2. Academic Validation
  3. Melatonin attenuates brain edema via the PI3K/Akt/Nrf2 pathway in rats with cerebral ischemia-reperfusion injury

Melatonin attenuates brain edema via the PI3K/Akt/Nrf2 pathway in rats with cerebral ischemia-reperfusion injury

  • J Stroke Cerebrovasc Dis. 2025 Jun;34(6):108299. doi: 10.1016/j.jstrokecerebrovasdis.2025.108299.
Yang Liu 1,  Xin Wang 1,  Zhen Li 1,  Xiaotian Gao 2,  Xiaoli Wu 3,  Jiayang Pi 1,  Xizhen Wang 4,  Qi Wang 3,  Fenghua Zhou 5,  Xiaoli Wang 6
Affiliations

Affiliations

  • 1 School of Medical Imaging, Shandong Second Medical University, Weifang, 261053, China; Medical Imaging Center, Affiliated Hospital of Shandong Second Medical University, Weifang, 261031, China.
  • 2 School of Medical Imaging, Shandong Second Medical University, Weifang, 261053, China.
  • 3 Department of Radiology, Weifang People's Hospital, Weifang 261041, China.
  • 4 Medical Imaging Center, Affiliated Hospital of Shandong Second Medical University, Weifang, 261031, China.
  • 5 Department of Pathology, School of Basic Medicine, Shandong Second Medical University, Weifang 261053, China.
  • 6 School of Medical Imaging, Shandong Second Medical University, Weifang, 261053, China; Medical Imaging Center, Affiliated Hospital of Shandong Second Medical University, Weifang, 261031, China. Electronic address: wxlpine@163.com.
PMID: 40158783 DOI: 10.1016/j.jstrokecerebrovasdis.2025.108299
Abstract

Objective: This study aimed to explore the neuroprotective effects of Melatonin (Mel) administration on cerebral ischemia-reperfusion injury (CIRI) and elucidate its underlying mechanism in vivo to provide a theoretical foundation for the clinical application of Mel.

Materials and methods: CIRI models were established in male adult Sprague Dawley rats by middle cerebral artery occlusion (MCAO) for 2 h. Water content of brain tissue was assessed using both dry/wet weight method and T2-weighted Imaging (T2WI). The infarct volume of the brain was measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Cell morphology changes and brain damage were detected through hematoxylin & eosin (H&E) staining and NeuN immunofluorescence staining. The integrity of blood-brain barrier (BBB) was examined using transmission electron microscopy (TEM). The expression of Aquaporin 4 (AQP4) protein was quantified through western blots analysis and immunofluorescence staining. The expression of p-PI3K, p-AKT and Nrf2 proteins were detected by immunohistochemistry staining and western blots analysis.

Results: Compared with the CIRI group, Mel administration significantly reduced the infarct volume and ameliorated the morphology alterations, accompanied by an increase in the number of neurons. The water content of brain tissue decreased significantly, and the value of relative average diffusion coefficient (rADC) of injured brain increased in the CIRI + Mel group as compared with the CIRI group. Compared with the CIRI group, Mel administration improved the damage to the tight junctions of endothelial cells in the cerebral cortex. The expression of AQP4 protein decreased, and that of p-PI3K, p-AKT and Nrf2 proteins increased in the CIRI + Mel group compared with the CIRI group. After administration of p-PI3K inhibitor LY294002, the expression of AQP4 was upregulated, and that of the p-PI3K, p-AKT and Nrf2 proteins decreased compared with the CIRI + Mel group.

Conclusions: Mel administration exerts neuroprotective effects against CIRI by mitigating brain edema through upregulating the PI3K/Akt/Nrf2 signaling pathway, and then attenuating brain damage in CIRI rats.

Keywords

Aquaporin 4; Cerebral ischemia-reperfusion injury; Cytotoxic edema; Magnetic resonance imaging; Melatonin; Rat.

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