{"title":"Inhibition of C3a/C3aR by SB290157 Attenuates Neuroinflammation via PKC/P38/NLRP3 Signaling Pathway After Intracerebral Hemorrhage.","authors":"Dongqing Qi, Pengju Wei, Yuhui Cui, Cameron Lenahan, Xiaogen Tao, Peng Jin","doi":"10.1007/s12028-025-02226-z","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>The C3a/C3aR axis has been shown to play an important role in a variety of neurological diseases. The aim of this study was to investigate the effects of the C3aR antagonist SB290157 on neuroinflammation in a mouse model of intracerebral hemorrhage (ICH) and the mechanism of the protein kinase C (PKC)/P38/NLRP3 signaling pathway in C3aR-mediated neuroinflammation.</p><p><strong>Methods: </strong>A total of 276 CD-1 mice were randomly assigned to different experimental groups. The ICH model was constructed by injecting autologous blood into the right basal ganglia, and SB290157 was administered intraperitoneally after 1 h. C3a (an endogenous ligand for C3aR), PMA (a specific PKC activator), and C3aR small interfering RNA (siRNA) were chosen to elucidate the underlying mechanisms. Western blots, immunofluorescence staining, Nissl staining, neurobehavioral tests, and brain water content tests were also performed.</p><p><strong>Results: </strong>C3aR was mainly expressed on microglia. The expression of C3a and C3aR was upregulated in the right hemisphere of the brain after ICH. Intraperitoneal injection of SB291057 improves short-term and long-term behavioral deficits, attenuates brain edema, and reduces the number of activated microglia and neutrophil infiltration after ICH and downregulates the expression of phosphorylated PKC, phosphorylated P38, and NLRP3, as well as tumor necrosis factor-α, interleukin-6 (IL-6), and IL-1β. Administration of C3aR siRNA and the C3aR endogenous agonist C3a reversed the protective effect of SB290157. In addition, selective activation of PKC/P38/NLRP3 signaling also attenuated the antiinflammatory effects of SB290157 after ICH.</p><p><strong>Conclusions: </strong>This study demonstrates that SB290157 inhibits neuroinflammation and improves short-term and long-term neurological function after ICH in mice, at least in part through regulation of the C3aR/PKC/P38/NLRP3 signaling pathway. Targeting C3aR to inhibit NLRP3-dependent neuroinflammation may provide a promising therapeutic approach for treating ICH.</p>","PeriodicalId":19118,"journal":{"name":"Neurocritical Care","volume":" ","pages":""},"PeriodicalIF":3.1000,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neurocritical Care","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s12028-025-02226-z","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: The C3a/C3aR axis has been shown to play an important role in a variety of neurological diseases. The aim of this study was to investigate the effects of the C3aR antagonist SB290157 on neuroinflammation in a mouse model of intracerebral hemorrhage (ICH) and the mechanism of the protein kinase C (PKC)/P38/NLRP3 signaling pathway in C3aR-mediated neuroinflammation.
Methods: A total of 276 CD-1 mice were randomly assigned to different experimental groups. The ICH model was constructed by injecting autologous blood into the right basal ganglia, and SB290157 was administered intraperitoneally after 1 h. C3a (an endogenous ligand for C3aR), PMA (a specific PKC activator), and C3aR small interfering RNA (siRNA) were chosen to elucidate the underlying mechanisms. Western blots, immunofluorescence staining, Nissl staining, neurobehavioral tests, and brain water content tests were also performed.
Results: C3aR was mainly expressed on microglia. The expression of C3a and C3aR was upregulated in the right hemisphere of the brain after ICH. Intraperitoneal injection of SB291057 improves short-term and long-term behavioral deficits, attenuates brain edema, and reduces the number of activated microglia and neutrophil infiltration after ICH and downregulates the expression of phosphorylated PKC, phosphorylated P38, and NLRP3, as well as tumor necrosis factor-α, interleukin-6 (IL-6), and IL-1β. Administration of C3aR siRNA and the C3aR endogenous agonist C3a reversed the protective effect of SB290157. In addition, selective activation of PKC/P38/NLRP3 signaling also attenuated the antiinflammatory effects of SB290157 after ICH.
Conclusions: This study demonstrates that SB290157 inhibits neuroinflammation and improves short-term and long-term neurological function after ICH in mice, at least in part through regulation of the C3aR/PKC/P38/NLRP3 signaling pathway. Targeting C3aR to inhibit NLRP3-dependent neuroinflammation may provide a promising therapeutic approach for treating ICH.
期刊介绍：
Neurocritical Care is a peer reviewed scientific publication whose major goal is to disseminate new knowledge on all aspects of acute neurological care. It is directed towards neurosurgeons, neuro-intensivists, neurologists, anesthesiologists, emergency physicians, and critical care nurses treating patients with urgent neurologic disorders. These are conditions that may potentially evolve rapidly and could need immediate medical or surgical intervention. Neurocritical Care provides a comprehensive overview of current developments in intensive care neurology, neurosurgery and neuroanesthesia and includes information about new therapeutic avenues and technological innovations. Neurocritical Care is the official journal of the Neurocritical Care Society.
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