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Updated: Jun 27, 2025
A Preclinical Model to Assess Brain Recovery After Acute Stroke in Rats
Published on: November 6, 2019
A novel p55PIK signaling peptide inhibitor alleviates neuroinflammation via the STAT3/NF-kB signaling pathway in
Yujing Liu1, Changlong Leng2, Youwei Li1
1Hubei Key Laboratory of Cognitive and Affective Disorder, Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China; Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan 430056, China.
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.
Insights
TAT-N15 polypeptide significantly reduces brain damage and improves outcomes in ischemic stroke by modulating microglia activation and polarization. This novel treatment targets the STAT3/NF-κB pathway, offering neuroprotection.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Ischemic stroke is a leading cause of global mortality and disability.
- Microglia activation and polarization drive neuroinflammation and tissue damage post-stroke.
- Targeting microglia-mediated neuroinflammation presents a promising therapeutic avenue.
Purpose of the Study:
- To investigate the therapeutic effects of TAT-N15 polypeptide on ischemic stroke.
- To elucidate the underlying mechanism of TAT-N15 in regulating neuroinflammation and neuroprotection.
Main Methods:
- A mouse model of transient cerebral ischemia was established.
- Mice were treated with TAT-N15 (10 mg/kg) via intraperitoneal injection.
- Neurological outcomes, infarct volume, histopathology, neuronal survival, apoptosis, and key molecular markers (STAT3, NF-κB, microglia phenotypes) were assessed.
Main Results:
- TAT-N15 significantly reduced infarct volume, neurological deficits, neuronal injury, and apoptosis.
- Treatment inhibited microglial and astrocyte activation and decreased pro-inflammatory cytokine expression.
- TAT-N15 promoted a shift from M1 to M2 microglia phenotype and inhibited STAT3/NF-κB phosphorylation.
Conclusions:
- TAT-N15 demonstrates neuroprotective effects in ischemic stroke.
- The mechanism involves inhibiting neuroinflammation by regulating microglia polarization via the STAT3/NF-κB pathway.
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