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Endocrinology Vol. 144, No. 7 2757-2760
Copyright © 2003 by The Endocrine Society

Coenzyme Q Induces Nigral Mitochondrial Uncoupling and Prevents Dopamine Cell Loss in a Primate Model of Parkinson’s Disease

Tamas L. Horvath, Sabrina Diano, Csaba Leranth, Luis Miguel Garcia-Segura, Michael A. Cowley, Marya Shanabrough, John D. Elsworth, Peter Sotonyi, Robert H. Roth, Edwin H. Dietrich, Russel T. Matthews, Colin J. Barnstable and D. Eugene Redmond, Jr.

Departments of Obstetrics and Gynecology (T.L.H., S.D., C.L., M.S., P.S.), Neurobiology (T.L.H., C.L., R.T.M., C.J.B.), Pharmacology (J.D.E., R.H.R.), Ophthalmology-Visual Science (C.J.B.), Psychiatry (D.E.R.), and Neurosurgery (D.E.R.), Yale University School of Medicine, New Haven, Connecticut 06520; Instituto Cajal (L.M.G.-S.), Consejo Superior de Investigaciones Cientificas, Madrid, Spain 28002; The Vollume Institute (M.A.C.), Oregon Health & Science University, Portland, Oregon 97006; Department of Anatomy and Histology (T.L.H., P.S.), Szent Istvan University, Faculty of Veterinary Sciences, Budapest 1078, Hungary; and The St. Kitts Biomedical Research Foundation (E.H.D., D.E.R.), St. Kitts-Nevis, West Indies

Address all correspondence and requests for reprints to: Tamas L. Horvath, Department of Obstetrics/Gynecology, Yale Medical School, 333 Cedar Street, FMB 339, New Haven, Connecticut 06520. E-mail: tamas.horvath{at}yale.edu


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Parkinson’s disease is characterized by dopamine cell loss of the substantia nigra. Parkinson’s disease and the neurotoxin 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine may destroy dopamine neurons through oxidative stress. Coenzyme Q is a cofactor of mitochondrial uncoupling proteins that enhances state-4 respiration and eliminate superoxides. Here we report that short-term oral administration of coenzyme Q induces nigral mitochondrial uncoupling and prevents dopamine cell loss after 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine administration in monkeys.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
PARKINSON'S DISEASE (PD) affects millions of people. Even in the early stages of the disorder, before emergence of devastating motor symptoms, due to the declining dopamine system, patients may be affected by decreased motivational aspects of key homeostatic mechanisms, including food intake (1). PD is most likely to be diagnosed by the emergence of motor impairments. Thus, it is not unreasonable to suggest that even if protective measures may be successful in slowing down the motor decline, other aspects of daily life, for example appropriate regulation of daily energy balance, may have already been damaged to an extent sufficient to limit the potential of recovery. Thus, enhancement of neuronal mechanisms that not only slow or diminish neurodegeneration related to the substantia nigra (SN) but also boost processes affecting homeostatic regulation may be useful for the treatment of PD.

Mirochondrial uncoupling proteins (UCP) are protonophores that are mainly associated with peripheral energy expenditure (2, 3, 4, 5, 6, 7). The first member of these mitochondrial inner membrane proteins, UCP1, plays a well-described role in thermogenesis by the brown adipose tissue (2, 8). To date, only two other members of the family, UCP2 and UCP3, have been shown to have uncoupling activity (9). These have different tissue distributions with UCP2 expressed in a number of different brain structures (10, 11, 12). Beyond their role in regulating mitochondrial inner membrane potential, ATP levels, and local thermogenesis, these three UCPs, including UCP2, are free radical scavengers (13, 14). UCP2 is induced by neuronal stress, and it suppresses apoptotic signaling (15); coenzyme Q (CoQ10), a molecule previously found beneficial in a rodent model of PD (16), activates UCP2 (17, 18), and activation of UCP2 supports a positive energy balance (19) that is the exact opposite observed in the initial phase of PD (1). Together, these observations suggest that this mitochondrial mechanism activated by CoQ10 would not only slow or diminish neurodegeneration related to the SN dopamine cells but could also boost processes affecting energy balance. To test this hypothesis, we assessed the effect of short-term oral CoQ10 treatment on brain mitochondrial uncoupling activity in primates. Furthermore, we analyzed UCP2 expression in the SN and evaluated the effect of short-term oral CoQ10 on dopamine cell loss in monkeys treated with 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine (MPTP).


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
We studied 24 age-matched, male African green monkeys (Cercopithecus aethiops sabeus) in the St. Kitts Biomedical Research Foundation. There were four groups of animals (intact control, CoQ10-treated, MPTP-treated, and MPTP + CoQ-treated animals) each containing six monkeys (n = 6).

