2. Academic Validation
  3. L-DOPA ameliorates hippocampus-based mitochondria respiratory dysfunction caused by GCI/R injury

L-DOPA ameliorates hippocampus-based mitochondria respiratory dysfunction caused by GCI/R injury

  • Biomed Pharmacother. 2024 Apr 27:175:116664. doi: 10.1016/j.biopha.2024.116664.
Wenzhu Wang 1,  Jingyu Zhao 2,  Zihan Li 3,  Xiaoyu Kang 4,  Ting Li 3,  Nickolay K Isaev 5,  Elena A Smirnova 6,  Hui Shen 7,  Lixu Liu 8,  Yan Yu 9
Affiliations

Affiliations

  • 1 China Rehabilitation Science Institute, China Rehabilitation Research Center, Beijing, PR China; Wenzhou Medical University, Wenzhou, PR China; Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, PR China.
  • 2 School of Biomedical Engineering and Technology, Tianjin Medical University, Tianjin, PR China.
  • 3 China Rehabilitation Science Institute, China Rehabilitation Research Center, Beijing, PR China; Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, PR China.
  • 4 China Rehabilitation Science Institute, China Rehabilitation Research Center, Beijing, PR China.
  • 5 Biological Faculty, M.V. Lomonosov Moscow State University, Moscow, Russia; Research Center of Neurology, Moscow, Russia.
  • 6 Biological Faculty, M.V. Lomonosov Moscow State University, Moscow, Russia; Department of Biology, MSU-BIT University, Shenzhen, PR China.
  • 7 Dept of Cellular Biology, School of Basic Medical Science, Tianjin Medical University, Tianjin, PR China. Electronic address: shenhui@tmu.edu.cn.
  • 8 China Rehabilitation Science Institute, China Rehabilitation Research Center, Beijing, PR China; School of Rehabilitation Medicine, Capital Medical University, Beijing, PR China. Electronic address: liulixu_crrc@163.com.
  • 9 China Rehabilitation Science Institute, China Rehabilitation Research Center, Beijing, PR China; Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, PR China; Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, PR China; School of Rehabilitation Medicine, Capital Medical University, Beijing, PR China. Electronic address: yuyancrrc@163.com.
PMID: 38678966 DOI: 10.1016/j.biopha.2024.116664
Abstract

Mitochondrial dysmorphology/dysfunction follow global cerebral ischemia-reperfusion (GCI/R) injury, leading to neuronal death. Our previous researches demonstrated that Levodopa (L-DOPA) improves learning and memory impairment in GCI/R rats by increasing synaptic plasticity of hippocampal neurons. This study investigates if L-DOPA, used in Parkinson's disease treatment, alleviates GCI/R-induced cell death by enhancing mitochondrial quality. Metabolomics and transcriptomic results showed that GCI/R damage affected the Tricarboxylic acid (TCA) cycle in the hippocampus. The results of this study show that L-DOPA stabilized mitochondrial membrane potential and ultrastructure in hippocampus of GCI/R rats, increased dopamine level in hippocampus, decreased succinic acid level, and stabilized CA2+ level in CA1 subregion of hippocampus. As a precursor of dopamine, L-DOPA is presumed to improves mitochondrial function in hippocampus of GCI/R rats. However, dopamine cannot cross the blood-brain barrier, so L-DOPA is used in clinical therapy to supplement dopamine. In this investigation, OGD/R models were established in isolated mouse hippocampal neurons (HT22) and primary rat hippocampal neurons. Notably, dopamine exhibited a multifaceted impact, demonstrating inhibition of mitochondrial Reactive Oxygen Species (mitoROS) production, stabilization of mitochondrial membrane potential and CA2+ level, facilitation of TCA circulation, promotion of aerobic respiratory metabolism, and downregulation of succinic acid-related gene expression. Consistency between in vitro and in vivo results underscores dopamine's significant neuroprotective role in mitigating mitochondrial dysfunction following global cerebral hypoxia and ischemia injury. Supplement dopamine may represent a promising therapy to the cognitive impairment caused by GCI/R injury.

Keywords

Dopamine; GCI/R; Hippocampus; L-DOPA; Mitochondria; Respiratory metabolism.

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