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

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.

352 Pharmacology and Nutritional Intervention in the Treatment of Disease

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

**4. Oxidative stress cause dystrophic changes**

One of the first observations that led to the oxidative stress hypothesis was the finding that vitamin E deficiency in animals leads to muscle degeneration with pathologic characteristics 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 detailed understanding of the nature of that susceptibility.

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 significantly reduced an index of muscle weakness in mdx mice.

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 would need to be assessed primarily as the slowing, not a reversal, of muscle loss. The difficulties and pitfalls of clinical trials for new treatments of muscular dystrophies are well known. Thus, based on both statistical power and theoretical benefit, none of these human trials would even be predicted to demonstrate any benefit, and the negative results do not in any way refute the oxidative stress hypothesis.

**7. Treatment of brain diseases with selenium**

it affected the brain via abnormal liver function.

**8. Hypotesis and intervention**

radical (O2-

Two children with severe neurodevelopmental retardation and elevated liver function tests developed intractable seizures during the first years of life. They were found systemically selenium deficient. Oral substitution with selenium supplements in both children (3–5 µg/kg body weight) resulted in reduction of seizures, improvement of the electroencephalogram (EEG) recordings, and return of normal liver function after 2 weeks (Ramaekers et al. 1994). It is unknown if selenium deficiency is a direct factor for the neurodevelopmental retardation or

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

Methamphetamine (MA) exposure of animals results in enhanced formation of superoxide

ynitrite is a potent oxidant, leading to dopaminergic damage (Imam and Ali 2000). Thus, multiple dose administration of MA to mice results in long-lasting toxic effects in the nigros‐ triatal dopaminergic system, which is a relevant model of PD. In selenium-replete mice, this dopaminergic toxicity was significantly attenuated, compared with selenium-deficient mice (Kim et al. 1999; Kim et al. 2000). Pre-treatment of animals with selenium and melatonin can completely protect against the depletion of striatal dopamine induced by MA exposure (Imam et al. 2001). The reason for the protective effects of selenium against MA was reported to be

6-hydroxydopamine (6-OHDA) is a neurotoxin specific for catecholamine neurons in both the central and peripheral nervous system. PD induced by this compound in rats was prevented by selenium in a dose-dependent manner, through up-regulating the antioxidant status and lowering the dopamine loss. This study revealed that selenium may be helpful in slowing

It is possible to improve the life quality of Duchenne patients by biological active substances (antioxidants), and psychotherapeutic intervention. Therapy of DMD has been an elusive goal. Studies with isolated myocytes have shown that lipid peroxidation with an enhanced free radical production can be activated by increasing Ca concentration. No wonder that several kinds of antioxidants have been proposed as a treatment since increased levels of thiobarbituric acid (TBA) reactive material has been found in the muscles and blood of patients with DMD.

Vitamin E has been observed to decrease the amount of TBA reactive material in dystrophic muscle. Previously we have reported that the biological half-life of selenium -75 (75Se) in DMD patients is significantly shorter than in healthy controls (Westermarck et al 1982). On the basis of these facts we started to treat some DMD patients with selenium and other antioxidants. Selenium is activating a well-known antioxidative enzyme glutathione peroxidase (GSH-Px, iodothyronine desiodinase, selenoprotein P, thioredoxin reductase and the selenoprotein W, that all contain selenocystein. Beside iodothyronine desiodinase that facilitates the activation

the efficient scavenging of peroxynitrite by selenoproteins (Sies and Arteel 2000).

down the progression of neurodegeneration in Parkinsonism (Zafar et al. 2003).

) and nitric oxide (NO), which interact to produce peroxynitrite (OONO-

). Perox‐

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