Molecular function of metallothionein-III in parkinsonism with drug treatment

为了阐明金属硫蛋白（MT），特别是MT-III在帕金森病和老年人中的功能、作用和参与机制，我们研究了MT-III的表达和功能，以及MT在多巴胺能药物、氧化应激和衰老过程中的变化。帕金森病动物模型脑内MT-III mRNA的表达左旋多巴诱导的对侧纹状体MT-III mRNA的表达增加，在6-羟基多巴胺（6-OHDA）损毁的偏侧帕金森病大鼠中未见，提示MT-III通过左旋多巴治疗帕金森病患者的大脑通过产生氧化应激来减轻疾病。衰老和炎症应激对脑中MT-Ⅲ表达的影响产生炎症的内毒素脂多糖的治疗显著诱导了MT-Ⅲ表达的增加，特别是在成年大鼠脑区域的少突胶质细胞和小胶质细胞中。然而，毒素的治疗并没有增加，而是抑制MT-III在老龄大鼠脑中的表达，这表明脑MT-III对抗氧化应激的责任随着年龄的增长而降低.分化后多巴胺能细胞中MT-III的表达及其亚细胞定位分化剂处理可增加多巴胺能细胞中MT-III的表达。此外，我们阐明了当脑提取物的额外处理产生凋亡性细胞死亡时，MT-III在分化的多巴胺能细胞中易位到细胞核中. 6-OHDA对MT-Ⅰ和-Ⅱ基因敲除小鼠黑质多巴胺能神经元的损伤MT-Ⅰ和-Ⅱ基因敲除小鼠黑质多巴胺能神经元损伤明显加重，提示MT-Ⅰ和-Ⅱ对6-OHDA的黑质多巴胺能神经毒性具有神经保护作用。

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.