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Vasoconstriction and vasospasm
A new study on endothelins reveals some of the mechanisms through which CoQ10 may exert neuroprotective effects. Endothelins are potent vasoconstrictors found in the body. Ongoing research implicates them in a host of vascular disorders contributing to hypertension, atherosclerosis, congestive heart failure and kidney failure, and evidence is mounting of their involvement in stroke. When endothelins are injected into the brains of animals, the result is cellular energy decline, acidosis, excitotoxicity, depletion of cellular antioxidants, and eventually the collapse of brain cell metabolism. However, when CoQ10 was administered prior to injection of the endothelins, it protected the antioxidant defenses of brain cells and restored them to normal metabolic function. In particular, CoQ10 exerted a marked sparing effect on the key cellular antioxidants glutathione and superoxide dismutase (SOD), and normalized cellular energy production (ATP) and lactate levels (acidosis) in 24 hours.
Endothelins play a particularly important role in cerebral vasospasm. About 2% of adults have aneurysms, a balloon-like deformation in cerebral blood vessels. When an aneurysm ruptures, the two out of three patients who survive the initial cerebral hemorrhage face several possible complications. The most common serious complication is “second stroke,” the cerebral vasospasm. This is a prolonged narrowing of a blood vessel that causes ischemia in the downstream brain tissue.
Researchers at the Polish Academy of Sciences Medical Research Center tested the protective effect of CoQ10 in a rabbit model of cerebral vasospasm. They blocked arteries to reduce cerebral blood supply and later injected blood into the brain to simulate hemorrhage. Following the injection, one group of rabbits was given CoQ10 orally three times a day while the other group was left untreated. All of the untreated rabbits displayed significant neurological deficits (Grade 3 or 4) or died. None of the rabbits given CoQ10 displayed a noticeable neurological deficit, and all of them survived. Microscopic examination revealed no lesions in the brain tissue of the CoQ10 treated group, whereas multiple lesions “suggestive of degeneration or disappearance of neurons… and of myelin disintegration” were found in brain tissue from the untreated rabbits (Grieb P et al., 1997).
The underlying causes of cerebrovascular disease suggest that CoQ10 may have a preventive effect. Most cerebrovascular disease results from atherosclerosis or hypertension. Atherosclerosis narrows blood vessels in the brain, making it easier for blockages to develop; dislodged atherosclerotic plaque can itself cause blockages. Hypertension is the most common cause of hemorrhagic stroke. As discussed earlier in this series, CoQ10 helps protect against the oxidative damage that leads to atherosclerosis, and may aid in controlling blood pressure. Animal studies suggest that CoQ helps reverse age-related loss of arterial tone, which contributes to both cerebrovascular and cardiovascular disease. And of course CoQ10 plays a unique role in sustaining brain bioenergetics. While the potential of CoQ10 in stroke prevention and treatment appears promising, we can only hope that clinical trials will soon be undertaken to test this propositon.
Stroke may mimic long-term genetic effects of aging. Research in mice recently found that stroke causes some of the same mitochondrial DNA deletions associated with aging. The researchers speculate that there could be a single mechanism at work, however much further research is needed before stroke research can be meaningfully applied to brain aging.
The politics of CoQ10
If CoQ10 were as ubiquitous in American households as it is in the cells of the body, there is little doubt that public health would benefit. Why isn’t CoQ10 as popular here as in Japan, where it is one of the top half dozen prescription medicines? CoQ10 researcher Peter Langsjoen (1994) answered a similar question this way:
The answer to this question is found in the fields of politics and marketing and not in the fields of science or medicine. The controversy surrounding CoQ10 likewise is political and economic, as the previous 30 years of research on CoQ10 have been remarkably consistent and free of major controversy. Although it is not the first time that a fundamental and clinically important discovery has come about without the backing of a pharmaceutical company, it is the first such discovery to so radically alter how we as physicians must view disease. While the pharmaceutical industry does a good job at physician and patient education on their new products, the distributors of CoQ10 are not as effective at this. This education is very costly and can only be done with the reasonable expectation of patent protected profit.
Langsjoen’s point concerning education is well taken, inasmuch as CoQ10 cuts across conventional diagnostic and therapeutic categories. Systemic bioenergetic therapy is not yet on the horizon of conventional medicine.
|U.S. pharmaceutical companies have nothing to gain by promoting or testing this expensive import, for which there is no domestic manufacturing infrastructure.|
The “Not Invented Here” syndrome may also play a part in making CoQ10 unwelcome to the American medical establishment. It was Japanese industry that developed the complex fermentation process used to grow natural CoQ10. To this day, all pharmaceutical grade CoQ10 comes from Japan. In the sixties and seventies, when mainstream medicine in the U.S. was yet more resistant to nutritional therapies than it is today, it was Japanese and European scientists who demonstrated the therapeutic effectiveness of CoQ10. Ironically, CoQ10 was invented here —American scientists discovered and first synthesized CoQ10 in the fifties.
What is most unpalatable of all to the U.S. pharmaceutical-medical establishment is that CoQ10 can neither be patented nor regulated as a drug. In fact, it is widely available as a nutritional supplement. U.S. pharmaceutical companies have nothing to gain by promoting or testing this expensive import, for which there is no domestic manufacturing infrastructure. It would cost billions of dollars to conduct the massive clinical trials that drugs undergo in all the potential areas of CoQ10 application. When the medical establishment does embrace CoQ10 it may be in the form of a patentable synthetic analogue (such as idebedone).
