Zymes llc. CoQ10 and Neurodegenerative Disease

CoQ₁₀ and Neurodegenerative Disease

The nervous system is comprised of the Central Nervous System (CNS), which includes the brain and spinal cord, and the Peripheral Nervous System (PNS) which connects the CNS to other parts of the body. The functional unit of the nervous system is the nerve cell, or neuron. Neurons communicate with each other using neurotransmitters, chemical “messengers” which transmit signals from one cell to another. The nervous system has three basic functions: 1) receive sensory input from internal and external environments 2) integrate the input and 3) respond to the input.

Sensory input exists in many forms, including pressure, taste, sound, light, blood pH, or hormone levels, which are converted into a signal and sent to the brain or spinal cord. In the sensory centers of the brain or spinal cord, input is integrated and a response is generated. The response, a motor output, converts the signal into some form of action such as movement, changes in heart rate, release of hormones, etc. The classic example is touching a hot stove. Heat is the sensory input that is converted into a signal transmitted to the CNS. The motor output generates the response to quickly remove your hand.

Neurodegenerative diseases affect brain function and result from deterioration and loss of neurons in the CNS. Changes in these nerve cells cause them to function abnormally, eventually bringing about their death. Neurodegenerative diseases are divided into two groups:

1. Conditions causing problems with movements (Parkinson’s disease, Huntington’s disease)
2. Conditions affecting memory or relating to dementia (Alzheimer’s disease)

There is a growing body of evidence to suggest that oxidative stress and damage to mitochondria play a role in neurodegenerative diseases. Oxidative stress is caused by cellular accumulation of reactive oxygen species (ROS) which are potentially harmful chemicals produced during normal metabolic processes and in response to various stimuli. These ROS, found primarily in the mitochondria, are “quenched” by antioxidants and converted into non-toxic compounds. However, accumulation of these species in tissues can result in cell dysfunction and death. This may result from excessive production of ROS, decreased antioxidants, or both. Excessive cell death is a common characteristic of neurodegenerative diseases and stroke.

Evidence of oxidative stress such as oxidized lipids, DNA, and proteins have been found in patients with Alzheimer’s disease, ¹ Huntington’s disease, ² Parkinson’s disease ³ and amyotrophic lateral sclerosis (ALS). ⁴ Decreased levels of antioxidant producing enzymes are found in patients with Parkinson’s disease. Some researchers have suggested that Alzheimer’s may be linked to diets low in antioxidants. ⁶

Coenzyme Q₁₀ is thought to play a beneficial role in neurodegenerative diseases due to both its antioxidant effects and its beneficial role in maintaining healthy mitochondria. Blood levels of Coenzyme Q₁₀ are lower in patients with Parkinson’s disease compared to age-matched controls. ⁷ Some researchers have found that blood levels of Coenzyme Q₁₀ are normal in patients with Alzheimer’s ⁸ and Parkinson’s disease. ^{9, 10} However, it has been suggested that it is more important to measure the level of coenzyme Q₁₀ in the cells, and mitochondria of cells, than in the blood. To support this notion, the amount of coenzyme Q₁₀ available to act as an antioxidant was found to be reduced in the platelets and in the mitochondria ¹² of patients with Parkinson’s disease. ¹¹

Parkinson’s Disease

Parkinson’s disease is the second most common neurodegenerative disorder after Alzheimer’s disease. It affects about 1 in every 100 persons over age 50. This brain disease is characterized by four major features:

• Resting tremor of a limb (shaking when the limb is at rest)
• Slowness of movement
• Rigidity (stiffness, increased resistance to movement) of the limbs or trunk
• Poor balance

When at least two of these symptoms are present, especially if they are more evident on one side than the other, a diagnosis of Parkinson’s disease is made.

Parkinson’s Disease is a progressive disease that results when nerve cells in a part of the brain, called the substantia nigra, are impaired or die. These nerve cells produce dopamine, an important neurotransmitter that conveys signals from the substantia nigra to another part of the brain called the corpus striatum. These signals facilitate coordinated movement. When the dopamine-secreting cells in the substantia nigra die, there is a breakdown in communication between neurons and the movement control centers in the brain become unregulated. Disturbances in the movement control centers of the brain cause the symptoms of PD, which develop when 80% of the dopamine-producing cells in the substantia nigra are depleted.

Although the causes of Parkinson’s disease are not well known, increased oxidative stress in the substantia nigra and decreased activity of the mitochondrial electron transport chain are thought to play a key role. Oxidative stress results in the production of substances (such as free radicals or reactive oxygen species) that may be harmful to cells and lead to their deaths. Cell loss in the substantia nigra is the cause of symptoms of Parkinson’s disease.

