Manganese and extrapyramidal disorders (a critical review and tribute to Dr. George C. Cotzias).

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.