results indicated that rh-NT-4 could be a promising therapeutic strategy to ameliorate neuroinflammation and hydrocephalus after GMH or other similar brain injuries.

  • NT-4 attenuates neuroinflammation via TrkB/PI3K/FoxO1 pathway after Germinal Matrix Hemorrhage in neonatal rats
    2020
    Co-Authors: Tianyi Wang, Yan Ding, Jiping Tang, Junyi Zhang, Gang Chen, John Zhang
    Abstract:

    Abstract Background: Neuroinflammation plays an important role in pathogenesis of Germinal Matrix Hemorrhage (GMH). Neurotrophin-4 (NT-4) is a member of the neurotrophin family, and it interacts with the tyrosine kinase B (TrkB) receptor. It has been studied that NT-4 has neuroprotective effects following cerebral ischemia. We aimed to investigate the neuroprotective function of NT-4 and it’s high affinity receptor TrkB as well as its downstream mediator phosphatidylinositol-3-kinases (PI3K)/protein kinase B (Akt)/Forkhead box protein O1 (FoxO1) following GMH in neonatal rats, with a specific focus on inflammation. Methods: GMH was induced by intraparenchymal injection of bacterial collagenase (0.3U) in P7 rat pups. A total of 163 seven-day-old pups were used in this study. The recombinant human NT-4 was administered intranasally at 1 hour after the collagenase injection. The selective TrkB antagonist ANA-12, selective PI3K inhibitor LY294002 and FoxO1 activating CRISPR were administered intracerebroventricularly at 24 hours prior to NT-4 treatment to investigate the potential mechanism. Short-and-long-term neurobehavior assessments, immunofluorescence staining, Nissl’s staining and Western blot were performed. Results ： The expression of p-TrkB increased after GMH with a peak at day3. The TrkB receptor was expressed by neurons, microglia, and astrocytes. The administration of rh-NT-4 increased phosphorylation of TrkB, expression of PI3K, phosphorylation of Akt and decreased FoxO1, IL-1beta and IL-6 levels. Selective inhibition of TrkB/PI3K/Akt signaling in microglia increased the expression levels of FoxO1 and pro-inflammatory cytokines. The use of FoxO1 activation CRISPR increased the expression of IL-6, suggesting that FoxO1 might potentially induce pro-inflammatory factors. These results demonstrated that PI3K/Akt/FoxO1 may be the downstream pathway of TrkB phosphorylation. The rat pups treated with rh-NT-4 performed better than untreated animals both in short-and-long-term behavior test. Conclusion： These data showed that rh-NT-4 can reduce the expression of pro-inflammatory cytokines, improve neurological function, attenuate neuroinflammation and post-hemorrhagic hydrocephalus after GMH by promoting TrkB/PI3K/Akt/FoxO1 pathway. These results indicated that rh-NT-4 could be a promising therapeutic target to ameliorate neuroinflammation and hydrocephalus after GMH or other similar brain injuries.

  • posthemorrhagic hydrocephalus development after Germinal Matrix Hemorrhage established mechanisms and proposed pathways
    Journal of Neuroscience Research, 2020
    Co-Authors: Damon Klebe, Jerry Flores, Jiping Tang, Devin W. Mcbride, Paul R. Krafft, John H. Zhang
    Abstract:

    In addition to being the leading cause of morbidity and mortality in premature infants, Germinal Matrix Hemorrhage (GMH) is also the leading cause of acquired infantile hydrocephalus. The pathophysiology of posthemorrhagic hydrocephalus (PHH) development after GMH is complex and vaguely understood, although evidence suggests fibrosis and gliosis in the periventricular and subarachnoid spaces disrupts normal cerebrospinal fluid (CSF) dynamics. Theories explaining general hydrocephalus etiology have substantially evolved from the original bulk flow theory developed by Dr. Dandy over a century ago. Current clinical and experimental evidence supports a new hydrodynamic theory for hydrocephalus development involving redistribution of vascular pulsations and disruption of Starling forces in the brain microcirculation. In this review, we discuss CSF flow dynamics, history and development of theoretical hydrocephalus pathophysiology, and GMH epidemiology and etiology as it relates to PHH development. We highlight known mechanisms and propose new avenues that will further elucidate GMH pathophysiology, specifically related to hydrocephalus.