Coenzyme Q₁₀ is an essential component of the electron transport chain, and is required for its function. It is also a potent antioxidant able to prevent oxidative damage caused by free radicals . Levels of coenzyme Q₁₀ have been found to be decreased in blood and in platelet mitochondria of individuals with Parkinson’s disease. ^{11, 12} Experimental models of Parkinson’s disease have further shown that coenzyme Q₁₀ can protect the dopamine secreting cells of the substantia nigra. This prompted investigators to examine the potential role of coenzyme Q₁₀ in the prevention and treatment of Parkinson’s disease and other neurodegenerative diseases.

In 2002 Shults and coworkers studied the safety and efficacy of coenzyme Q₁₀ to slow the progression of Parkinson disease in the first multicenter, randomized, placebo-controlled, double-blind trial. Eighty patients with early Parkinson disease were treated with either placebo or coenzyme Q₁₀ at dosages of 300, 600, or 1200 mg per day and followed for 16 months or until their disability required treatment with levodopa. The study showed that less disability developed in patients taking coenzyme Q₁₀ than in those taking the placebo. The benefit was greatest in patients taking the highest doses of coenzyme Q₁₀. There was also a dose dependent increase in blood levels of coenzyme Q₁₀. These promising preliminary findings need to be confirmed in larger clinical trials. ¹³

A 16-month randomized, placebo-controlled trial evaluated the safety and efficacy of 300, 600, or 1200 mg/d of coenzyme Q₁₀ in 80 people with early Parkinson’s disease. ¹³ Coenzyme Q₁₀ supplementation was well tolerated at all doses and associated with slower deterioration of function in Parkinson’s disease patients compared to patients taking placebo. However, the difference was statistically significant only in the group taking 1200 mg/d. Although these preliminary findings are promising, they need to be confirmed in larger clinical trials before recommending the use of coenzyme Q₁₀ in early Parkinson’s disease.

To prepare for a larger clinical study of higher doses of coenzyme Q₁₀, the safety of doses greater than 1200 mg/day was evaluated in 17 patients with Parkinson’s disease in an open label study. ¹⁴ The patients received increasing doses of coenzyme Q₁₀ from 1200 to 3000 mg/day. Thirteen of the 17 patients reached the highest dose of 3000 mg/day. No adverse events were attributed to coenzyme Q₁₀. Blood levels of coenzyme Q₁₀ reached a plateau with the 2400 mg/day establishing this as the suggested dosage for future studies of Parkinson’s disease with coenzyme Q₁₀. ¹⁵

Alzheimer’s Disease

Alzheimer’s is a neurodegenerative disease and the most common cause of dementia. The most striking early symptom is short term memory loss, which usually manifests as minor forgetfulness which becomes more pronounced over time. There is relative preservation of long term memory. As Alzheimer’s progresses, intellectual impairment extends to the domains of language (aphasia), skilled movements (apraxia), recognition (agnosia), and functions such as decision-making and planning. The underlying disease is characterized by loss of nerve cells together with inflammation caused by protein deposits (amyloid plaques and neurofibrillary tangles) in tissues of the brain. The ultimate cause of the disease is unknown. Genetic factors are known to be important, and mutations in three different genes have been identified that account for a small number of cases of familial, early-onset Alzheimer’s Disease. For late onset Alzheimer’s Disease, only one susceptibility gene has been identified to date.

Knowledge of the role of coenzyme Q₁₀ in patients with Alzheimer’s disease is not as broad as it is for Parkinson’s disease. However, advances are being made with in vitro (in test tubes) experiments and animal models of this disease.

Proteins fold in specific ways to enable them to perform their biochemical functions in the body. In Alzheimer’s disease some proteins fold improperly, forming deposits of non-functional proteins in the brain known beta-amyloid fibrils. Decreasing the formation of beta-amyloid fibrils or disrupting already formed beta-amyloid fibrils would be a potential way to treat patients with Alzheimer’s disease. In vitro experiments showed that coenzyme Q₁₀ was able to decrease the formation of beta-amyloid fibrils and disrupt already formed beta-amyloid fibrils. ¹⁶

Bragin and co-workers studied the effect of the combination of multivitamins, vitamin E, alpha-lipoic acid, omega-3 fatty acids and coenzyme Q₁₀ on cognition in 35 ill patients about 71 years of age who were diagnosed with mild dementia and depression. The combination of multivitamins, vitamin E, alpha-lipoic acid, omega-3 fatty acids and coenzyme Q₁₀ slowed the decline in and even improved cognition. ¹⁷

Rats trained to run through a maze can be treated with a chemical called streptozotocin that causes them to lose their memory of the maze. This loss of memory is associated with oxidative damage to the brain. Memory loss and oxidative damage to the brain are also characteristics of Alzheimer’s dementia. When rats were treated with streptozotocin and then supplemented with coenzyme Q₁₀, the memory loss and oxidative damage improved, suggesting that coenzyme Q₁₀ may be effective in patients with Alzheimer’s dementia. ¹⁸

Huntington’s Disease

Huntington’s disease, formerly known as Huntington’s chorea, is a rare, fatal, inherited neurodegenerative disorder in which there is degeneration of specific nerve cells known as striatal spiny neurons. The symptoms, such as movement disorders and impaired cognitive function, generally develop between 40 and 50 years of life and deteriorate with time.

