**3. Oxidative stress**

Both disorders are caused by mutations in the DMS gene that encodes a 427-kDa cytoskeletal protein called dystrophin. The vast majority of DMD mutations result in the complete absence of dystrophin, whereas the presence of low levels of a truncated protein is seen in BMD patients. The defected gene causes a shortage or absence of the structural protein dystrophin, which is near the sites of Ca 2+ release from sarcoplasmic reticulum and uptake of intracellular Ca 2+. The genetic alteration produces an abnormality in the membrane of muscular fibers that consists of a disturbance in the calcium transport (Ca++), inside the muscular fibers, which is the base mechanism of cellular degeneration, necrosis, and apoptosis (Simonian and Coyle 1996). A nucleotide degeneration and decreased muscle AP and ADP content has been reported. Of the total body selenium reserves consists of muscle selenium supply. Selenium is gradually wasted out by the kidneys during the proceeding of the dystrophy of the legs (Westermarck et al 1982). Open follow-up trials with antioxidants are indicating positive

clinical response (Gebre-Medhin et al 1985; Timberg 1989; Westermarck et al 1997).

Typically, DMD patients are clinically normal at birth, although serum levels of muscle isoform of creatine kinase are elevated. The onset of pseudohypertrophy of the calf muscles, proximal limb muscle weakness suggests DMD. Weakness of the arms occurs later along with progres‐

Most patients die in their early twenties as a result of respiratory complications due to intercostal muscle weakness and respiratory infection. Death can also be the result of cardiac dysfunction with cardiomyopathy. BMD and DMD patients also present with mild cognitive impairment, indicating that brain function is also abnormal in these disorders (Blak and

Fetal DMD is histologically normal except for occasional eosinophilic hypercontracted fibers (Bertorini et al. 1984). Necrotic or degenerating muscle fibers are seen in all postnatal DMD muscle biopsies even before muscle weakness is clinically seen. The necrotic fibers are phagocytized, and muscle biopsies from DMD patients reveal the presence of inflammatory cells at perimysial and endomysiel sites (Arahata and Engel 1984). The regenerative capacity of the muscle is lost and muscle fibers are gradually replaced by adipose and fibrous connective tissue, giving rise to the clinical appearance of pseudohypertrophy followed by atrophy (Emery 1993), resulting in muscle wasting and ultimately muscle weakness (Blake et al 2002). Most patients die in their early twenties as a result of respiratory complications due to intercostal muscle weakness and respiratory infection. Death can also be the result of cardiac dysfunction with cardiomyopathy. BMD and DMD patients also present with mild cognitive impairment, indicating that brain function is also abnormal in these disorders (Blake and

DMD muscle shows signs of oxidative damage (Murphy and Kehrer 1989). Muscle diseases in which oxidative damage may play a primary role show features in common with DMD (Mendell Et al 1971). Moreover, muscle cells from mdx mice have an increased susceptibility

**2. Description and clinical features of Duchenne**

350 Pharmacology and Nutritional Intervention in the Treatment of Disease

sive kyphoscoliosis (Dubowitz. Major Probl Clin Pediatr 1978).

Martin-Rendon, 2002).

Kroger 2000).

Oxidative stress is often defined as an imbalance between the generation of reactive oxygen species and the removal of such species by enzymatic and nonenzymatic cellular defense systems (Figure 1). This imbalance could arise from overproduction of reactive species, as occurs under certain pathologic conditions and in association with inflammation, or from an impairment of the defense mechanisms, as occurs in certain genetic loss-of-function disorders and deficiency states. Implicit in this definition is the notion that such an imbalance is sufficient to lead to the oxidation of various cellular constituents and to cause cellular dysfunction and injury. As such, oxidative stress may also be viewed as a condition in which the production of oxidative products exceeds their removal by cellular repair mechanisms. Such conditions may lead to acute cellular dysfunction or cell death, and chronic tissue degeneration, if such changes accumulate.

