A novel p55PIK signaling peptide inhibitor alleviates neuroinflammation via the STAT3/NF-kB signaling pathway in experimental stroke.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: Saunders Country of Publication: United States NLM ID: 9111633 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1532-8511 (Electronic) Linking ISSN: 10523057 NLM ISO Abbreviation: J Stroke Cerebrovasc Dis Subsets: MEDLINE
    • Publication Information:
      Publication: Philadelphia, PA : Saunders
      Original Publication: New York, NY : Demos Publications, [1991-
    • Subject Terms:
      STAT3 Transcription Factor*/metabolism ; STAT3 Transcription Factor*/antagonists & inhibitors ; Signal Transduction*/drug effects ; Disease Models, Animal* ; Microglia*/drug effects ; Microglia*/metabolism ; Microglia*/pathology ; NF-kappa B*/metabolism ; NF-kappa B*/antagonists & inhibitors ; Neuroinflammatory Diseases*/drug therapy ; Neuroinflammatory Diseases*/metabolism ; Neuroprotective Agents*/pharmacology ; Anti-Inflammatory Agents*/pharmacology ; Apoptosis*/drug effects ; Mice, Inbred C57BL* ; Inflammation Mediators*/metabolism; Animals ; Male ; Brain/drug effects ; Brain/metabolism ; Brain/pathology ; Ischemic Attack, Transient/drug therapy ; Ischemic Attack, Transient/metabolism ; Ischemic Attack, Transient/pathology ; Ischemic Stroke/drug therapy ; Ischemic Stroke/metabolism ; Ischemic Stroke/pathology ; Infarction, Middle Cerebral Artery/drug therapy ; Infarction, Middle Cerebral Artery/metabolism ; Infarction, Middle Cerebral Artery/pathology
    • Abstract:
      Background: Ischemic stroke remains the predominant contributor to mortality and disability globally. Microglia undergo rapid activation and initiate inflammatory cascade reactions by phenotypic polarization, participating in the regulation of inflammatory injury and tissue repair post-ischemic stroke. Regulating microglia-mediated neuroinflammation is a promising therapeutic strategy for ischemic stroke. Previously, we designed and synthesized a novel p55PIK inhibitor, TAT-N15 polypeptide, which presents inhibitive activity on NF-κB signaling-mediated inflammation in acute conjunctivitis and allergic rhinitis. The present study aimed to explore the therapeutic effect and mechanism of TAT-N15 on ischemia stroke.
      Methods: The mouse model of transient cerebral ischemia was made using the intraluminal filament method. After being treated with daily intraperitoneal injections of TAT-N15 (10 mg/kg) for 7 d, the neurological outcomes and the cerebral infarction volume were evaluated. Histopathology of the ischemia cerebral hemisphere was observed by H&E and Nissl staining. Neuronal survival, astrogliosis, and co-labeling of CD86/Iba1 and CD206/Iba1 were detected by immunofluorescence. The cell apoptosis was estimated by TUNEL staining. The expression levels of apoptosis-associated proteins, proinflammatory cytokines, protein markers of M1 and M2 microglia, and the phosphorylation of NF-κB and STAT3 proteins in the ischemic penumbra were detected by Western blot.
      Results: TAT-N15 treatment significantly decreased the infarct volume and alleviated neurological functional impairment, neuronal injury, and neuron apoptosis. Meanwhile, TAT-N15 treatment restrained the activation of microglia and astrocytes as well as the protein expression of proinflammatory cytokine in ischemic penumbra. Additionally, the administration of TAT-N15 treatment resulted in a significant reduction in the density of M1 phenotype microglia while concurrently increasing the density of M2 phenotype microglia within the ischemic penumbra. Finally, mechanical analysis unveiled that TAT-N15 exerted a substantial inhibitory effect on the protein expression of phosphorylated STAT3 and NF-κB.
      Conclusion: TAT-N15 may inhibit neuroinflammation via regulating microglia activation and polarization through the STAT3/NF-κB pathway, which exhibits the neuroprotection effect in ischemic stroke.
      Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
      (Copyright © 2024 Elsevier Inc. All rights reserved.)
    • Contributed Indexing:
      Keywords: Ischemic stroke; Microglia polarization; Neuroinflammation; STAT3/NF-κB pathway; TAT-N15
    • Accession Number:
      0 (STAT3 Transcription Factor)
      0 (Stat3 protein, mouse)
      0 (NF-kappa B)
      0 (Neuroprotective Agents)
      0 (Anti-Inflammatory Agents)
      0 (Inflammation Mediators)
    • Publication Date:
      Date Created: 20240428 Date Completed: 20240605 Latest Revision: 20240613
    • Publication Date:
      20240613
    • Accession Number:
      10.1016/j.jstrokecerebrovasdis.2024.107736
    • Accession Number:
      38679216