The Huntington Study Group conducted a multicenter, parallel group, double-blind, randomized study of 347 patients with early Huntington’s disease to evaluate the effects of coenzyme Q₁₀ (300 mg twice a day), remacemide 200 mg three times a day, or both for 30 months. Neither treatment significantly slowed the decline in total functional capacity. However, there was a trend toward a reduction in the decline of total functional capacity of 13% in patients treated with coenzyme Q₁₀. ¹⁹ Studies of coenzyme Q₁₀ in patients with Parkinson’s disease suggest that higher doses may be required to provide a demonstrable clinical benefit. ¹³

Koroshetz et al. studied a measure of brain metabolic health, lactate concentrations (using MRI), in patients with Huntington’s disease and compared it with healthy control subjects. Brain lactate concentrations were increased in patients with Huntington’s disease compared to controls. Lactate concentration decreased with coenzyme Q₁₀ treatment and increased again upon discontinuation of coenzyme Q₁₀ treatment - suggesting a possible benefit of this antioxidant in Huntington’s disease. ²⁰

Andrich and colleagues compared blood levels of coenzyme Q₁₀ in patients with Huntington’s disease who were untreated and treated, and compared them to healthy controls. There was no difference between blood levels of coenzyme Q₁₀ in treated patients with Huntington’s disease and healthy controls. However, blood levels of coenzyme Q₁₀ were significantly lower in untreated patients compared to those that were treated and compared to healthy controls. ²¹

Feigin et al. conducted a 6-month open-label study of coenzyme Q₁₀ in 10 patients with Huntington’s disease. There was no significant effect of coenzyme Q₁₀ on the clinical ratings of Huntington’s disease Rating Scale, the Huntington’s disease Functional Capacity Scale (HDFCS), or the standardized neuropsychological measures. ²²

On the other hand, several studies evaluating the effect of coenzyme Q₁₀ in animal models of Huntington’s disease have shown promising results. ^23-29

Learn more about ongoing studies of coenzyme Q₁₀.

References:

