Meldonium, as a potential neuroprotective agent, promotes neuronal survival by protecting mitochondria in cerebral ischemia-reperfusion injury

被引:3
作者
Yang, Weijie [1 ]
Lei, Xiuxing [2 ]
Liu, Fengying [1 ]
Sui, Xin [1 ]
Yang, Yi [1 ]
Xiao, Zhenyu [1 ]
Cui, Ziqi [1 ]
Sun, Yangyang [1 ]
Yang, Jun [1 ]
Yang, Xinyi [1 ]
Lin, Xueyang [1 ]
Bao, Zhenghao [1 ]
Li, Weidong [1 ]
Ma, Yingkai [1 ]
Wang, Yongan [1 ]
Luo, Yuan [1 ]
机构
[1] Beijing Inst Pharmacol & Toxicol, State Key Lab Toxicol & Med Countermeasures, Beijing, Peoples R China
[2] LuAn Hosp Tradit Chinese Med, Hefei, Anhui, Peoples R China
基金
中国国家自然科学基金;
关键词
Meldonium; Cerebral ischemia-reperfusion injury; Neurons; Mitochondria; PERMEABILITY TRANSITION PORE; MILDRONATE TREATMENT; GAMMA-BUTYROBETAINE; PROTEIN EXPRESSION; OXIDATIVE STRESS; ARTERY OCCLUSION; DOUBLE-BLIND; STROKE; BRAIN; CARNITINE;
D O I
10.1186/s12967-024-05222-7
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
BackgroundStroke is a globally dangerous disease capable of causing irreversible neuronal damage with limited therapeutic options. Meldonium, an inhibitor of carnitine-dependent metabolism, is considered an anti-ischemic drug. However, the mechanisms through which meldonium improves ischemic injury and its potential to protect neurons remain largely unknown.MethodsA rat model with middle cerebral artery occlusion (MCAO) was used to investigate meldonium's neuroprotective efficacy in vivo. Infarct volume, neurological deficit score, histopathology, neuronal apoptosis, motor function, morphological alteration and antioxidant capacity were explored via 2,3,5-Triphenyltetrazolium chloride staining, Longa scoring method, hematoxylin and eosin staining, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay, rotarod test, transmission electron microscopy and Oxidative stress index related kit. A primary rat hippocampal neuron model subjected to oxygen-glucose deprivation reperfusion was used to study meldonium's protective ability in vitro. Neuronal viability, mitochondrial membrane potential, mitochondrial morphology, respiratory function, ATP production, and its potential mechanism were assayed by MTT cell proliferation and cytotoxicity assay kit, cell-permeant MitoTracker (R) probes, mitochondrial stress, real-time ATP rate and western blotting.ResultsMeldonium markedly reduced the infarct size, improved neurological function and motor ability, and inhibited neuronal apoptosis in vivo. Meldonium enhanced the morphology, antioxidant capacity, and ATP production of mitochondria and inhibited the opening of the mitochondrial permeability transition pore in the cerebral cortex and hippocampus during cerebral ischemia-reperfusion injury (CIRI) in rats. Additionally, meldonium improved the damaged fusion process and respiratory function of neuronal mitochondria in vitro. Further investigation revealed that meldonium activated the Akt/GSK-3 beta signaling pathway to inhibit mitochondria-dependent neuronal apoptosis.ConclusionOur study demonstrated that meldonium shows a neuroprotective function during CIRI by preserving the mitochondrial function, thus prevented neurons from apoptosis.
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页数:19
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