Menaquinone-4 alleviates hypoxic-ischemic brain damage in neonatal rats by reducing mitochondrial dysfunction via Sirt1-PGC-1α-TFAM signaling pathway

  • Int Immunopharmacol. 2024 Jun 15:134:112257. doi: 10.1016/j.intimp.2024.112257.
Xiaoli Feng  1 ,  Yihui Zheng  1 ,  Niping Mao  1 ,  Ming Shen  1 ,  Liuxi Chu  2 ,  Yu Fang  1 ,  Mengdan Pang  1 ,  Zhouguang Wang  3 ,  Zhenlang Lin  4
Affiliations
  • 1. Department of Neonatology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Perinatal Medicine of Wenzhou, Wenzhou, Zhejiang 325027, China.
  • 2. National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Affiliated Cixi Hospital, Wenzhou Medical University, Cixi, Zhejiang 315300, China.
  • 3. National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: [email protected].
  • 4. Department of Neonatology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Perinatal Medicine of Wenzhou, Wenzhou, Zhejiang 325027, China; Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou, Zhejiang 325027, China. Electronic address: [email protected].
PMID: 38759366 DOI: 10.1016/j.intimp.2024.112257
Abstract

Background: Hypoxic-ischemic encephalopathy (HIE) is a major contributor to neonatal mortality and neurodevelopmental disorders, but currently there is no effective therapy drug for HIE. Mitochondrial dysfunction plays a pivotal role in hypoxic-ischemic brain damage(HIBD). Menaquinone-4 (MK-4), a subtype of vitamin K2 prevalent in the brain, has been shown to enhance mitochondrial function and exhibit protective effects against ischemia-reperfusion injury. However, the impact and underlying molecular mechanism of MK-4 in HIE have not been fully elucidated.

Methods: In this study, we established the neonatal rats HIBD model in vivo and oxygen-glucose deprivation and reperfusion (OGD/R) of primary neurons in vitro to explore the neuroprotective effects of MK-4 on HI damage, and illuminate the potential mechanism.

Results: Our findings revealed that MK-4 ameliorated mitochondrial dysfunction, reduced oxidative stress, and prevented HI-induced neuronal Apoptosis by activating the Sirt1-PGC-1α-TFAM signaling pathway through SIRT1 mediation. Importantly, these protective effects were partially reversed by EX-527, a SIRT1 Inhibitor.

Conclusion: Our study elucidated the potential therapeutic mechanism of MK-4 in neonatal HIE, suggesting its viability as an agent for enhancing recovery from HI-induced cerebral damage in newborns. Further exploration into MK-4 could lead to novel interventions for HIE therapy.

Keywords
Hypoxic-ischemic encephalopathy; Menaquinone-4; Mitochondrial dysfunction; Sirt1.
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