Abstract
Parkinson’s disease involves the loss of dopaminergic function in neural cells, primarily those within the substantia nigra pars compacta. Mitochondrial dysfunction and free-radical damage appear to be underlying components of the apoptotic process of these cells. Coenzyme Q10 (ubiquinone 10) is a known mitochondrial nutrient that also has the capacity to scavenge free radicals. Oral administration of coenzyme Q10 has been established to increase levels in brain tissue and benefit several mitochondrial-defect diseases. Coenzyme Q10, therefore, may be an ideal candidate for early intervention in Parkinson’s disease. Literature of the theory and evidence to date are included in this review.
Introduction
Parkinson’s disease (PD) is a neurodegenerative disorder marked by resting tremors, rigidity of movement, postural abnormalities, and akinesia. The “trigger” for the onset of PD is not known and is presumed to be multifactorial, involving genetic susceptibility and environmental agents. Sporadic cases, meaning those without known genetic causation, account for 95% of the cases. The most important risk factor is age, with a prevalence of approximately 1% of Americans over 65 years old.1 There is also a gender bias, with the overall incidence of PD 1.5 times higher in men than in women.2
Neurodegenerative diseases, including PD, are by definition a loss of function of neural cells. In the case of PD, it is primarily dopaminergic cells within the substantia nigra that are affected. Central to PD progression is impaired energy metabolism and oxidative stress. As both the major energy producing organelle and the primary generator of free radicals in cells, the mitochondria play a central role in all neurodegenerative diseases.3 It is not surprising that improving mitochondrial function is fast becoming a target of pharmaceutical research.4 The nontoxic compound, coenzyme Q or ubiquinone, is a known neuroprotectant in animal studies.5 Preliminary human data suggests that coenzyme Q may represent a means of slowing the progression of many neurodegenerative diseases, including PD.6,7
Structurally, coenzyme Q is a lipid-soluble molecule with that has a hydrophobic “tail” composed of isoprenoid units. CoQ10, the most common form in humans, has 10 isoprenoid units. The classic biochemical role of CoQ10 is its integral role in ATP production within the inner membrane of mitochondria. There, it transfers an electron between complexes I/II and complex III as part of the respiratory electron transport chain. Separately, CoQ10 can act as a free-radical scavenger, protecting lipid membranes of mitochondria as well as regenerating alpha tocopherol from its oxidized state as alpha tocopheroxyl.8 Perhaps less well known is the role of CoQ10 as a cofactor for mitochondrial uncoupling proteins (UCPs). The process of uncoupling reduces reactive oxygen species (ROS) and absolutely requires CoQ10.9
Oral administration of CoQ10 was found to increase the levels within the cerebral cortex of mice and to confer a survival benefit in mouse models of amylotrophic lateral sclerosis (ALS) and Huntington's Disease.
Oral administration of CoQ10 was found to increase the levels within the cerebral cortex of mice and to confer a survival benefit in mouse models of amylotrophic lateral sclerosis (ALS) and Huntington’s Disease.5,10 Mouse models using orally administered CoQ10 have also demonstrated attenuation of damage from excitotoxins such as cocaine and amphetamines.11 The use of oral CoQ10 has also shown a decrease in the progression of PD in both mouse and primate models.12,13 Further evidence that CoQ10 reaches the brain can be found in case reports of oral CoQ10 improving symptoms in patients with known cerebral mitochondrial disorders.14,15,16
Pathogenesis of Parkinson’s Disease
According to National Institute of Neurological Disorders and Stroke, the pathogenesis of PD involves overlapping mechanisms of excitotoxicity, calcium accumulation within cells, increased ROS production, mitochondrial defects, cytoskeletal abnormalities, and aberrations in nerve growth factors.17 It is postulated that normal aging of neural cells may also be driven by some of these mechanisms, in particular the accumulation of ROS that leads to apoptotic pathway activation.18 The late onset of neurodegenerative diseases in general is corroborating evidence for the possible role of ROS accumulation in neurodegenerative diseases.
