Therapeutic Potential of Radical Scavengers in Parkinsons Disease

The Parkinson's-Reversing Breakthrough

What is Parkinsons Disease

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Silvia Mandel, Edna Griinblatt, and Moussa B. H. Youdim

Technion Faculty of Medicine, Haifa, Israel


Free radicals and other reactive oxygen species (ROS) are formed as side products of oxygen metabolism in every aerobic organism. Acceptance of a single electron by an oxygen molecule forms the superoxide radical, O2", which has an unpaired electron. Superoxide is formed in vivo in a variety of ways. A major source is the mitochondrial electron transport chain. The electrons passing through this chain are captured by O2 leading to water as the end-product. Because O2 accepts one electron at a time, O2~ is formed. Efficient antioxidant systems have been developed to prevent uncontrolled free radical formation before they can cause damage to cellular structures (Fig. 1). Superoxide dismutase is involved in detoxification by dismutation of O2- to hydrogen peroxide (H2O2), which is rapidly converted to water by the reducing enzymes catalase or glutathione peroxidase (1-3). When the balance between the production of oxygen-derived species, such as O2- and H2O2, and antioxidant defenses against them is disturbed, competing mechanisms can lead to abnormal levels of these molecules. H2O2 can react with ferrous ion (Fe2+) to undergo Fenton-type activation, giving rise to the highly cytotoxic hydroxyl radical (Off), as schematized in Figure 1.

Dopamine (DA) neurons within the substantial nigra may be particularly vulnerable to oxidant stress. Autooxidation or monoamine oxidase (MAO)-cata-lyzed DA oxidation could increase the likelihood of H2O2 formation with consequent Off production, by means of iron-catalyzed Fenton reaction. Indeed, postmortem studies conducted in brain from parkinsonian patients indicate that a state of oxidant stress exists in the substantial nigra pars compacta, as manifested by

Figure 1 Biochemical reactions hypothesized to cause oxidative stress in dopaminergic neurons.

increased levels of brain lipid hydroperoxides, accumulation of iron, and decreased levels of glutathione, the primary mechanism for clearing peroxides in the brain.

Catecholamines may also interfere with the cellular oxygen metabolism in several ways including their MAO metabolic transformation which leads to formation of H2O2. In addition, they also may undergo autooxidation in the presence of iron to generate H2O2, O2", and reactive quinones and semiquinones. Furthermore, catecholamines and their metabolites, as well as neuromelanin, are excellent iron chelators and are capable of maintaining the low molecular weight iron (Fe3+) pool. On the other hand, neuromelanin reduces Fe3+ to Fe2+ thus releasing Fe2+ back into the cytosol (4).

The reaction between H2O2, iron, and DA may be a source of endogenous 6-hydroxydopamine (6-OHDA) formation. This risk is increased in Parkinson's disease (PD) where the concentrations of iron in the striatum are relatively high. 6-OHDA by itself liberates iron from ferritin (5). In addition, 6-OHDA, as well as DA, have been shown to inhibit complex I and IV of the mitochondrial respiratory chain (6,7).

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