  • a comprehensive review of therapeutic targets that induce microglia macrophage mediated hematoma resolution after Germinal Matrix Hemorrhage
    Journal of Neuroscience Research, 2020
    Co-Authors: Jerry Flores, Damon Klebe, Jiping Tang, John H. Zhang
    Abstract:

    Currently, there is no effective treatment for Germinal Matrix Hemorrhage and intraventricular Hemorrhage (GMH-IVH), a common and often fatal stroke subtype in premature infants. Secondary brain injury after GMH-IVH is known to involve blood clots that contribute to inflammation and neurological deficits. Furthermore, the subsequent blood clots disrupt normal cerebrospinal fluid circulation and absorption after GMH-IVH, contributing to posthemorrhagic hydrocephalus (PHH). Clinically, GMH-IVH severity is graded on a I to IV scale: Grade I is confined to the Germinal Matrix, grade II includes intraventricular Hemorrhage, grade III includes intraventricular Hemorrhage with extension into dilated ventricles, and grade IV includes intraventricular Hemorrhage with extension into dilated ventricles as well as parenchymal hemorrhaging. GMH-IVH hematoma volume is the best prognostic indicator, where patients with higher grades have worsened outcomes. Various preclinical studies have shown that rapid hematoma resolution quickly ameliorates inflammation and improves neurological outcomes. Current experimental evidence identifies alternatively activated microglia as playing a pivotal role in hematoma clearance. In this review, we discuss the pathophysiology of GMH-IVH in the development of PHH, microglia/macrophage's role in the neonatal CNS, and established/potential therapeutic targets that enhance M2 microglia/macrophage phagocytosis of blood clots after GMH-IVH.

Jerry Flores - One of the best experts on this subject based on the ideXlab platform.

  • rh relaxin 2 attenuates degranulation of mast cells by inhibiting nf κb through pi3k akt tnfaip3 pathway in an experimental Germinal Matrix Hemorrhage rat model
    Journal of Neuroinflammation, 2020
    Co-Authors: Yan Ding, Jerry Flores, Tongyu Zhang, Shengpeng Liu, Tianyi Wang, Gang Zhao, Fanfan Chen, Umut Ocak, John H. Zhang
    Abstract:

    Mast cells play an important role in early immune reactions in the brain by degranulation and the consequent inflammatory response. Our aim of the study is to investigate the effects of rh-relaxin-2 on mast cells and the underlying mechanisms in a Germinal Matrix Hemorrhage (GMH) rat model. One hundred seventy-three P7 rat pups were subjected to GMH by an intraparenchymal injection of bacterial collagenase. Clodronate liposome was administered through intracerebroventricular (i.c.v.) injections 24 h prior to GMH to inhibit microglia. Rh-relaxin-2 was administered intraperitoneally at 1 h and 13 h after GMH. Small interfering RNA of RXFP1 and PI3K inhibitor LY294002 were given by i.c.v. injection. Post-GMH evaluation included neurobehavioral function, Western blot analysis, immunofluorescence, Nissl staining, and toluidine blue staining. Our results demonstrated that endogenous relaxin-2 was downregulated and that RXFP1 level peaked on the first day after GMH. Administration of rh-relaxin-2 improved neurological functions, attenuated degranulation of mast cells and neuroinflammation, and ameliorated post-hemorrhagic hydrocephalus (PHH) after GMH. These effects were associated with RXFP1 activation, increased expression of PI3K, phosphorylated AKT and TNFAIP3, and decreased levels of phosphorylated NF-κB, tryptase, chymase, IL-6, and TNF-α. However, knockdown of RXFP1 and PI3K inhibition abolished the protective effects of rh-relaxin-2. Our findings showed that rh-relaxin-2 attenuated degranulation of mast cells and neuroinflammation, improved neurological outcomes, and ameliorated hydrocephalus after GMH through RXFP1/PI3K-AKT/TNFAIP3/NF-κB signaling pathway.

