Dopamine Therapy and the Regulation of Oxidative Stress and Mitochondrial DNA Copy Number in Patients with Parkinson's Disease.

Shih-Hsuan Chen,Chung-Wen Kuo,Tsu-Kung Lin,Meng-Han Tsai,Chia-Wei Liou

doi:10.3390/antiox9111159

Abstract

Few studies have reported on changes to oxidative stress and mitochondrial DNA copy numbers in patients with Parkinson’s disease (PD), particularly those undergoing long-term dopamine therapy. This study measured mitochondrial copy numbers, thiobarbituric acid reactive substances (TBARS), and thiols in 725 PD patients and 744 controls. The total prescribed dopamine dose was calculated for each PD patient. A decreased mitochondrial copy number and antioxidant thiols level, but an elevated oxidative TBARS level presented in PD patients. Stratification into age subgroups revealed a consistently lower mitochondrial copy number and thiols in all PD subgroups, but increased TBARS levels compared with those of the controls. Further study found an association between lower serum TBARS and dopamine administration. There appears to be an indirect relationship with the mitochondrial copy number, where a decrease in TBARS was found to diminish the effect of pathogenetic and age-related decrease in mitochondrial copy number in PD patients. Follow-up evaluations noted more significant decreases of mitochondrial copy numbers in PD patients over time; meanwhile, dopamine administration was associated with an initial decrease of the TBARS level which attenuated with high-dose and long-term therapy. Our study provides evidence that moderate dopamine dose therapy benefits PD patients through attenuation of oxidative stress and manipulation of the mitochondrial copy number.

Highlights

Mitochondrial dysfunctions and their consequent generation of oxidative stress have been identified as significant causes of neuronal cell damage, leading to the development of neurodegenerative disease, including sporadic Parkinson’s disease (PD) [1]
The unraveling of the mechanisms regulating to mitochondrial biogenesis have enhanced our understanding of how, through increasing replication and transcription of mitochondrial DNA, cells exert themselves to overcome environmental challenges and maintain cellular life [17]
We identified a significantly lower mitochondrial DNA (mtDNA) copy number in the peripheral blood cells of PD patients in comparison with the non-PD

Summary

Introduction

Mitochondrial dysfunctions and their consequent generation of oxidative stress have been identified as significant causes of neuronal cell damage, leading to the development of neurodegenerative disease, including sporadic Parkinson’s disease (PD) [1]. The dopaminergic neurons located within the substantia nigra of the mid-brain are direct targets of the free radical by-products created during the process of energy production, and the by-products of dopamine metabolism [2,3]. To overcome insufficient cellular energy supply due to this dysfunction, the process of mitochondrial biogenesis is triggered [6]. This process increases the mtDNA copy number and translated respiratory enzymes to sustain normal mitochondrial function in cells. Failure to increase mitochondrial respiration may render an insufficient energy supply for overcoming cellular stress, eventually leading to the development of disease. A serial cascade scenario, involving oxidative stress, mtDNA damage, and mtDNA copy number change, plausibly takes place in cells during the progress of PD. We report the results of our investigation into the baseline and long-term changes of oxidative stress and the mtDNA copy number, and the probable effects of continuous dopamine therapy on these biomarkers in PD patients

Methods

Results

Conclusion