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

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

Oxidative stress and generation of reactive oxygen species (ROS) are strongly implicated in a number of neuronal and neuromuscular disorders, including stroke and cerebrovascular disease, Alzheimer's disease, Parkinson's disease, familial amyotrophic lateral sclerosis, and Duchenne muscular dystrophy (Dexter et al. 1989a,b; Smith et al. 1991; Ragusa et al. 1997; Cornett et al. 1998b; Facchinetti et al. 1998; Sagara et al. 1998; Tan et al. 1998). Selenium is known to provide protection from ROS-induced cell damage, and the proposed mechanisms mainly

Considerable evidence exists linking heavy metals to neurodegenerative diseases (Thompson et al. 1988; Deibel et al. 1996; Cuajungco and Lees 1997; Schionning et al. 1997; Cornett et al. 1998b; Ely 2001). Heavy metals trigger the conversion of hydrogen peroxide to hydroxyl radical through Fenton reaction. Selenium has long been known to function as an antidote to toxicity of heavy metals. Co-administration of selenium was reported to play a role in reducing the toxic effects of mercury as early as the 1970s (Koelman et al. 1973; Kosta et al. 1975). Among the selenoproteins, SelP has been reported in several studies to possess metal-binding function (see below). The GPxs might also detoxify heavy metals through their well-known function of

**Figure 2.** Complementary actions of selenium (GSH-Px) in free radical formation and lipid peroxidation (from Para‐

invoke the functions of glutathione peroxidases (GPxs) and selenoprotein P (SelP).

any way refute the oxidative stress hypothesis.

354 Pharmacology and Nutritional Intervention in the Treatment of Disease

eliminating peroxides (Figure 2).

ntainen et al., 1987)

**6. Selenium in the brain and brain diseases**

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 it affected the brain via abnormal liver function.

Methamphetamine (MA) exposure of animals results in enhanced formation of superoxide radical (O2- ) and nitric oxide (NO), which interact to produce peroxynitrite (OONO- ). Perox‐ 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 the efficient scavenging of peroxynitrite by selenoproteins (Sies and Arteel 2000).

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