  • Rh-relaxin-2 attenuates degranulation of mast cells by inhibiting NF-κB through PI3K-AKT/TNFAIP3 pathway in an experimental Germinal Matrix Hemorrhage rat model.
    Journal of neuroinflammation, 2020
    Co-Authors: Gang Zhao, Yan Ding, Jerry Flores, Shengpeng Liu, Tianyi Wang, Fanfan Chen, Umut Ocak
    Abstract:

    Mast cells play an important role in early immune reactions in the brain by degranulation and the consequent inflammatory response. Our aim of the study is to investigate the effects of rh-relaxin-2 on mast cells and the underlying mechanisms in a Germinal Matrix Hemorrhage (GMH) rat model. One hundred seventy-three P7 rat pups were subjected to GMH by an intraparenchymal injection of bacterial collagenase. Clodronate liposome was administered through intracerebroventricular (i.c.v.) injections 24 h prior to GMH to inhibit microglia. Rh-relaxin-2 was administered intraperitoneally at 1 h and 13 h after GMH. Small interfering RNA of RXFP1 and PI3K inhibitor LY294002 were given by i.c.v. injection. Post-GMH evaluation included neurobehavioral function, Western blot analysis, immunofluorescence, Nissl staining, and toluidine blue staining. Our results demonstrated that endogenous relaxin-2 was downregulated and that RXFP1 level peaked on the first day after GMH. Administration of rh-relaxin-2 improved neurological functions, attenuated degranulation of mast cells and neuroinflammation, and ameliorated post-hemorrhagic hydrocephalus (PHH) after GMH. These effects were associated with RXFP1 activation, increased expression of PI3K, phosphorylated AKT and TNFAIP3, and decreased levels of phosphorylated NF-κB, tryptase, chymase, IL-6, and TNF-α. However, knockdown of RXFP1 and PI3K inhibition abolished the protective effects of rh-relaxin-2. Our findings showed that rh-relaxin-2 attenuated degranulation of mast cells and neuroinflammation, improved neurological outcomes, and ameliorated hydrocephalus after GMH through RXFP1/PI3K-AKT/TNFAIP3/NF-κB signaling pathway.

  • Rh-relaxin-2 Attenuates Degranulation of mast cells by Inhibiting NF-κB through PI3K-AKT/TNFAIP3 Pathway in an Experimental Germinal Matrix Hemorrhage Rat Model
    2020
    Co-Authors: Gang Zhao, Yan Ding, Jerry Flores, Shengpeng Liu, Tianyi Wang, Fanfan Chen, Umut Ocak
    Abstract:

    Abstract Background: Mast cells play an important role in early immune reactions in the brain by inducing degranulation and releasing inflammatory mediators. Our aim of the study is to investigate the effects of rh-relaxin-2 on mast cells and the underlying mechanisms in a GMH rat model. Methods: One hundred and sixty-four P7 rat pups were subjected to Germinal Matrix Hemorrhage (GMH) by an intraparenchymal injection of bacterial collagenase. Clodronate liposome was administered through intracerebroventricular (i.c.v.) injections 24 hours prior to GMH to inhibit microglia. Rh-relaxin-2 was administered intraperitoneally at 1 hour and 12 hours after GMH. Small interfering RNA of RXFP1 and PI3K inhibitor LY294002 were given by i.c.v. injections. Post-GMH evaluation included neurobehavioral function, Western blot analysis, immunofluorescence, Nissl staining, and Toluidine staining. Results: Our results demonstrated that endogenous relaxin-2 was downregulated and that RXFP1 level peaked on the first day after GMH. Administration of rh-relaxin-2 improved neurological functions, attenuated degranulation of mast cells and neuroinflammation, and ameliorated post-hemorrhagic hydrocephalus after GMH. These effects were associated with RXFP1 activation, increased expression of PI3K, phosphorylated AKT and TNFAIP3, and decreased levels of phosphorylated NF-κB, tryptase, chymase, IL-6 and TNF-α. However, knockdown of RXFP1 and PI3K abolished the protective effects of rh-relaxin-2. Conclusions: Our findings showed that rh-relaxin-2 attenuated degranulation of mast cells and neuroinflammation, improved neurological outcomes and ameliorated hydrocephalus after GMH through RXFP1/PI3K-AKT/TNFAIP3/NF-κB signaling pathway.