All experimental procedures were approved by Institutional Animal Care and Use Committees of Yale University and/or the St. Kitts Biomedical Research Foundation.

CoQ10 and MPTP treatment of nonhuman primates
Animals were fed 100 mg CoQ10 (Natrol, Inc., Chatsworth, CA) per day spread on the longitudinally cut (then reattached) surface of a banana. This resulted in doses ranging from 15–22 mg/kg·d per animal. Control animals received banana only. Ten days later, a group of six CoQ10-treated and six nontreated animals received MPTP, with cumulative doses of 1.5 mg/kg MPTP/animals. Tissues were collected and processed 20 d later.

Analysis of UCP2 mRNA
Real time RT-PCR analyses was used to assess UCP2 mRNA levels in the substantia nigra of control and experimental animals. Total RNA was extracted and cDNA prepared as previously described by Horvath and colleagues (11, 15, 19, 20). Primers to amplify UCP2 were forward 5'-CTACAAGACCATTGCACGAGAGG-3' and reverse 5'-AGCTGCTCATAGGTGACAAACAT-3' and gave a 396-bp product. A 603-bp fragment of ß-actin was amplified as control. The PCR was performed as previously described by Horvath and colleagues (11, 15, 19, 20). Reactions were analyzed by gel electrophoresis, and identity of bands was confirmed by sequencing of selected samples.

Detection of UCP2 in the SN of nonhuman primates
Mesencephalic sections of monkeys were double immunostained for UCP2 and tyrosine hydroxylase using different fluorescent dyes as described elsewhere by Horvath et al. (11).

Analysis of uncoupling activity
To test the level of mitochondrial uncoupling, oxygen consumption in state-3 and state-4 respiration and respiratory control ratio (RCR: the ratio of these levels) were assessed from SN homogenates of primates as described elsewhere by Horvath and colleagues (11, 15, 19, 20). In short, dissected SN was homogenized in a medium containing 320 mM sucrose, 10 mM Tris, and 1 mM EGTA adjusted to pH 7.4 with HCl. The samples were diluted 10 times with isolation medium. The pellet was gently resuspended and stored on ice. Mitochondrial oxygen consumption was determined using a Clark-type oxygen electrode in an incubation medium containing 80 mM KCl, 50 mM HEPES (pH 7), 1 mM EGTA, 5 mM K2HPO4, 4 µM rotenone, 80 ng/ml nigericine, and 1 µg/ml oligomycin using a saturating amount of succinate as substrate at 37 C. State-3 respiration was initiated by the addition of ADP (300 µM) and subsequently state-4 and -3 respiration and RCR were assessed.

Histological analyses
We analyzed dopamine cell numbers in the SN of control and experimental monkeys using unbiased stereology. The unbiased stereological methods for cell number assessment used a systematic random sampling method and met the statistical requirements necessary to ensure an unbiased estimate of the feature of interest. We chose to sample every 10th section (30 µm thick) to assess cell number; the starting point of the series for each animal was randomly selected from the first 10 sections. Because an F test analysis of cell counts in different experimental and control groups revealed a significant nonhomogeneity of variances between groups, the Kruskal-Wallis one-way nonparametric ANOVA test was selected for statistical comparisons. A level of confidence of P < 0.05 was adopted.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
UCP2 in the monkey SN
In monkeys (male Cercopithecus aethiops sabaeus), we detected UCP2 mRNA in the SN (Fig. 1AGo) and revealed that UCP2 was expressed in SN dopamine cells (Fig. 1BGo).



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  		Figure 1. A, RT-PCR analyses showed the expression of UCP2 mRNA in the SN of intact control (C) and CoQ10-treated (CoQ) monkeys. M, Molecular weight. B, Immunolabeling for tyrosine hydroxylase (TH) and UCP2 revealed coexpression of these substances in neurons of the SN. UCP2 expression provides the potential for CoQ10 to induce mitochondrial uncoupling in the SN. C, Measurement of state-3 and -4 mitochondrial respiration (5 ) showed elevation of oxygen consumption in state-3 respiration (graph on the left) of the SN (a, P < 0.01). We also detected elevation of state-4 respiration (increased mitochondrial uncoupling activity; middle graph; b, P < 0.01) and, thus, no elevation of the RCR was present in the SN. D, Photomicrographs showing TH-immunolabeled dopamine cells in the SN of control (intact, left panel; CoQ10, panel second to the left) and experimental animals (MPTP, panel second to the right; CoQ10 + MPTP, right panel). MPTP induced a large significant decline in the number of dopamine cells that was prevented by CoQ10. Scale bar, 50 µm. E, Bar graphs illustrating dopamine cell counts in control, CoQ-treated, MPTP-treated, and CoQ + MPTP-treated monkeys. *, Value significantly (P < 0.05) different from control.

