OXIDATIVE STRESS AND INFLAMMATION IN MPTP PARKINSONISM AND IDIOPATHIC PARKINSON'S DISEASE: STUDIES FROM cDNA MICROARRAY GENE EXPRESSION
1Moussa B.H. Youdim, 2Gila Maor and Silvia Mandel
1Eve Topf and US National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology and 2Department of Cell Biology ,Technion-Faculty of Medicine, Haifa, Israel.
Cell death whether it occurs in systemic organs or CNS involves a set
of complex processes, many of which have not been identified
biochemically. In Parkinson's disease environmental factors and genetic
vulnerability of nigro-striatal dopamine-containing neurons have been
implicated. It is possible that both events are involved. At the
present biochemical techniques can not adequately establish this.
However, the advent of cDNA microarray or microchips (genomics) and
proteomics, by which the expression of thousands of genes and their
proteins can be measured at once to give a global assessment of the
disease pathology progress, is simplifying this. We have employed
these techniques to study the mechanism of neurotoxicity induced by
MPTP and 6-hydroxydopamine in neuronally-derived cells in culture and
in the animal models of Parkinson's disease, and the neuroprotection
initiated by the monoamine oxidase-B inhibitor/anti-Parkinson drug
rasagiline, iron chelators (R-apomorphine, green tea polyphenol EGCG
and VK-28) and other neuroprotective drugs. Our studies have clearly
indicated that MPTP-induced early (first 24 hr) gene expression, prior
to nigro-striatal dopamine neuron death, are a prerequisite for the >50
late gene changes implicated at the time of neuronal death. The latter
include genes involved in iron metabolism, oxidative stress,
inflammatory processes, glutamatergic excitotoxicity, nitric oxide,
growth factors, cytokines, transcription factors, cell cycle,
apoptosis, intermediatory metabolism and others (huntingtin,
prostaglandines and neurotrophic factors), previously not identified.
The expression changes of many of the latter genes, also identified by
in-situ hybridization, is prevented when the animals are pretreated
with the aforementioned neuroprotective drugs, such as R-apomorphine,
EGCG and rasagiline. These studies clearly show that neurodegeneration
is a complex cascade of "domino effect" in which single neuroprotective
drug treatment may not be adequate in clinical therapy. But rather,
similar to the treatment of cancer, AIDS and cardiovascular diseases, a
cocktail of neuroprotective drugs may be of greater effectiveness for
the treatment of neurodegenerative diseases. Our goal is to understand
the interplay of early gene changes with the process of
neurodegeneration and neuroprotective pharmacological activities.
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