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. 2025 Jul 2;33(7):3177-3194.
doi: 10.1016/j.ymthe.2025.03.002. Epub 2025 Mar 8.

Pro-inflammatory microglia-targeted peptide therapy ameliorates neonatal hypoxic-ischemic encephalopathy in mice

Rika Zen  1 , Shunichiro Tsuji  2 , Tomoko Maeda  1 , Makoto Urushitani  3 , Takashi Murakami  1 , Tomoya Terashima  4
Affiliations

Pro-inflammatory microglia-targeted peptide therapy ameliorates neonatal hypoxic-ischemic encephalopathy in mice

Rika Zen et al. Mol Ther. .

Abstract

Neonatal hypoxic-ischemic encephalopathy is aggravated by intracerebral inflammation. As pro-inflammatory microglia in the brain become activated in this condition, we aimed to establish a novel peptide therapy for neonatal hypoxic-ischemic encephalopathy by investigating the therapeutic effects of pro-inflammatory microglial depletion. MG1 homing peptide, which selectively targets and binds pro-inflammatory microglia, was conjugated with the pro-apoptotic peptide D[KLAKLAK]2 (KLA), creating MG1-KLA. After confirming that MG1-KLA selectively bound pro-inflammatory microglia and decreased cell viability by inducing apoptosis in a dose-dependent manner, the in vivo therapeutic effect of MG1-KLA was assessed following intracerebroventricular injection in hypoxic-ischemic encephalopathy model mice through histological, behavioral, and biochemical analyses. In these mice, MG1-KLA selectively bound to microglia and induced their apoptosis. Brain atrophy was significantly suppressed in the mice treated with MG1-KLA compared with non-treated mice. Additionally, motor function and locomotor hyperactivity were improved in mice treated with MG1-KLA compared with non-treated mice. Gene expression analysis further revealed that pro-inflammatory cytokine expression was downregulated in mice treated with MG1-KLA compared with non-treated mice. These findings suggest that novel MG1-KLA peptide therapy has high potential for treating neonatal patients with hypoxic-ischemic encephalopathy through the selective induction of apoptosis in pro-inflammatory microglia.

Keywords: MG1-KLA; apoptosis; neonatal hypoxic-ischemic encephalopathy; peptide therapy; pro-inflammatory microglia.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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