  • a comprehensive review of therapeutic targets that induce microglia macrophage mediated hematoma resolution after Germinal Matrix Hemorrhage
    Journal of Neuroscience Research, 2020
    Co-Authors: Jerry Flores, Damon Klebe, Jiping Tang, John H. Zhang
    Abstract:

    Currently, there is no effective treatment for Germinal Matrix Hemorrhage and intraventricular Hemorrhage (GMH-IVH), a common and often fatal stroke subtype in premature infants. Secondary brain injury after GMH-IVH is known to involve blood clots that contribute to inflammation and neurological deficits. Furthermore, the subsequent blood clots disrupt normal cerebrospinal fluid circulation and absorption after GMH-IVH, contributing to posthemorrhagic hydrocephalus (PHH). Clinically, GMH-IVH severity is graded on a I to IV scale: Grade I is confined to the Germinal Matrix, grade II includes intraventricular Hemorrhage, grade III includes intraventricular Hemorrhage with extension into dilated ventricles, and grade IV includes intraventricular Hemorrhage with extension into dilated ventricles as well as parenchymal hemorrhaging. GMH-IVH hematoma volume is the best prognostic indicator, where patients with higher grades have worsened outcomes. Various preclinical studies have shown that rapid hematoma resolution quickly ameliorates inflammation and improves neurological outcomes. Current experimental evidence identifies alternatively activated microglia as playing a pivotal role in hematoma clearance. In this review, we discuss the pathophysiology of GMH-IVH in the development of PHH, microglia/macrophage's role in the neonatal CNS, and established/potential therapeutic targets that enhance M2 microglia/macrophage phagocytosis of blood clots after GMH-IVH.

  • posthemorrhagic hydrocephalus development after Germinal Matrix Hemorrhage established mechanisms and proposed pathways
    Journal of Neuroscience Research, 2020
    Co-Authors: Damon Klebe, Jerry Flores, Jiping Tang, Devin W. Mcbride, Paul R. Krafft, John H. Zhang
    Abstract:

    In addition to being the leading cause of morbidity and mortality in premature infants, Germinal Matrix Hemorrhage (GMH) is also the leading cause of acquired infantile hydrocephalus. The pathophysiology of posthemorrhagic hydrocephalus (PHH) development after GMH is complex and vaguely understood, although evidence suggests fibrosis and gliosis in the periventricular and subarachnoid spaces disrupts normal cerebrospinal fluid (CSF) dynamics. Theories explaining general hydrocephalus etiology have substantially evolved from the original bulk flow theory developed by Dr. Dandy over a century ago. Current clinical and experimental evidence supports a new hydrodynamic theory for hydrocephalus development involving redistribution of vascular pulsations and disruption of Starling forces in the brain microcirculation. In this review, we discuss CSF flow dynamics, history and development of theoretical hydrocephalus pathophysiology, and GMH epidemiology and etiology as it relates to PHH development. We highlight known mechanisms and propose new avenues that will further elucidate GMH pathophysiology, specifically related to hydrocephalus.

Tianyi Wang - One of the best experts on this subject based on the ideXlab platform.

