Molecular function of metallothionein-III in parkinsonism with drug treatment

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To clarify the function, role and involvement of metallothionein (MT), especially MT-III, in parkinsonian and aged, we investigated the expression and function of MT-III, and changes in MT with the treatment of dopaminergic drugs, oxidative stress and aging, as follows:1. Expression of MT-III mRNA in the brain of animal models of Parkinson's diseaseLevodopa-induced increase in MT-III mRNA which shown in the contralateral side of the striatum was not seen in the ipsilateral side of the striatum in hemi-parkinsonian rats which lesioned by 6-hydroxydopamine (6-OHDA), suggesting that low inducibility of MT-III by levodopa treatment in the parkinsonian brain aggravates the disease through generation of oxidative stress.2. Effects of aging and inflammatory stress on MT-III expression in the brainThe treatment of an endotoxin lipopolysaccaride which produces inflammation markedly induced increases in MT-III expression, especially in the oligodendroglial cells and the microglial cells, in the young-adult rat brain regions. However, the treatment of the toxin did not increase rather suppress MT-III expression in the aged rat brain, suggesting that the responsibility of brain MT-III against oxidative stress is decreased as aging.3. MT-III expression and its subcellular localization in the differenciated dopaminergic cellsThe treatment of differentiating reagent increased MT-III expression in dopaminergic cells. Furthermore, we clarified that MT-III was translocated into the nucleus in the differentiated dopaminergic cells when additional treatment of brain extract produced apoptotic cell death.4. Dopaminergic lesions by 6-OHDA in metallothionein-I and -II knock-out mice brainThe loss of nigral dopamine neurons induced by the 6-OHDA injection was significantly aggravated in the MT-I, II knock-out mice, suggest that MT-I and -II exert neuroprotective effects against the dopaminergic neurotoxicity of 6-OHDA in the substantia nigra.