2. Academic Validation
  3. Melatonin regulates the MST1/Nrf2 pathway to alleviate oxidative stress injury after hypoxic-ischemic brain damage in neonatal rats

Melatonin regulates the MST1/Nrf2 pathway to alleviate oxidative stress injury after hypoxic-ischemic brain damage in neonatal rats

  • Neurol Res. 2025 Nov 28:1-14. doi: 10.1080/01616412.2025.2591278.
Yuexia Zhang 1 2,  Wenliang Gao 1 2,  Xiaoqing Jing 1 2,  Wei Shang 1 2,  Xiaoli Wang 3,  Shuna Yu 1 2
Affiliations

Affiliations

  • 1 Department of Anatomy, School of Basic Medical Sciences, Shandong Second Medical University, Weifang, Shandong, China.
  • 2 Neurologic Disorders and Regenerative Repair Lab of Shandong Higher Education, Shandong Second Medical University, Weifang, Shandong, China.
  • 3 School of Medical Imaging, Shandong Second Medical University, Weifang, Shandong, China.
PMID: 41312691 DOI: 10.1080/01616412.2025.2591278
Abstract

Objective: Oxidative stress is a key factor in neonatal hypoxic-ischemic encephalopathy (HIE). Despite the widespread attention on melatonin (Mel) as a potential therapeutic agent, its antioxidative mechanisms in HIE remain incompletely understood. This study seeks to determine the neuroprotective action of Mel on HIE and elucidate the underlying molecular mechanisms.

Methods: The rat hypoxic-ischemic brain damage (HIBD) model and the neuronal cell oxygen-glucose deprivation (OGD) model were constructed. The extent of brain damage was assessed 24 hours after modeling using hematoxylin-eosin staining and Nissl staining. Immunofluorescence staining and Western blotting were used to analyze the expression levels of mammalian STE20-like kinase1 (MST1), nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) proteins. SOD activity, MDA content and ROS levels were measured using colorimetric methods and fluorescent probe DCFH-DA.

Results: In vivo, Mel treatment not only significantly reduced HIBD-induced cortical injury in rats but also inhibited the activation of MST1 while simultaneously promoting the activation of Nrf2. Further in vitro, Mel could alleviate oxidative stress-induced neuronal damage, which was blocked by the Nrf2 inhibitor ML385, indicating its action is dependent on the Nrf2 pathway. Additionally, the specific MST1 inhibitor XMU-MP-1 demonstrated neuroprotective effects similar to those of Mel in both in vivo and in vitro models, with mechanisms related to enhanced activation of Nrf2.

Conclusions: Melatonin protects against HIBD by reducing oxidative stress via MST1 inhibition and subsequent Nrf2/HO-1 pathway activation. The MST1-Nrf2 axis is a key mechanism, offering new insights and a potential therapeutic target for neonatal HIE.

Keywords

Melatonin; heme oxygenase 1; hypoxic-ischemic brain damage; mammalian STE20-like kinase1; nuclear factor erythroid 2-related factor 2; oxidative stress.

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