Brains of patients with PD have shown both a decrease in antioxidant enzymes as well as decreased antioxidant nutrients within cells of the substantia nigra.19 Interestingly, it appears that early in the disease process there is an increase in dopaminergic receptors on neurons surrounding those that have died, presumably a compensatory upregulation. As the disease progresses, however, there is an accumulation of dopamine within the synapses from continued loss of neurons. As this excess dopamine is degraded by monoamine oxidase enzymes, hydrogen peroxide (H2O2) accumulates as a byproduct. This may lead to the production of highly reactive hydroxyl (OH) radical, particularly if there is less glutathione available to degrade H2O2, as is the case in PD. Accumulation of free radicals can then damage surrounding cells and lead to further cell death. This destructive cycle has been postulated to be one of the underlying causes of the inevitable progression of PD. Therefore, at least in theory, antioxidants that can reduce the accumulation of OH free radicals have the potential to interrupt disease progression.20
Metabolism of dopamine is only one of many cellular processes that are producing free radicals in neural cells. Many normal cellular processes, most notably energy generation within the mitochondria, result in the production of several types of free radicals, including superoxide anion, hydrogen peroxide and hydroxyl. Excitotoxicity, whether by endogenous glutamate or exogenous toxins, is also a known contributor of ROS generation within cells. Higher free iron levels, which are found in patients with PD, also promote oxidation and result in the production of free radicals. CoQ10 acts as a potent antioxidant within cells and may help to reduce oxidative damage to the mitochondrial membrane, thus protecting cells from ROS driven triggers of apoptosis.21
If there is enough accumulation of free radical species within any cells, apoptosis is triggered within the mitochondria of the cells and they die a “programmed cell death.” This is thought to be the mechanism of normal cellular aging. In PD not only do free radicals accumulate, but this is coupled with dysfunction of the master organelle of cellular energy, the mitochondria. Impaired function of the mitochondria is a contributing factor of sporadic PD and has been known for decades to have a contributing role in the disease.
The most well established mitochondrial defect in PD appears to be in complex I of the respiratory chain. MPTP, or 1-methyl-4-phenyl-1,2,5,6 tetrahydropynidine, is a neurotoxin that not only induces Parkinson’s-like symptoms in humans and animals, but has been found to do so via damage to complex I of the respiratory chain, mimicking the known histopathology of cells from brains of patients with sporadic PD. This effect is so reliable that MPTP exposure, either acute or chronic, is used routinely in animal models of PD. Several experiments in animals have shown that oral administration of CoQ10 attenuates the neurotoxic effects of MPTP to cells in the substantia nigra, specifically through protection of damage to complex I of the respiratory chain.12,22,23
Interestingly, MPTP is structurally related to several pesticides, the most notable of which are rotenone and paraquat. These pesticides are associated with higher rates of PD in certain geographical regions with high exposure.24,25 Further, both rotenone and paraquat have been proposed as reliable agents to induce Parkinson’s-like conditions in rodent models.26 The neurotoxic mechanism is thought to be analogous with that of MPTP, namely damage to complex I of the respiratory chain within the mitochondria. CoQ10 has been shown to protect rodents from the damage induced by these pesticides.27,28,29 Whether this protective role of CoQ10 can be extrapolated to humans with high pesticide exposures remains unproven.
Emerging evidence suggests that uncoupling proteins (UCPs) play a role in the production and accumulation of ROS, particularly superoxides. These proteins are called “uncoupling” proteins for their role in dissociating ATP production from oxygen utilization in the mitochondrial membrane. This process uses CoQ10 as a cofactor. Experiments in rodents lacking UCP2 show a greater sensitivity to the neurotoxic effects of agents such as MPTP.30 Further, administration of CoQ10 has been shown to induce UCP2 activity and result in the prevention of loss of dopiminergic cells of the substantia nigra in a primate model using MPTP.31 Since loss of function of UCP2 is congruent with dopaminergic cell death and CoQ10 is a cofactor for UCP2 activity, any deficiency of CoQ10 can be presumed to lessen UCP2 activity and result in neuronal cell death.
