Anti Oxidants
Oxidative stress and Duchenne dystrophy
Protantdim:
Joe McCord of the University of Colorado and the company LifeVantage Corp. in Denver
discussed a new way, at the PPUK (now Action Duchenne) confernce in London 2006, of therapeutic control of oxidative stress. Oxidative stress is an important component of more than 100 diseases, among them Duchenne dystrophy. Every cell, also each muscle cell, contains many mitochondria. They are oval-shaped organelles typically about 0.002 mm in length and 0.0005 mm in diameter, about the size of a bacterium. They are the power stations of the cell because they synthesize the energy-rich compound adenosine triphosphate, ATP, by the process of oxidative phosphorylation. The end products of this energy production are carbon dioxide and water. But about 1-2% of the oxygen consumed is not converted to water, but rather to the superoxide free radical. It has an odd number of electrons which makes it especially reactive. The cell defends itself against this toxic product with two very efficient enzymes. One is superoxide dismutase, SOD, which converts the radical to hydrogen peroxide, that is less reactive but still an oxidant. The other enzyme is catalase, which converts the hydrogen peroxide into water and oxygen, which are completely non-toxic. When the production of the superoxide radicals exceeds the normal limit of 2%, the cells experience oxidative stress.
This happens any time a cell is injured. Muscle cells become dystrophic when large amounts of calcium ions enter through the cell membrane into the interior where they cause the mitochondria to swell and to disrupt with the consequence that more than normal superoxide radicals are made, more than the cell can destroy. The excess radicals can oxidize lipids, oxidize proteins, modify enzymes, damage DNA and cause even cancer. They are also contributing to the aging process.
Another source of oxidative stress is inflammation. White blood cells are the only cells that make free radicals intentionally in order to kill and digest invading microbes and viruses. But this process also damages the host cells, and cause muscle cells to releases proteins into the blood stream like, for instance, creatine kinase. Inflammation also changes the signaling processes and may cause apoptosis, the self destruction of cells. Also fibrosis is triggered by oxidative stress, the forming of scar tissue in diseases with chronic inflammation, among them Duchenne dystrophy where elastic muscle tissue is replaced by inflexible connective tissue.
Twenty years ago, it was found that the most prevalent products of oxidative stress, the peroxidized lipids, were increased by an average of 35% in Duchenne boys. But until very recently, it was impossible to restore the oxidative balance when, in 2006, Werner Boecker and his colleagues in Germany showed that in Duchenne and Becker patients, the muscle fibers and the vasculature, the blood vessels, undergo massive oxidative stress resulting in a reduction of bioactive NO, nitric oxide, a “good” free radical. This gaseous hormone is produced by the enzyme NO synthase, NOS, and regulates, among other processes, the elasticity of blood vessels, the vascular tone. The enzyme NOS is upregulated in muscle tissue which tries to normalize the amount of NO, but this process is insufficient because of the muscle degeneration and also because NO reacts with the superoxide radicals. The product of this reaction is peroxynitrite, OONO, another reactive oxidant which intensifies the oxidative stress. In earlier laboratory experiments, it was shown that the addition of the enzymes superoxide dismutase and catalase to isolated perfused hearts could block the oxidative stress by destroying the excess of the free radicals and prevent the release of the enzyme creatine kinase.
In other studies, superoxide dismutase was shown to reduce the elevated levels of the protein factor TGF-beta which is a signal for fibroblasts to produce fibrosis. The muscles of Duchenne boys function relatively well until about three years of age. After this time, the consequences of oxidative stress overcome more and more the normal muscle regeneration. These consequences are chronic inflammation, fibrosis and also cognitive impairment.
For a therapy of Duchenne dystrophy, it would be important to interrupt these processes at this age or earlier. It was believed that one rather easy way to do this would be the ingestion of the known antioxidants vitamin E and vitamin C. But it had been shown in many studies, that large quantities of these vitamins do not have an effect on oxidative stress. Also eating 600 grams of fruits and vegetables per day had no effect on oxidative damage to DNA. The “antioxidant” vitamins are important for other reasons, but they do not reduce oxidative stress. The other possibility is to increase the level of the two enzymes superoxide dismutase and catalase which, as mentioned, can destroy the excessive amount of free radicals. After all, one molecule of vitamin C can eliminate two molecules of free radicals, but not more, whereas one molecule of superoxide dismutase can eliminate one million free radicals 17 every second and maintain this activity for a long time.
