2. Academic Validation
  3. MyD88 inhibitory Peptide-2 (MIP2) improves neurological outcomes and reduces neuroinflammation after intracerebral Hemorrhage-mediated secondary brain injury

MyD88 inhibitory Peptide-2 (MIP2) improves neurological outcomes and reduces neuroinflammation after intracerebral Hemorrhage-mediated secondary brain injury

  • J Adv Res. 2026 Mar 23:S2090-1232(26)00271-7. doi: 10.1016/j.jare.2026.03.052.
Rabeea Siddique 1,  Pingping Guo 1,  Qingli Wang 1,  Qiuyang Su 1,  Lingxiao Qi 1,  Maham Mazhar 1,  Muhammad Aaqib 1,  Xiangyu Zhang 2,  Suliman Khan 3,  Voon Wee Yong 4,  Mengzhou Xue 5
Affiliations

Affiliations

  • 1 Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China.
  • 2 Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China; Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary T2N 4N1, AB, Canada.
  • 3 Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Medical Research Center, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. Electronic address: [email protected].
  • 4 Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary T2N 4N1, AB, Canada. Electronic address: [email protected].
  • 5 Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China. Electronic address: [email protected].
PMID: 41881250 DOI: 10.1016/j.jare.2026.03.052
Abstract

Introduction: Intracerebral hemorrhage (ICH) is a highly debilitating brain condition due to the limited availability of treatment options. MyD88 inhibitory peptide-2 (MIP2) is a broad-range TLR-targeting peptide. It provides neuroprotection by regulating neuroinflammatory and oxidative-stress responses. However, the underlying mechanisms by which MIP2 contributes to neuroinflammation remain unclear.

Objectives: To investigate the underlying neuroprotective, anti-inflammatory, and anti-oxidative stress-related therapeutic potential of MIP2 against secondary brain injury induced by ICH.

Methods: ICH was induced by injecting collagenase into the striatum. MIP2 was administered at 0, 1, and 3 days post-ICH for subsequent behavioral and molecular analyses. Neurobehavioral function was evaluated using the focal neurological deficit score and corner test and the on days 1, 3, and 7 after ICH. Hematoma volume was measured by HE staining. Apoptosis was assessed by TUNEL staining and Evans blue assay. Tight junction proteins, MMP9, and vWF expression were investigated to assess blood-brain barrier (BBB) permeability after MIP2 treatment. To elucidate the molecular mechanism of MIP2-mediated neuroprotection, markers of neuroinflammation, glial activation, neutrophil recruitment, and oxidative stress were quantified on day 3 post-ICH using western blot, immunohistochemistry, and immunofluorescence analyses.

Results: The MIP2 treatment improved neurological function, reduced hematoma volume, and enhanced BBB integrity by upregulating tight junction proteins (ZO-1, Claudin-5, and Occludin) and lowering the expression of MMP9. MIP2 reduced neuroinflammation by suppressing glial cell activation, neutrophil infiltration, and inflammatory mediators (HO-1, MyD88, NF-κB, TLR4, and IL-1β). Moreover, MyD88 inhibitory peptide-2 increased the expression of anti-oxidative stress markers (GPX4, AIFM2, and Nrf2), likely through modulation of the MyD88-mediated signaling pathway.

Conclusion: These findings suggest that MyD88 inhibitory peptide-2 confers neuroprotection against secondary brain injury following ICH. This therapeutic strategy preserves blood-brain barrier integrity, suppresses Apoptosis, and attenuates neuroinflammation by suppressing glial activation, neutrophil infiltration, and pro-inflammatory mediators, while enhancing antioxidative defense post-ICH-mediated brain damage.

Keywords

Intracerebral hemorrhage; Molecular regulations; MyD88 inhibitory peptide-2 (MIP2); Neuroinflammation; Secondary brain injury.

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