Summary of Clinical Trials
In 2002 Shultz and colleagues published a phase II dose escalation study of CoQ10 in early stage PD patients who were treatment naive. Eighty patients were enrolled. Wafers containing 300 mg of CoQ10 and 300 IU alpha tocopherol were used as the study drug. The placebo contained 300 IU of alpha tocopherol only. The intervention lasted 16 months or until progression of disease required levodopa. Dosages used in the intervention groups were 300 mg CoQ10/day, 600 mg CoQ10/day or 1,200 mg CoQ10/day. Assessment was carried out using the Unified Parkinson’s Disease Rating Scale (UPDRS), which includes mental (part I), activities of daily living (part II), and motor (part III) categories. All doses of CoQ10 were well tolerated with only the highest dose (1,200 mg/day) having a significant slowing of progression of PD symptoms in all categories of the UPDRS vs. baseline measurement (P=0.04).32 However, there was no delay in the time to progression that necessitated levodopa. Earlier work by this same group showed there was no change in subjective symptoms using UPDRS in doses up to 800 mg/day.33 Given that statistically significant benefit of subjective symptoms was only found in the highest dosage (1,200 mg/day) group, the authors propose that doses at least as high, if not higher, be considered in future studies.
An editorial letter in response to the 2002 publication by Shultz and colleagues from Dr. M Horstick included his results of an open-label pilot study of 12 PD patients using 500 mg/day of CoQ10 for 3 months. In his small pilot, he reported no effect on subjective symptoms as assessed by UPDRS.34 There are several possible reasons for this discrepancy in outcomes. First, the use of CoQ10 capsules (100 mg/capsule) without any lipophilic compound such as vitamin E may have affected absorption. Second, the dosage of 500 mg/day agrees with the results of Shultz’s study in that doses under 1,200 mg/day did not show statistically significant benefit. Lastly, 8 of the 12 participants were receiving active pharmaceutical treatment; this, as well as the inclusion of mid-stage disease patients, may have affected the outcome. Nonetheless, Horstink proposes that the failure of Shultz’s study to lessen time until usage of levodopa suggests that CoQ10 may be acting on symptoms without affecting the pathophysiology of progression. Certainly, this possibility needs further clarification in future studies of CoQ10.
Horstink and colleagues published another earlier report in 1997 of a 3-month open-label trial of 10 PD patients who were given 200 mg/day. Motor symptoms were assessed using motor tests and UPDRS. He reported there was no clinical benefit in this trial. Again, this is in keeping with Shultz’s results, as the dose may have been too low to be of benefit.
A small placebo-controlled trial of 28 PD patients with stable disease was done using 360 mg of CoQ10 daily. As visual acuity is often impaired in PD, this trial assessed both subjective symptoms as well as visual acuity, using the Farnworth-Munsell 100 Hue test (FMT). This was a short trial, lasting only 4 weeks. Nonetheless, CoQ10 provided a significant mild improvement in symptoms (P=0.01) and a significant improvement of FMT scores (P=0.008) versus placebo. The authors conclude that CoQ10 at 360mg/day provided moderate benefit for patients in the intervention group.35
A study using 300 mg/day of a lipophilic emulsion nanoparticular CoQ10 in mid-stage PD patients failed to show any effect on symptoms using the UPDRS. One hundred six patients were enrolled to receive either placebo or 300 mg of CoQ10 nanoparticle formulation. While serum levels at 300 mg of nanoparticular CoQ10 matched the serum levels of patients in prior studies taking 1,200 mg/day of standard formulation CoQ10, this study failed to show any slowing in the progression of disease. Given the patients were mid-stage disease and on pharmacological treatments, it is assumed the disease may have been more recalcitrant to intervention. The non-response to therapy then, cannot be definitively attributed to the form of CoQ10, since there is no comparable study done in mid-stage PD patients using standard formulation CoQ10.36
Discussion
The molecular characteristics of PD include a decrease in antioxidant enzyme systems as well as impaired energy metabolism in affected cells of the substantia nigra and to a lesser extent the locus ceruleus. There is little discrepancy in the data to date on the role of CoQ10 as an active neuroprotectant in animal models using high doses. Clinical trials of PD patients suggest that doses in excess of 1,200 mg/day along with vitamin E as alpha tocopherol begin to show symptomatic benefit in patients with early-stage PD. This is in keeping with animal data, in which doses as high as 1,600 mg/kg body weight were used to protect the brain from neurodegenerative processes.
