Studies on specific genes in the brain induced by DOPA and their function.

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To clarify the molecular events in the brain of parkinsonian who treated with levodopa of anti-parkinsonian drugs, we investigated the genes in the nigrostriatal pathway of parkinsonian model animals specifically induced by levodopa treatment, and also analyzed their function, as follows :1.Screening of expressed genes in the brain of parkinsonian models after levodopa treatmentWe screened the specific genes which expressed in the striatum of hemi-parkinsonian model rats after levodopa treatment by using differential display method. A proapoptotic gene, p53-activated gene 608(PAG608) was identified as a DOPA-induced gene in parkinsonian brain.2.Role of PAG608 in oxidative stress-induced apoptosis in dopaminergic neuronal cellsIn the catecholaminergic cells, inhibition of PAG608 expression by the transfection with antisense PAG608 cDNA blocked 6-hydroxydopamine-or hydrogen peroxide-induced cell death, increases in p53 and Bax expression, reduction of mitochondrial membrane potential, ac … More tivation of caspase-3 and DNA fragmentation. Although PAG608 is activated by p53, overexpression of PAG608 by the transfection of PAG608 gene inversely increased p53 expression. Furthermore, we clarified that the translocation of PAG608 to the nucleus and nucleolus is necessary for induction of apoptosis.3.Involvement of PAG608 in_dopamine-or methamphetamine-induced neurotoxicityThe inhibition of PAG608 expression by the transfection with antisense PAG608 cDNA also blocked excess dopamine-or methamphetamine-induced dopaminergic cell death and their apoptotic morphological changes.4.Expression of PAG608 in the brain of levodopa-treated parkinsonian model ratsPAG608 constitutively expressed in the pontine nucleus, motor nuclei of trigeminal nerve and facial nerve. In the internal capsule, PAG608 expression was strongly induced in the parkinsonian side of levodopa-treated group.These experimental results suggest that PAG608 is generally involved in the common pathway of dopaminergic neuronal death induced by the treatment of levodopa or methamphetamine and that it is a molecule specifically induced by excess amount of dopamine in the basal ganglia of parkinsonian models. Less