Mitochondrial Defects Play Role in Parkinson’s Disease
Abstract & Commentary
Source: Shults CW, et al. Effects of coenzyme Q10 in early Parkinson disease. Arch Neurol. 2002;59:1541-1550.
There is substantial evidence that mitochondrial defects and oxidative damage play a role in the pathogenesis of Parkinson’s disease (PD). For instance, decreased complex-I activity has been found in the substantia nigra, platelets, and muscle of PD patients. There is substantial evidence showing that there is increased oxidative damage in PD substantia nigra. The present report, on which I am author, is the first clinical trial to examine whether administration of coenzyme Q10 can slow the functional decline of PD. Coenzyme Q10 is an essential component of the electron transport chain. It is the electron acceptor for complexes I and II and is also a potent anti-oxidant.
The present clinical trial was carried out by the Parkinson Study Group. Clifford Shults at the University of California in San Diego was the principal investigator. The trial enrolled 80 patients who were randomly assigned to placebo or coenzyme Q10 at doses of 300, 600, or 1200 mg/d. The primary outcome measure was the Unified Parkinson’s Disease Rating Scale (UPDRS), which was administered at screening, baseline, and 1, 4, 8, 12, and 16 months. The subjects were patients with early PD who did not require treatment (levodopa) for their disability. They were followed up for 16 months or until disability requiring treatment with levodopa had developed. Only 1 patient was lost to follow-up. The primary response variable was the change in the total score on the UPDRS from baseline to the last visit. The subjects were very well matched with regard to their ages, gender, and clinical disability at baseline. No significant side effects were encountered.
The findings were an increase in the adjusted mean total UPDRS score of 11.99 for the placebo group, 8.81 for the 300 mg/d, 10.82 for the 600 mg/d group, and 6.69 for the 1200 mg/d group. The primary analysis was a test of the linear trend between the dosage and the mean change in the UPDRS, which had a P value of 0.09 and was the prespecified criteria for a positive effect. Secondary analysis was a comparison of each treatment group with placebo group. The difference between the 1200 mg/d and placebo groups was significant with a P = .04. The overall slowing of disability in the 1200 mg/d group was 44% at 16 months.
A number of other biochemical end points were examined. Plasma coenzyme Q10 levels showed dose-dependent increases. Interestingly, the 300-mg and 600-mg doses produced increases in plasma concentrations, which were roughly comparable, at approximately 2 mg/mL. The 1200-mg dose, however, produced a 2-fold increase above the 300-mg and 600-mg doses to approximately 4 mg/mL. An assay of mitochondrial complex I activity, which depends on the endogenous levels of coenzyme Q10 in the mitochondria, showed increases in all of the treated groups.
Interestingly, all 3 subscores of the UPDRS showed improvement. This included the mental score, the activities of daily living score, as well as the motor score. Another interesting aspect was that the initial changes in the total UPDRS score were roughly comparable to the varying groups over the first month, and only at the 4-month and later time points was there increasing separation of the groups, consistent with a possible neuroprotective effect. The number of patients who completed 16 months without needing levodopa were 5 in the placebo group, 7 in the 300 mg/d, 0 in the 600 mg/d group, and 11 in the 1200 mg/d group.
Commentary
The importance of coenzyme Q10 for central nervous system function is corroborated by children in whom a marked coenzyme Q10 deficiency has been documented. Patients have suffered from progressive muscle weakness, seizures, and cerebellar ataxia. The symptoms resolve with coenzyme Q10 supplementation. In some patients with mitochondrial encephalopathy, lactic acidosis and stroke (MELAS) coenzyme Q10 produces both biochemical and clinical improvement. On account of this we became interested in it as a possible neuroprotective agent for treatment of neurodegenerative diseases, in which there is substantial evidence for mitochondrial dysfunction. The MPTP model of PD involves metabolism into MPP+, which then inhibits complex I of the electron transport chain. Other mitochondrial toxins such as malonate and 3-nitropropionic acid are succinate dehydrogenase inhibitors, which have been used to model Huntington’s disease. We showed that oral administration of coenzyme Q10 could significantly attenuate MPTP neurotoxicity and it significantly attenuated malonate, and 3-nitropropionic acid induced toxicity. It improved ATP levels and reduced increases in lactate concentrations and attenuated oxidative damage.
We subsequently demonstrated that coenzyme Q10 administration significantly extended survival and attenuated the pathologic changes in transgenic mouse models of both ALS and Huntington’s disease. Coenzyme Q10 administration produces time-dependent increases in brain concentrations both in tissue homogenates, as well as in mitochondria.
The results of the present trial appear extremely promising. The studies showed dose-dependent slowing of disease progression. There were no significant side effects. The finding that there was improved complex I activity suggests that the beneficial effects may be mediated by improvements in mitochondrial function. It, however, remains possible that the major benefits may be through a reduction in oxidative damage, or recently described effects of coenzyme Q10 on mitochondrial uncoupling proteins, which may exert protective effects against neuronal damage.
What do these findings mean in terms of patient care? As yet, coenzyme Q10 cannot be definitely recommended. Although the results of this study are extremely promising, they need to be replicated in a much larger patient sample. The results reached significance, but the number of patients in each subgroup were relatively small. A major issue is the cost of coenzyme Q10 at the doses used in the study, which at the 1200-mg dose is about $200 monthly. This at present is a deterrent to using coenzyme Q10. Nevertheless, this is still less than the cost of levodopa. We are planning a much larger phase III trial. If these preliminary results can be confirmed in a larger study, this will be a major breakthrough in our ability to achieve neuroprotection for PD. —M. Flint Beal
Dr. Beal, Professor and Chairman, Department of Neurology, Cornell University Medical College, New York, NY, is Editor of Neurology Alert.
There is substantial evidence that mitochondrial defects and oxidative damage play a role in the pathogenesis of Parkinsons disease.
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