So how much is enough? In a phase I dosage escalation study, serum levels of CoQ10 plateaued at 2,400 mg/day.37 Doses as high as 3,000 mg/day were used in this study, and no side effects were attributable to CoQ10. Since there is a plateau seen at 2,400 mg/day, the authors postulate this represents the high-end dose that should be used in future studies of PD.
With this in mind, there is currently a phase III double-blind trial enrolling two intervention groups as well as a placebo group. The intervention groups are receiving either 1,200 mg/day CoQ10 with 1,200 mg alpha tocopherol or 2,400 mg/day with 1,200 IU alpha tocopherol. This trial is currently enrolling patients, and no preliminary data has been published at the time of this writing. The principal investigator has reported that results are predicted to be published in 2012.38
While the role of CoQ10 in oxidative processes, energy metabolism, and as a nutrient cofactor are all implicated in the neuroprotective effects, the simplest explanation for the benefit of CoQ10 in PD patients would be as a treatment of an underlying deficiency of the nutrient. This has been looked at, and whether patients with PD have lower levels of CoQ10 in peripheral circulation and in platelets than controls is equivocal.39,40 Recently however, postmortem analysis of brain tissue has shown that PD-afflicted brains have significantly less CoQ10 in the cerebral cortex versus controls (P=0.007).41 This has not been substantiated by further studies. It does indicate, however, that there is a possible repletion effect from administration of CoQ10 in PD patients.
It should be noted that CoQ10 is unlikely to be a singular agent of intervention from a networked pathways perspective. Combinations of mitochondrial nutrients have been proposed as the most promising means of slowing the progressive “mitochondrial decay” seen in PD.42 Several other agents that alter the function of energy pathways within the mitochondria have the potential to mitigate the production of ROS including creatine, acetyl-L-carnitine, and nicotinamide.43 Indeed, rodent studies have suggested that the combination of CoQ10 with creatine has an additive neuroprotective effect.44 The role of singular antioxidants such as vitamin E, which was once thought promising in PD, have not lived up to expectations. While precise combinations are not yet known, our growing understanding of mitochondrial function and antioxidants that are compartment-specific to the mitochondria may provide direction for future clinical interventions.45
Conclusion
Parkinson’s Disease is a multifactoral process that involves both genetic and environmental mediators to trigger the disease. Common to the pathophysiology are energy pathway impairment and oxidative stress. Coenzyme Q10 is a mitochondrial nutrient with the potential to mitigate both of these processes. In addition, there is strong evidence for the absorption and distribution of Coenzyme Q10 to neural tissues as well as preliminary evidence for its role as a neuroprotectant in several animal models.
Early intervention trials indicate that high doses must be used to achieve benefit. In addition, intervening early in the disease process shows more favorable benefit versus intervening at mid-stage disease. Current ongoing phase III trials may help definitively guide the use and dosage of CoQ10 in PD. Until these are published, CoQ10 recommendations fall under the clinician’s discretion. Without any apparent downside risk, however, the patient and practitioner may be left asking, “Why not?”
