Barbeau A
Neurotoxicology. 1984 Spring;5(1):13-35.
In this essay we first review the important contributions of Dr. George Cotzias to the understanding of chronic manganese intoxication and of manganese metabolism in man and animals. We also indicate the original contribution of Dr. John Donaldson to the mechanism of the neurotoxicity of manganese. In a second phase, the author challenges the tenet that Parkinson's disease is a form of chronic manganese intoxication and that manganism is an experimental model for Parkinson's disease. Clinical, pathological, experimental and biochemical evidence are brought to bear on this argument. Thirdly the author proposes that the necessary event to the so-called "depigmentation" of the substantia nigra and subsequent bradykinetic "low dopamine" syndrome is an early enhanced turnover of dopamine. Manganese intoxication is only one of the factors which may serve as a trigger to this event. Many others are also listed. In opposition to current views, who look for causal factors in Parkinson's disease along the pathways for melanogenesis, the author thus proposes a novel hypothesis which envisions a variety of transient "trigger factors" acting at the dopamine synapse to increase dopamine turnover. In turn, this increased synthesis of dopamine favours the production of large quantities of free radicals within the cell bodies in the substantia nigra, eventually overflowing the scavenging capacity of neuromelanin and their protective barrier, and causing cell death. The resulting decreased pool of dopamine-producing cells leads to a self-perpetuating situation of ever increasing demand on the remaining cells, and "progression" of the disease. Finally the author stresses the fact that genetic factors may play a role in an individual's susceptibility to such triggers. Again defective manganese transport, metabolism or binding are only some of the mechanisms possibly underlying such genetic predisposition to induced basal ganglia disorders. Further studies relating to manganese in these disorders and particularly in Parkinson's disease should focus not on the "intoxication" part of the overload and its striatopallidal consequences, but on the intimate mechanism of destabilization of the homeostatic regulator in neuromelanin bearing cells, even after the exposure period.
在本文中，我们首先回顾乔治·科齐亚斯博士在理解慢性锰中毒以及人类和动物锰代谢方面所做出的重要贡献。我们还指出约翰·唐纳森博士对锰神经毒性机制的原创性贡献。在第二阶段，作者对帕金森病是慢性锰中毒的一种形式以及锰中毒是帕金森病实验模型这一观点提出质疑。临床、病理、实验和生化证据都被用于支持这一论点。第三，作者提出，黑质所谓的“色素脱失”以及随后的运动迟缓“低多巴胺”综合征的必要事件是多巴胺早期周转率的提高。锰中毒只是可能引发这一事件的因素之一。还列出了许多其他因素。与目前沿着黑色素生成途径寻找帕金森病病因的观点相反，作者因此提出了一个新的假说，设想有多种短暂的“触发因素”作用于多巴胺突触以增加多巴胺周转率。反过来，多巴胺合成的增加有利于在黑质细胞体内产生大量自由基，最终超过神经黑色素及其保护屏障的清除能力，导致细胞死亡。由此产生的多巴胺生成细胞池减少导致对剩余细胞的需求不断增加的自我持续状态，以及疾病的“进展”。最后，作者强调遗传因素可能在个体对这类触发因素的易感性中起作用。同样，锰运输、代谢或结合缺陷只是这种遗传易感性导致基底神经节疾病的一些可能潜在机制。与这些疾病尤其是帕金森病中的锰相关的进一步研究不应集中在过载的“中毒”部分及其纹状体苍白球后果上，而应集中在含神经黑色素细胞内稳态调节因子不稳定的内在机制上，即使在接触期之后。