 
In support of CoQ10’s role as a cofactor of UCPs, quantitative RT-PCR analyses revealed no differences in the amounts of UCP2 mRNA between control and CoQ10 animals.

State-3 and -4 respirations and RCR in control and CoQ10-treated monkeys
To assess whether short-term (30 d) oral CoQ10 affects the brain, we analyzed state-3 and -4 respirations and RCR = state-3/state-4 in the SN of control (n = 6) and CoQ10-treated monkeys. Oxygen consumption in state-3 respiration (phosphorylation) was elevated in CoQ10-treated animals (Fig. 1CGo). However, RCR values of CoQ10-treated SN did not change because state-4 respiration (oxygen consumption related to mitochondrial proton leak regulated by UCP2) was also enhanced (Fig. 1CGo).

Nigral dopamine cell counts in control, CoQ10-, MPTP-, and CoQ10 + MPTP-treated monkeys
We analyzed dopamine cell numbers in the SN of control and experimental monkeys using unbiased stereology. We found that in intact and CoQ10-treated animals, the numbers of SN dopamine cells/mm3 were 7480.33 ± 1492.04 SEM and 6734.5 ± 951.41 SEM, respectively. MPTP treatment induced a 70% loss of dopamine cells in the SN (1958.8 ± 140.97 cells/mm3; P < 0.01). Pretreatment of MPTP monkeys with CoQ10 resulted in dopamine cell counts (5891.66 ± 621.57) statistically not different from intact and CoQ10 values (Fig. 1Go, D and E).


   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our results demonstrated that oral administration of CoQ10 alters nigral metabolism by increasing both state-3 and -4 respiration. This altered metabolism was associated with a significantly diminished toxicity of MPTP on the nigrostriatal dopamine system. Nigral dopamine cell counts in MPTP-treated monkeys that received CoQ10 were significantly higher than those found in monkeys subjected to MPTP treatment alone. In fact, the dopamine cell number of CoQ10/MPTP-treated animals was statistically indistinguishable from the values of intact and CoQ10-treated controls.

State-4 respiration is enhanced by oral CoQ10, most likely due to the activation of UCP2, which was found to be constitutively expressed in the SN dopamine cells in nonhuman primates. In fact, a controlled reduction of mitochondrial membrane potential (i.e. increased state-4 respiration) by UCP2 has been shown to be neuroprotective and has been proposed to be a self-defense mechanism that may be up-regulated in some neurodegenerative disorders (15). However, the mechanism responsible for the beneficial effects of oral CoQ10 in PD may be the consequence of the enhancement of other mitochondrial mechanisms as well.

To date, only limited information is available on the regulation of UCP2 mRNA expression and translation, and the function of the protein in the brain. UCP2 activity as a protonophore, similar to UCP1, requires fatty acids and is nucleotide dependent (3, 9, 17, 18, 21, 22). There are in vitro and in vivo data available on peripheral UCP2 expression that show varying levels of regulation of UCP2 by different hormones, including leptin and thyroid hormone (23, 24, 25). It appears, however, that the regulation of UCP2 by these hormones is tissue specific and most likely involves indirect mechanisms of action. Other biologically active substances were also shown to affect transcription, translation, and/or activity of UCP2. These include retinoic acid (26, 27), lipopolysaccharides (28), superoxides (9, 21, 22), and CoQ10 (17, 18). In particular, after the revelations that superoxides regulate UCP2 transcriptionally and postranslationally (21), Klingenberg and his colleagues (17, 18) showed that the functionality of UCP2 as a mitochondrial uncoupler requires CoQ10 as mandatory cofactor.

CoQ10 has been shown to reduce the effects of MPTP on striatal dopamine concentrations in mice but is unable to protect SN dopamine neurons from cell death (16). Our observations of a robust effect of CoQ10 in the protection of SN dopamine neurons in primates demonstrate the importance of species differences in the PD models and suggest that the potent effects of CoQ10 may result from activation of UCP2. Because CoQ10 was shown to be safe and well tolerated in humans (29, 30), and to slow the progression of symptom development in PD patients (31), our data implicating UCPs in this process offer an alternative mechanism of action of oral CoQ10 in neuroprotection. Furthermore, these observations highlight the potential that other substances and metabolic and endocrine conditions that favor mitochondrial uncoupling may exhibit neuroprotective properties that will be useful in slowing the progression of PD.


   Footnotes
 
This work was supported by NIH Grants RR-14451 and NS-41725 (to T.L.H.). T.L.H. was an Albert Szent-Gyorgyi Fellow.

Abbreviations: CoQ10, Coenzyme Q; MPTP, 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine; PD, Parkinson’s disease; RCR, respiratory control ratio; SN, substantia nigra; UCP, uncoupling proteins.

Received February 3, 2003.

Accepted for publication March 13, 2003.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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