Thus Dr. McCord with the company LifeVantage developed a dietary supplement containing “adaptogenic” compounds from five plant species for effectively inducing the two antioxidant enzymes to reduce the oxidative stress, mainly the peroxidation of lipids. This supplement, tradenamed Protandim®, contains extracts of the plants Bacopa monnieri, Silibum marianum or milk thistle, Withania somnifera also known as ashwagandha, Curcuma longa from which the spice turmeric is derived, and Camellia sinensis or green tea. The last one provides one of the active ingredients of green tea, (-)-epigallocatechin gallate or EGCG, which had been shown before by Urs Rüegg in Geneva to have a beneficial effect on Duchenne dystrophy. In 2006, Protandim has been clinically tested in 29 healthy persons in age from 20 to 78 years. Several parameters were measured at the beginning of the study and after 30 and 120 days of daily supplementation with Protandim, among them superoxide dismutase and catalase.
The average increase after 120 days were 30% for superoxide dismutase and 54% for catalase and the peroxidation of lipids was significantly inhibited. Important for the age-related increase of oxidative stress was the fact that after 30 days Protandim, the age-related increase of lipid peroxidation virtually disappeared, and its average level dropped by 40%. In conclusion: While Duchenne muscular dystrophy is caused by a specific genetic defect, there is abundant evidence that oxidative stress becomes an increasingly important factor in the progression of the disease. The new developments in the effective management of oxidative stress justify immediate consideration of clinical trials with Duchenne patients
SNT-MC17/idebenone in clinical development: Thomas Meier, Chief Scientific Officer at Santhera Pharmaceuticals
in Liestal near Basel could not come to the meeting in London. He sent the following summary: SNT-MC17/idebenone is a molecule that protects mitochondria, the power stations in the cells where the universal energy carrier, adenosine triphosphate, ATP, is made by oxidative phosphorylation. This compound SNTMC17, or idebenone, has recently successfully completed a clinical trial in the US in collaboration with the NIH demonstrating efficacy on neurological aspects of Friedreich’s Ataxia, another devastating neuromuscular disease.
A phase-III clinical trial for Friedreich's Ataxia is already ongoing in Europe. Friedreich’s Ataxia is a rare neuromuscular disease which besides neurological symptoms is frequently associated with cardiomyopathy, a severe disease of the heart muscle. SNT-MC17/idebenone is a potent antioxidant with a chemical structure derived from natural coenzyme Q10. The optimized chemical structure has a much shorter and different side chain which results in an improved pharmacokinetic profile allowing the molecule to enter muscle cells easier than coenzyme Q10. SNT-MC17/idebenone has also been shown to facilitate the ATP production in the mitochondria. It can be given orally as a tablet. The absence of dystrophin also negatively affects the oxidative phosphorylation in the mitochondria of the heart muscles of Duchenne patients and probably in those of their skeletal muscles, too. A phase-IIa double-blind, placebo- controlled randomized clinical trial with SNT-MC17/ idebenone is currently underway in Belgium under the leadership of Dr. Gunnar Buyse. The study has completely enrolled 21 Duchenne boys at 8 to 16 years of age. The primary objective of this study is to determine the effect of SNT-MC17/idebenone on heart muscle function. In addition several different tests will be performed to detect the possible functional benefit on muscle strength in Duchenne boys treated with SNT-MC17/idebenone.
The boys are receiving the study medication three times a day in form of tablets containing either 150 mg SNT-MC17/idebenone or placebo for the duration of 12 months. This trial is called Duchenne Efficacy Study in Longterm Protocol of High dose Idebenone, DELPHI. Its results will be available in the second half of 2007.
From Günter Scheuerbrandt Report of the PPUK (now Action Duchenne) Conference 2006