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Neuroendocrinology Letters incl. Psychoneuroimmunology & Chronobiology

 

NeuroendocrinologyİLetters
ISSNİ0172ñ780X Copyrightİ©İ1997 NeuroendocrinologyİLetters

NEL Vol. 18 No. 2/3
Original Article

1998; 18:111-122
pii: NEL182397A03

 

Glutathione and Metallothionein in Neurodegeneration-Neuroprotection of Parkinson's Disease
by Manuchair Ebadi, Jorge F. Rodriguez-Sierra and Neil S. Norton

Abstract

Parkinson's disease, known also as striatal dopamine deficiency syndrome, is a degenerative disorder of the central nervous system (CNS) characterized by akinesia, muscular rigidity, tremor at rest, and postural abnormalities. In early stages of parkinsonism, there appears to be a compensatory increase in the number of dopamine receptors to accommodate the initial loss of dopamine neurons. As the disease progresses, the number of dopamine receptors decreases, apparently due to the concomitant degeneration of dopamine target sites on striatal neurons. The loss of dopaminergic neurons in Parkinson's disease results in enhanced metabolism of dopamine, augmenting the formation of H2O2, thus leading to generation of highly neurotoxic hydroxyl radicals (OH'). The generation of free radicals can also be produced by 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) which destroys striatal dopaminergic neurons causing parkinsonism in experimental animals as well as human beings. Studies of the substantia nigra after death in Parkinson's disease have suggested the presence of oxidative stress and depletion of reduced glutathione; a high level of total iron with reduced level offerritin; and a deficiency of mitochondrial complex I.

New approaches designed to attenuate the effects of oxidative stress and to provide neuroprotection of striatal dopaminergic neurons in Parkinson's disease include blocking dopamine transporter by mazindol, blocking NMDA receptors by dizocilpine maleate, enhancing the survival of neurons by giving brain-derived neurotrophic factors (BDNF) and glial cell line-derived neurotrophic factor (GDNF), providing antioxidants such as vitamin E, or inhibiting monoamine oxidase B (MAO-B) by selegiline. Among all of these experimental therapeutic refinements, the use of selegiline has been most successful in that it has been shown that selegiline may have a neurotrophic factor-like action rescuing striatal neurons and prolonging the survival of patients with Parkinson's disease. Selegiline in addition to inhibiting MAO-B, may avert neurodegeneration of striatal neurons by reducing the production of nitric oxide (NO), superoxide anions, and peroxynitrite; and/or selegiline may foster neuroprotection by augmenting the actions of superoxide dismutase, metallothionein (MT), or neurotrophins.

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