  • rh relaxin 2 attenuates degranulation of mast cells by inhibiting nf κb through pi3k akt tnfaip3 pathway in an experimental Germinal Matrix Hemorrhage rat model
    Journal of Neuroinflammation, 2020
    Co-Authors: Yan Ding, Jerry Flores, Tongyu Zhang, Shengpeng Liu, Tianyi Wang, Gang Zhao, Fanfan Chen, Umut Ocak, John H. Zhang
    Abstract:

    Mast cells play an important role in early immune reactions in the brain by degranulation and the consequent inflammatory response. Our aim of the study is to investigate the effects of rh-relaxin-2 on mast cells and the underlying mechanisms in a Germinal Matrix Hemorrhage (GMH) rat model. One hundred seventy-three P7 rat pups were subjected to GMH by an intraparenchymal injection of bacterial collagenase. Clodronate liposome was administered through intracerebroventricular (i.c.v.) injections 24 h prior to GMH to inhibit microglia. Rh-relaxin-2 was administered intraperitoneally at 1 h and 13 h after GMH. Small interfering RNA of RXFP1 and PI3K inhibitor LY294002 were given by i.c.v. injection. Post-GMH evaluation included neurobehavioral function, Western blot analysis, immunofluorescence, Nissl staining, and toluidine blue staining. Our results demonstrated that endogenous relaxin-2 was downregulated and that RXFP1 level peaked on the first day after GMH. Administration of rh-relaxin-2 improved neurological functions, attenuated degranulation of mast cells and neuroinflammation, and ameliorated post-hemorrhagic hydrocephalus (PHH) after GMH. These effects were associated with RXFP1 activation, increased expression of PI3K, phosphorylated AKT and TNFAIP3, and decreased levels of phosphorylated NF-κB, tryptase, chymase, IL-6, and TNF-α. However, knockdown of RXFP1 and PI3K inhibition abolished the protective effects of rh-relaxin-2. Our findings showed that rh-relaxin-2 attenuated degranulation of mast cells and neuroinflammation, improved neurological outcomes, and ameliorated hydrocephalus after GMH through RXFP1/PI3K-AKT/TNFAIP3/NF-κB signaling pathway.

  • Rh-relaxin-2 attenuates degranulation of mast cells by inhibiting NF-κB through PI3K-AKT/TNFAIP3 pathway in an experimental Germinal Matrix Hemorrhage rat model.
    Journal of neuroinflammation, 2020
    Co-Authors: Gang Zhao, Yan Ding, Jerry Flores, Shengpeng Liu, Tianyi Wang, Fanfan Chen, Umut Ocak
    Abstract:

    Mast cells play an important role in early immune reactions in the brain by degranulation and the consequent inflammatory response. Our aim of the study is to investigate the effects of rh-relaxin-2 on mast cells and the underlying mechanisms in a Germinal Matrix Hemorrhage (GMH) rat model. One hundred seventy-three P7 rat pups were subjected to GMH by an intraparenchymal injection of bacterial collagenase. Clodronate liposome was administered through intracerebroventricular (i.c.v.) injections 24 h prior to GMH to inhibit microglia. Rh-relaxin-2 was administered intraperitoneally at 1 h and 13 h after GMH. Small interfering RNA of RXFP1 and PI3K inhibitor LY294002 were given by i.c.v. injection. Post-GMH evaluation included neurobehavioral function, Western blot analysis, immunofluorescence, Nissl staining, and toluidine blue staining. Our results demonstrated that endogenous relaxin-2 was downregulated and that RXFP1 level peaked on the first day after GMH. Administration of rh-relaxin-2 improved neurological functions, attenuated degranulation of mast cells and neuroinflammation, and ameliorated post-hemorrhagic hydrocephalus (PHH) after GMH. These effects were associated with RXFP1 activation, increased expression of PI3K, phosphorylated AKT and TNFAIP3, and decreased levels of phosphorylated NF-κB, tryptase, chymase, IL-6, and TNF-α. However, knockdown of RXFP1 and PI3K inhibition abolished the protective effects of rh-relaxin-2. Our findings showed that rh-relaxin-2 attenuated degranulation of mast cells and neuroinflammation, improved neurological outcomes, and ameliorated hydrocephalus after GMH through RXFP1/PI3K-AKT/TNFAIP3/NF-κB signaling pathway.