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3. Sohmiya M, Tanaka M, Tak NW, Yanagisawa M, Tanino Y, Suzuki Y, Okamoto K, Yamamoto Y. Redox status of plasma coenzyme Q₁₀ indicates elevated systemic oxidative stress in Parkinson’s disease. J Neurol Sci. 2004 Aug 30;223(2):161-6.
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7. Matsubara et al. Serum coenzyme Q₁₀ level in Parkinson syndrome. In: Folkers K, Littaru GP, Yamagami eds. Biochemical and Clinical Aspects of Coenzyme Q1. New York, NY Elsevier Science Publishers; 1991:159-166.
8. de Bustos F, Molina JA, Jimenez-Jimenez FJ, Garcia-Redondo A, Gomez-Escalonilla C, Porta-Etessam J, Berbel A, Zurdo M, Barcenilla B, Parrilla G, Enriquez-de-Salamanca R, Arenas J. Serum levels of coenzyme Q₁₀ in patients with Alzheimer’s disease. J Neural Transm. 2000;107(2):233-9.
9. Ebadi M, Govitrapong P, Sharma S, Muralikrishnan D, Shavali S, Pellett L, Schafer R, Albano C, Eken J. Ubiquinone (coenzyme Q₁₀) and mitochondria in oxidative stress of parkinson’s disease. Biol Signals Recept. 2001;10(3-4):224-53.
10. Jimenez-Jimenez FJ, Molina JA, de Bustos F, Garcia-Redondo A, Gomez-Escalonilla C, Martinez-Salio A, Berbel A, Camacho A, Zurdo M, Barcenilla B, Enriquez de Salamanca R, Arenas J. Serum levels of coenzyme Q₁₀ in patients with Parkinson’s disease. J Neural Transm. 2000;107(2):177-81.
11. Gotz ME, Gerstner A, Harth R, Dirr A, Janetzky B, Kuhn W, Riederer P, Gerlach M. Altered redox state of platelet coenzyme Q₁₀ in Parkinson’s disease. J Neural Transm. 2000;107(1):41-48.
12. Shults CW, Haas RH, Passov D, Beal MF. Coenzyme Q10 levels correlate with the activities of complexes I and II/III in mitochondria from parkinsonian and nonparkinsonian subjects. Ann Neurol. 1997;42(2):261-264.
13. Shults CW, Oakes D, Kieburtz K, Beal MF, Haas R, Plumb S, Juncos JL, Nutt J, Shoulson I, Carter J, Kompoliti K, Perlmutter JS, Reich S, Stern M, Watts RL, Kurlan R, Molho E, Harrison M, Lew M; Parkinson Study Group. Effects of coenzyme Q₁₀ in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol. 2002;59(10):1541-1550.
14. Shults CW, Flint Beal M, Song D, Fontaine D. Pilot trial of high dosages of coenzyme Q₁₀ in patients with Parkinson’s disease. Exp Neurol. 2004;188(2):491-494.
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16. Ono K, Hasegawa K, Naiki H, Yamada M. Preformed beta-amyloid fibrils are destabilized by coenzyme Q10 in vitro. Biochem Biophys Res Commun. 2005;330(1):111-6.
17. Bragin V, Chemodanova M, Dzhafarova N, Bragin I, Czerniawski JL, Aliev G. Integrated treatment approach improves cognitive function in demented and clinically depressed patients. Am J Alzheimers Dis Other Demen. 2005;20(1):21-6.
18. Ishrat T, Khan MB, Hoda MN, Yousuf S, Ahmad M, Ansari MA, Ahmad AS, Islam F. Coenzyme Q₁₀ modulates cognitive impairment against intracerebroventricular injection of streptozotocin in rats. Behav Brain Res. 2006;171(1):9-16.
19. Huntington Study Group. A randomized, placebo-controlled trial of coenzyme Q₁₀ and remacemide in Huntington’s disease. Neurology. 2001;57(3):397-404.
20. Koroshetz WJ, Jenkins BG, Rosen BR, Beal MF. Energy metabolism defects in Huntington’s disease and effects of coenzyme Q10. Ann Neurol. 1997;41(2):160-5.
21. Andrich J, Saft C, Gerlach M, Schneider B, Arz A, Kuhn W, Muller T. Coenzyme Q₁₀ serum levels in Huntington’s disease. J Neural Transm Suppl. 2004;(68):111-6.
22. Feigin A, Kieburtz K, Como P, Hickey C, Claude K, Abwender D, Zimmerman C, Steinberg K, Shoulson I. Assessment of coenzyme Q₁₀ tolerability in Huntington’s disease. Mov Disord. 1996;11(3):321-3.
23. Beal MF. Coenzyme Q₁₀ as a possible treatment for neurodegenerative diseases. Free Radic Res. 2002;36(4):455-60.
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26. Kasparova S, Sumbalova Z, Bystricky P, Kucharska J, Liptaj T, Mlynarik V, Gvozdjakova A. Effect of coenzyme Q₁₀ and vitamin E on brain energy metabolism in the animal model of Huntington’s disease. Neurochem Int. 2006;48(2):93-9.
27. Schilling G, Savonenko AV, Coonfield ML, Morton JL, Vorovich E, Gale A, Neslon C, Chan N, Eaton M, Fromholt D, Ross CA, Borchelt DR. Environmental, pharmacological, and genetic modulation of the HD phenotype in transgenic mice. Exp Neurol. 2004;187(1):137-49.
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29. Stack EC, Smith KM, Ryu H, Cormier K, Chen M, Hagerty SW, Del Signore SJ, Cudkowicz ME, Friedlander RM, Ferrante RJ. Combination therapy using minocycline and coenzyme Q₁₀ in R6/2 transgenic Huntington’s disease mice. Biochim Biophys Acta. 2006;1762(3):373-80.

• Coenzyme Q₁₀
  • History of CoQ₁₀
  • What is CoQ₁₀?
  • Where Does CoQ₁₀ Come From?
    • CoQ₁₀ Biosynthesis
    • Dietary CoQ₁₀
    • CoQ₁₀ Can Be Taken as a Dietary Supplement
    • CoQ₁₀ Can Be Applied Topically to the Skin
  • What Does CoQ₁₀ Do?
    • CoQ₁₀ is Required to Produce Energy (ATP)
    • CoQ₁₀ is a Powerful Antioxidant
  • Lipid Solubility
• CoQ₁₀ and Health
  • CoQ₁₀ and Aging
  • CoQ₁₀ and Obesity
• CoQ₁₀ and Disease
  • CoQ₁₀ and Statin Therapy
  • CoQ₁₀ and Neurodegenerative Disease
  • CoQ₁₀ and Diabetes
• Become an Empowered, Educated Consumer
  • Anatomy of a Scientific Article
  • Understanding Statistics in Science and Medicine
  • Drug Discovery
  • How to Search the Scientific Literature
  • How to Find Out About Ongoing Clinical Trials
• Appendices
  • Glossary