During normal cellular metabolism, the primary generation of reactive oxygen species comes from the leakage of superoxide anions from the electron transport chain. A series of linked enzymatic reactions are responsible for the detoxification of superoxide. Superoxide is converted to hydrogen peroxide by the action of superoxide dismutase (SOD). Most animal cells contain two forms of SOD, a cytoplasmic Cu,Zn-SOD and a mitochondrial Mn-SOD. In addition, there is an extracellular form of the enzyme. Hydrogen peroxide is subsequently metabolized to oxygen and water by the selenium-containing enzyme glutathione peroxidase, which uses glutathione (GSH) as a cofactor in the reaction. Glutathione peroxidase converts most of the hydrogen peroxide in the cytoplasm. At sites of relatively high concentrations of hydrogen peroxide, such as peroxisomes, catalase is an important antioxidant enzyme that also converts hydrogen peroxide to water. Hydrogen peroxide can react with metal ions in the cell to produce the highly reactive hydroxyl radical, and superoxide can react with nitric oxide (NO•) to produce peroxynitrite. Hydroxyl radical and peroxynitrite are among the most reactive species present in biological systems and are capable of oxidizing nucleic acids, proteins, lipids, and carbohydrate moieties in the cell.

very similar to those of the muscular dystrophies. The similarities are most striking in avian species in which vitamin E deficiency myopathies closely mimic the hereditary dystrophies both anatomically and biochemically. In humans, vitamin E deficiency is associated with myopathic changes, and in these disorders, there is selective involvement of type IIB fibers as in the inherited muscular dystrophies. Vitamin E refers to a group of compounds of which [alpha]-tocopherol is the most potent and most prevalent in animal tissues as the major lipidsoluble antioxidant in the cell. Deficiencies of vitamin E are associated with increases in lipid peroxidation and decreases in polyunsaturated fatty acids in muscle and compensatory increases in muscle antioxidant enzymes and GSH levels. Although it is clear that inherited muscular dystrophies are not due to primary deficiencies in vitamin E, as was once proposed, the cumulative data strongly support the proposition that the mechanism of muscle injury is

Pharmacological Interventions of Selenium in Duchene Muscular Dystrophy: The Role of Reactive...

http://dx.doi.org/10.5772/57370

353

**5. Can antioxidant treatment ameliorate muscular dystrophy**

detailed understanding of the nature of that susceptibility.

significantly reduced an index of muscle weakness in mdx mice.

In addition to evidence of oxidative damage preceding pathologic changes, amelioration of the pathology of a muscular dystrophy by antioxidant treatment would be strong support for the hypothesis that oxidative stress is a primary pathogenetic process. Various antioxidant treatments have been tried in humans and animals with muscular dystrophy. However, the benefit from any individual antioxidant treatment would depend on the actual nature of the oxidative stress that is occurring in the muscle tissue. For example, supplementation of vitamin E–deficient animals with the most prevalent cellular soluble antioxidant, ascorbic acid (vitamin C), does not significantly improve the myopathy. Different susceptibilities to oxidative stress are not identical. Even if oxidative stress is indeed the primary pathophysiologic process leading to muscle cell death in the dystrophies, effective treatment will need to be targeted to the specific deficit in antioxidant defense in the dystrophic muscle and thus will depend on a

Antioxidant treatments in animals with hereditary muscular dystrophies have provided modest benefits. Penicillamine, a sulfhydryl compound with antioxidant properties, and vitamin E slowed the degenerative process in avian dystrophy. Research showed that iron deprivation resulted in a significant reduction of necrosis in the mdx mouse, presumably by a decrease in the production of hydroxyl radical. Dietary supplementation rich in antioxidants

Clinical trials of antioxidant therapy in humans with Duchenne muscular dystrophy have included treatments with tocopherols, ascorbate, penicillamine, and SOD. No clear benefit has been found from any of these treatments. However, these trials have been very limited in duration and size. Furthermore, in no human study has antioxidant treatment begun early in the course of the disease. In fact, all of these studies involved boys with advanced disease (average age, >=10 yr). Based on the notion that oxidative injury is critical to the pathogenesis of muscle cell death and that antioxidant treatment might be effective to prevent such death, trials in humans would need to be initiated early in the course of the disease, and efficacy

the same in both conditions.

**Figure 1.** The role of free radical in inflammation
