**1. Introduction**

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348 Pharmacology and Nutritional Intervention in the Treatment of Disease

The muscular dystrophies are a group of muscle diseases which have three features in common: they are hereditary; they are progressive; and each causes a characteristic, selective pattern of weakness. Duchenne muscular dystrophy (DMD) is the most common inherited muscular disease, affecting one in 3,500 male births. DMD is characterized by rapid, progres‐ sive muscle wasting that typically kills patients in their twenties. Complete muscle dystrophin deficiency is a common mechanism for DMD.

Duchenne muscular dystrophy (DMD) is a severe X-linked recessive, progressive musclewasting disease affecting one in 3500 boys (Emery AEH, 1993). Patients are usually confined to a wheelchair before the age of 12 and die in their late teens or early twenties usually of respiratory failure. A milder form of the disease, Becker muscular dystrophy (BMD), has a later onset and a much longer survival.

The most widely studied dystrophies are those due to mutations in the dystrophin gene. In humans, dystrophin deficiency leads to the severe disease, Duchenne muscular dystrophy, whereas reductions or truncations of dystrophin lead to a milder disease, Becker muscular dystrophy. Numerous animal models of dystrophin deficiency are actively studied, but none more so than the *mdx* mouse. Despite over a decade of study of dystrophin and its associated proteins, some of which themselves cause muscular dystrophies when deficient or defective, the mechanisms by which the primary biochemical defects lead to muscle cell death remain to be determined.

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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).

to oxidative stress (Rando et al 1998). The lack of neuronal-type nitric oxide synthase (nNOS) seen in DMD causes disregulation of vascular tone, and ischemia (Crosbie 2001, Blake et al 2002). This henomenon may increase the generation of free radicals. Open follow-up trials with antioxidants are indicating positive clinical response (Gebre-Medhin et al 1985; Timber 1989;

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

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A low blood selenium level has previously been observed in healthy inhabitants of Finland (WESTERMARCK, 1977). In this study even lower blood selenium values were observed in patients with acrodermatitis enteropathica, dystrophia musculorum progressiva (Duchenne), infantile and juvenile type of neuronal ceroid lipofuscinosis (NCL), severe mental retardation caused by various factors, and myocardial infarction. The selenium content of the brain, heart, kidney and liver in patients of different ages was also determined. The highest selenium level was found in the kidney. The mean liver selenium concentrations in stillborn, premature and full-term neonates were 1.11 +/- 0.23 (8), 1.21 +/- 0.17 (12) and 0.93 +/- 0.16 microgram/g dry weight (12) respectively (the number of subjects in parentheses). The selenium values are considerably higher than those in infants of from one to nine months of age and adults, whose liver selenium values were 0.58 +/- 0.21 (8) and 0.67 +/- 0.08 microgram/g dry weight (8) respectively. The vitamin E levels of serum in patients with NCL, as well as in subjects with severe mental retardation (controls), were low compared with values in healthy normal subjects. Sodium selenite supplementation in patients with NCL produced at least a transitory improvement without causing any toxic effects during one year of administration. In Duch‐ enne muscular dystrophy we found that 75Se-selenite was not absorbed in the lower extremities

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

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

Westermarck et al 1997).

in the equal level compared to healthy ones.

**3. Oxidative stress**

accumulate.
