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.