  • nt 4 attenuates neuroinflammation via trkb pi3k foxo1 pathway after Germinal Matrix Hemorrhage in neonatal rats
    Journal of Neuroinflammation, 2020
    Co-Authors: Yan Ding, Jiping Tang, Tianyi Wang, Junyi Zhang, Gang Chen, John H. Zhang
    Abstract:

    Neuroinflammation plays an important role in pathogenesis of Germinal Matrix Hemorrhage (GMH). Neurotrophin-4 (NT-4) is a member of the neurotrophin family and interacts with the tropomyosin receptor kinase B (TrkB). NT-4 has been shown to confer neuroprotective effects following cerebral ischemia. We aimed to investigate the neuroprotective function of NT-4-TrkB signaling, as well as its downstream signaling cascade phosphatidylinositol-3-kinases (PI3K)/protein kinase B (Akt)/forkhead box protein O1 (FoxO1), following GMH in neonatal rats. GMH was induced by intraparenchymal injection of bacterial collagenase (0.3 U) in P7 rat pups. A total of 163 pups were used in this study. Recombinant human NT-4 was administered intranasally at 1 h after the collagenase injection. The selective TrkB antagonist ANA-12, selective PI3K inhibitor LY294002, and FoxO1 activating CRISPR were administered intracerebroventricularly at 24 h prior to NT-4 treatment to investigate the underlying mechanism. Short-term and long-term neurobehavioral assessments, immunofluorescence staining, Nissl’s staining, and Western blot were performed. Expression of phosphorylated TrkB increased after GMH, reaching the peak level at day 3 after Hemorrhage. TrkB receptors were observed on neurons, microglia, and astrocytes. The administration of rh-NT-4 induced phosphorylation of TrkB, expression of PI3K, and phosphorylation of Akt. Meanwhile, it decreased FoxO1 and IL-6 levels. Selective inhibition of TrkB/PI3K/Akt signaling in microglia increased the expression levels of FoxO1 and pro-inflammatory cytokines. FoxO1 activating CRISPR increased the expression of IL-6, suggesting that FoxO1 might be a potential inducer of pro-inflammatory factors. These results suggested that PI3K/Akt/FoxO1 signaling may be the downstream pathway of activation of TrkB. The rat pups treated with rh-NT-4 performed better than vehicle-treated animals in both short-term and long-term behavioral tests. These data showed that rh-NT-4 reduced the expression levels of pro-inflammatory cytokines, improved neurological function, attenuated neuroinflammation, and thereby mitigated post-hemorrhagic hydrocephalus after GMH by TrkB/PI3K/Akt/FoxO1 pathway. These results indicated that rh-NT-4 could be a promising therapeutic strategy to ameliorate neuroinflammation and hydrocephalus after GMH or other similar brain injuries.

  • NT-4 attenuates neuroinflammation via TrkB/PI3K/FoxO1 pathway after Germinal Matrix Hemorrhage in neonatal rats
    Journal of neuroinflammation, 2020
    Co-Authors: Tianyi Wang, Yan Ding, Jiping Tang, Junyi Zhang, Gang Chen, John H. Zhang
    Abstract:

