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Life Extension Magazine

LE Magazine October 2001


Conclusion of a 3-Part Series on Cellular Bioenergetics and CoQ10
How CoQ10 Protects Brain Cells

Page 1 of 4

The source of life and death for neurons (nerve cells) lies in the mitochondria. These tiny organelles generate the neuron's energy and control its death. The mitochondria tend to develop defects with age. As these defects accumulate, they cause increasing mitochondrial dysfunction in the nondividing cells of the brain, heart and muscle. The result is reduced cellular energy production and increased cell death, as occurs in neurodegenerative disease and stroke. Recent research provides us with an opportunity to protect against this destructive process by minimizing mitochondrial dysfunction and preventing other pathological events that cause brain cells to die.

Life Extension magazine published the first two installments of this three part series in the April, 2000 and February, 2001 issues. The articles were titled "How CoQ10 Protects Your Cardiovascular System" and "Cellular Nutrition for Vitality and Longevity" (April 2000), "Bioenergetic Therapy for Aging" and "The Metabolic Syndrome" (February 2001). These features detail CoQ10's role in cellular bioenergetics, and provide a foundation for this final installment.

A review article in Brain Research Reviews on the role of the mitochondria in neurodegeneration notes that “it is becoming clear that subtle functional alterations in these essential cellular dynamos can lead to insidious pathological changes in neurons” (Cassarino DS et al., 1999). The authors outline a theory of neurodegeneration based upon a vicious cycle of mitochondrial DNA mutation, bioenergetic decline and oxidative stress. Their recommendations echo the antiaging functions of CoQ10 discussed in the previous installments of this series, namely improving cellular respiration, normalizing or preventing oxidative stress, and inhibiting programmed cell death.

If aging and neurodegeneration have similar basic causes, neurodegeneration research could turn out to be a laboratory for understanding the processes of aging and how to influence them. However, the physiology of the brain is in certain ways unique, and its pathologies present some unique mechanisms and features.

The brain is especially vulnerable to oxidative stress due to its rich oxygen supply and high fatty acid content. It would seem logical that the brain’s antioxidant defense system would be especially robust. Unfortunately, the opposite is the case. The brain is relatively underdefended against oxidative stress. Consequently neurons, which are for the most part irreplaceable, gradually accumulate oxidative damage over time.

The brain’s vulnerability increases with age. Most of the fatty acid content of the brain is contained in the membranes that surround brain cells, their extensions (such as axons) and the mitochondria. As we age, more of these lipids become polyunsaturated, which makes them more susceptible to lipid peroxidation. Polyunsaturated fats exposed to the brain’s rich supply of oxygen and oxygen byproducts are like dry tinder near fire.

Oxidative stress and bioenergetic failure are fundamental to neurodegeneration. Scientists use neurotoxins that work in just these ways to mimic neurological diseases in lab animals. CoQ10 protects lab animals from the effects of such neurotoxins, according to a series of studies by neurologist M. Flint Beal and colleagues at the Massachusetts General Hospital and Harvard Medical School. They found that the neurotoxins malonate, 3-NP and MTPT inflicted significantly less brain damage on animals treated with CoQ10. Beal’s studies provided the first demonstration that oral CoQ10 supplements exert neuroprotective effects in the living brain, and significantly raise CoQ10 levels in brain tissue and brain mitochondria.


These neurotoxins also lead to a major cause of cell death in neurodegenerative disease called excitotoxicity. The neurotransmitter glutamate normally transmits excitatory impulses. In neurodegeneration the brain becomes chronically oversensitive to glutamate, which then acts as a slow-acting “excitatory toxin” on brain cells.

A seminal paper by NIH (National Institutes of Health) scientists in 1988 proposed that excitotoxicity develops when the energy level of neurons declines, and subsequent research has borne out their theory. Studies show that CoQ10 protects against excitotoxicity by raising neuronal energy levels. Italian scientists discovered that CoQ10 protects neurons cultured in glutamate from excitotoxicity. Beal’s group extended these findings to rats. They gave the rats a neurotoxin (malonate) that induces excitotoxic brain lesions. When the rats were fed CoQ10 in their chow for 10 days before exposure to the toxin, lesions were reduced by 30%. CoQ10 also restored energy production in the neurons to nearly normal levels.