Mitochondrial and Neuromuscular Diseases
Since the discovery of the first genetic disease of the mitochondria in 1988, the number of recognized mitochondrial diseases has ballooned. These diseases present extraordinarily complicated genetic and clinical pictures that cut across established diagnostic categories. They primarily affect the brain, nerve, muscle, heart, kidney and endocrine system, whose high energy requirements can no longer be fully met. In addition, a wide range of degenerative diseases have been found to involve one or more of hundreds of known mitochondrial mutations.
Patients with genetic CoQ10 deficiency may suffer dysfunctions in brain, nerve and muscle, often including exertional fatigue and seizures. Such patients appear to respond to CoQ10 supplementation, but observations are limited since diagnosis of this disorder is in its infancy. CoQ10 deficiency is one of the mitochondrial diseases caused by mutations in non-mitochondrial DNA, that is DNA in the cell nucleus.
Case reports and pilot studies have found that some patients with mitochondrial diseases respond to long-term CoQ10 therapy. For example, promising results have been reported in MELAS, Kearns-Sayre syndrome and maternally inherited diabetes with deafness. An Italian study demonstrated the impact of CoQ10 therapy on the living tissue of six patients with mitochondrial cytopathies. They measured the bioenergetic activity in the brain and skeletal muscle of the patients using high-technology diagnostic equipment (phosphorus magnetic resonance spectroscopy). After six months of CoQ10 therapy at 150 mg per day, brain bioenergetics returned to normal in all patients, and skeletal muscle energetics improved significantly. A new study applies this diagnostic technology to Friedrich’s Ataxia, which is characterized by a deficiency of a mitochondrial protein called frataxin recently discovered to activate cellular respiration. The study found that supplementation with CoQ10 plus vitamin E brought a “dramatic improvement of cardiac and skeletal muscle bioenergetics. . . after only three months of therapy” (Lodi R et al., 2001). A just-published study of familial ataxias with no known genetic cause reports that CoQ10 supplementation improved patients’ scores by 25% on a scale measuring balance, speech and movement. The five patients who could not walk at the beginning of the trial were able to walk with some assistance after supplementation (dose levels varied).
Since all cells (except red blood cells) contain mitochondria, mitochondrial diseases tend to affect multiple body systems. Of course some organs and tissues depend more than others upon the energy the mitochondria produce.
At the genetic level, the picture is more complex. The level of inherited mitochondrial DNA defects may establish an individual’s “bioenergetic baseline.” As additional mitochondrial DNA defects develop over the course of a lifetime, bioenergetic capacity may decline until thresholds are crossed where organs malfunction or become susceptible to degeneration.
Another genetic complication is that each mitochondrion contains many copies of mitochondrial DNA, and each cell and tissue contains many mitochondria. At both these levels, there may be many different defects in different copies of the mitochondrial genome. This is especially true of the defects that cause clinical pathologies.
For a particular tissue or organ to become dysfunctional, a critical number of its mitochondrial DNA’s must be mutated. This is called the “threshold effect.” Each organ or tissue is more susceptible to some mutations than others and has its own particular mutational threshold, energy requirement and sensitivity to oxidative stress. All these factors combine to determine how it will respond to genetic damage. The picture is further complicated by interactions between DNA in mitochondria and in the cell nucleus. The result is that the same mitochondrial DNA mutations can produce remarkably different symptoms in members of the same family, while different mutations can produce the same symptoms.
Some of the specific mitochondrial mutations found in mitochondrial diseases develop spontaneously in the aged. More generally, the picture we have sketched of mitochondrial disease illuminates the consequences of Linnane’s theory: it helps explain how mitochondrial mutation-driven bioenergetic decline can have such varied and complex effects over the course of aging.
There is a heterogeneous group of neuromuscular disorders whose exact cause and effective treatment remain largely unknown. These include muscular dystrophy, some encephalomyopathies and various neurogenic atrophies. Several small trials and case reports suggest that some patients with these diseases respond to CoQ10 therapy.
CoQ10 pioneer Karl Folkers observed that cardiovascular disorders are associated with these conditions, as might be expected if cellular energy production were impaired. He therefore conducted a double-blind trial to assess the effect of CoQ10 on cardiac performance in patients with muscular dystrophies and neurogenic atrophies. After three months of treatment with 100 mg of CoQ10 per day, cardiac function was significantly improved in all patients and half the patients showed distinct improvement in movement and exercise capacity. Folkers hypothesized that these conditions have in common a deficiency of CoQ10.
By the same token, mitochondrial defects may contribute to heart disease in some patients. A recent study of dilated cardiomyopathy found that about one in four patients had pathological mutations in the mitochondrial DNA of heart tissue.
In this series of articles we have explored fundamental life processes—cellular bioenergetics, antioxidant defense, mitochondrial genetics—intertwined with mechanisms of aging and degeneration. It will take many years before these biomedical research frontiers revolutionize the practice of conventional medicine. A common theme running through our exploration has been CoQ10’s unique point of leverage on these life processes. Insofar as health—and aging—begins in the cell, CoQ10 may be a cornerstone of vitality and longevity.