    Neuroinflammation plays an important role in pathogenesis of Germinal Matrix Hemorrhage (GMH). Neurotrophin-4 (NT-4) is a member of the neurotrophin family and interacts with the tropomyosin receptor kinase B (TrkB). NT-4 has been shown to confer neuroprotective effects following cerebral ischemia. We aimed to investigate the neuroprotective function of NT-4-TrkB signaling, as well as its downstream signaling cascade phosphatidylinositol-3-kinases (PI3K)/protein kinase B (Akt)/forkhead box protein O1 (FoxO1), following GMH in neonatal rats. GMH was induced by intraparenchymal injection of bacterial collagenase (0.3 U) in P7 rat pups. A total of 163 pups were used in this study. Recombinant human NT-4 was administered intranasally at 1 h after the collagenase injection. The selective TrkB antagonist ANA-12, selective PI3K inhibitor LY294002, and FoxO1 activating CRISPR were administered intracerebroventricularly at 24 h prior to NT-4 treatment to investigate the underlying mechanism. Short-term and long-term neurobehavioral assessments, immunofluorescence staining, Nissl’s staining, and Western blot were performed. Expression of phosphorylated TrkB increased after GMH, reaching the peak level at day 3 after Hemorrhage. TrkB receptors were observed on neurons, microglia, and astrocytes. The administration of rh-NT-4 induced phosphorylation of TrkB, expression of PI3K, and phosphorylation of Akt. Meanwhile, it decreased FoxO1 and IL-6 levels. Selective inhibition of TrkB/PI3K/Akt signaling in microglia increased the expression levels of FoxO1 and pro-inflammatory cytokines. FoxO1 activating CRISPR increased the expression of IL-6, suggesting that FoxO1 might be a potential inducer of pro-inflammatory factors. These results suggested that PI3K/Akt/FoxO1 signaling may be the downstream pathway of activation of TrkB. The rat pups treated with rh-NT-4 performed better than vehicle-treated animals in both short-term and long-term behavioral tests. These data showed that rh-NT-4 reduced the expression levels of pro-inflammatory cytokines, improved neurological function, attenuated neuroinflammation, and thereby mitigated post-hemorrhagic hydrocephalus after GMH by TrkB/PI3K/Akt/FoxO1 pathway. These results indicated that rh-NT-4 could be a promising therapeutic strategy to ameliorate neuroinflammation and hydrocephalus after GMH or other similar brain injuries.

  • Rh-relaxin-2 Attenuates Degranulation of mast cells by Inhibiting NF-κB through PI3K-AKT/TNFAIP3 Pathway in an Experimental Germinal Matrix Hemorrhage Rat Model
    2020
    Co-Authors: Gang Zhao, Yan Ding, Jerry Flores, Shengpeng Liu, Tianyi Wang, Fanfan Chen, Umut Ocak
    Abstract:

    Abstract Background: Mast cells play an important role in early immune reactions in the brain by inducing degranulation and releasing inflammatory mediators. Our aim of the study is to investigate the effects of rh-relaxin-2 on mast cells and the underlying mechanisms in a GMH rat model. Methods: One hundred and sixty-four P7 rat pups were subjected to Germinal Matrix Hemorrhage (GMH) by an intraparenchymal injection of bacterial collagenase. Clodronate liposome was administered through intracerebroventricular (i.c.v.) injections 24 hours prior to GMH to inhibit microglia. Rh-relaxin-2 was administered intraperitoneally at 1 hour and 12 hours after GMH. Small interfering RNA of RXFP1 and PI3K inhibitor LY294002 were given by i.c.v. injections. Post-GMH evaluation included neurobehavioral function, Western blot analysis, immunofluorescence, Nissl staining, and Toluidine staining. Results: Our results demonstrated that endogenous relaxin-2 was downregulated and that RXFP1 level peaked on the first day after GMH. Administration of rh-relaxin-2 improved neurological functions, attenuated degranulation of mast cells and neuroinflammation, and ameliorated post-hemorrhagic hydrocephalus after GMH. These effects were associated with RXFP1 activation, increased expression of PI3K, phosphorylated AKT and TNFAIP3, and decreased levels of phosphorylated NF-κB, tryptase, chymase, IL-6 and TNF-α. However, knockdown of RXFP1 and PI3K abolished the protective effects of rh-relaxin-2. Conclusions: Our findings showed that rh-relaxin-2 attenuated degranulation of mast cells and neuroinflammation, improved neurological outcomes and ameliorated hydrocephalus after GMH through RXFP1/PI3K-AKT/TNFAIP3/NF-κB signaling pathway.