Newly published research suggests that CoQ10 can protect brain cells from neurotoxicity and excitotoxicity, while even powerful antioxidants cannot. CoQ10 proved highly effective, while simple antioxidants were ineffective, in protecting PC-12 cells (neuron-like rat adrenal cells commonly used in neurobiological research) from the excitotoxic effects of glutamate and from the Parkinson’s disease-like effects of the neurotoxin MPP+. L-deprenyl (the drug selegilene) also proved effective, though not as effective as CoQ10. The scientists conclude that there may be “a greater role for mitochondrial dysfunction and cellular energy than free radicals, in both models of cell death. And, it seems that energy compromise plays a large role in the progression of Parkinson’s disease” (Mazzio E et al., 2001).

Parkinson’s disease

In Parkinson’s disease, cell death is highly selective. Neurons that produce the neurotransmitter dopamine die in a part of the brain that coordinates movement. This depletes dopamine stores and leads to muscle rigidity, tremor and difficulty initiating movement.

Cellular Energy Generation

Structure of a cell (upper left), with detail of a mitochondrion (upper right). The cellular respiratory chain (bottom) generates energy.

Mitochondria are the power plants of the cell. They transform oxygen and nutrients into energy and water through a process called cellular respiration. The many finger-like folds in the mitochondrial inner membrane house respiratory chains (bottom panel) where energy is produced. CoQ10 (yellow) carries electrons across the chain while pumping protons (red) through the inner membrane (purple). The return flow of protons into the last component of the chain (blue) drives synthesis of ATP, the energy storage molecule.

The specific brain region affected in Parkinson’s disease, the substantia nigra, has the highest level of mitochondrial DNA mutation in the brain. Evidence is mounting that mitochondrial DNA mutations cause cellular respiration to malfunction in Parkinson’s disease, exactly as Linnane’s theory would predict (see sidebar “A Model of Bioenergetic Aging”). Parkinson’s disease patients show defective cellular respiration in the first complex of the cellular respiratory chain.

Beal and colleagues found that the bioenergetic deficit in Parkinson’s disease patients correlates strongly with CoQ10 levels. In follow-up research, they tested CoQ10 on mice treated with a neurotoxin (MPTP) whose effects mimic Parkinson’s disease. The toxin caused significantly less damage to the dopamine system in the brains of mice that had been fed CoQ10 for the previous five weeks.

Beal’s group also tested the bioenergetic effect of oral CoQ10 supplements in Parkinson’s disease patients. They found that CoQ10 restored the depressed activity of the first complex of the cellular respiratory chain to approximately normal levels, and was most effective at 600 mg per day. The scientists emphasized, however, that a larger study is required to determine whether the trend toward significance of these results will be validated. Furthermore, a new study shows that oral CoQ10 also increases the activity of the second complex of the cellular respiratory chain in the brains of normal mice.

Scientists hypothesize that the bioenergetic defect in Parkinson’s disease “lowers the threshold” for programmed cell death. Energetically deficient neurons are less able to tolerate oxidative stress, which then triggers the cellular “decision to die.” Oxidative stress is particularly high even under normal conditions in the region of the brain affected by Parkinson’s disease, which may help explain why additional oxidative stress depresses cells in that particular region beyond the threshold for programmed cell death.

Huntington’s disease

Huntington’s is an inherited genetic disease that destroys neurons in brain regions governing movement. Symptoms include involuntary movements, lack of coordination and cognitive difficulties.

Huntington’s disease is thought to involve a bioenergetic defect. A pilot study conducted by Beal and associates showed that energy production in the central nervous system and muscle of Huntington’s disease patients is impaired. After two or more months of CoQ10 supplementation (360 mg per day), 83% of patients showed significant improvements in biochemical markers of energy production.

In 1997, a multicenter clinical trial began comparing CoQ10 and the drug remacemide, each at 600 mg per day, in early stage Huntington’s disease. The results of this two and a half year study are due to be released in mid August as this magazine goes to press. Preliminary media reports indicate that the drug remacemide (a glutamate blocker) had no effect on the decline in Total Functional Capacity of Huntington’s Disease patients, and was found to confer no clinical benefit. On the other hand, CoQ10 slowed the decline by 13%, and also slowed decline on the Huntington’s Disease Independence Scale by 17%. Reports indicate that these results showed a trend toward significance but are regarded as inconclusive. The Huntington Study Group, which organized the study, hopes to conduct a larger trial in order to determine whether CoQ10 therapy does significantly reduce the rate of decline in the early stages of the disease.

Continued on Page 2 of 4
References on Page 4


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