Neuromelanin synthesis in rat and human substantia nigra
A relation between neuromelanin synthesis and vulnerability of dopaminergic neurons is suggested by the fact that heavily pigmented cells are preferentially lost in aging and Parkinson's disease and that the dopaminergic neurotoxin MPP+ (1-methyl-4-phenyl-pyridine) binds to neuromelanin. To elucidate the mechanism of neuromelanin synthesis, we studied the formation of melanin in homogenates of human and rat substantia nigra tissue “in vitro”. It was found that enzymatic processes accounted for 70% and 90% of the melanin formation in homogenates of human and rat tissue, respectively. The enzymatic synthesis was due to the activity of monoamine oxidase (MAO), since it was prevented by selective inhibitors of this enzyme. Both MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and MPP+ inhibited melanin formation, probably due to their ability to inhibit MAO. No evidence was found for involvement of cytochrome P-450 monooxigenases, which have been postulated to exist in central catecholaminergic neurons. Proadifen reduced melanin formation, not necessarily because it is an inhibitor of P-450 monooxigenases, but rather as it is also a potent inhibitor of MAO. Some antioxidants like ascorbic acid, but not agents destroying hydrogen peroxide, inhibited melanin formation. The findings suggest that the formation of neuromelanin in the substantia nigra involves MAO and non-enzymatic oxidative processes.
KeywordsMPTP MPP+ neuromelanin Parkinson's disease
Unable to display preview. Download preview PDF.
- Del Zompo M, Piccardi MP, Bernardi F, Bonuccelli U, Corsini GU (1986) Involvement of monoamine oxidase enzymes in the action of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine, a selective neurotoxin in the Squirrel monkey: binding and biochemical studies. Brain Res 378: 320–324CrossRefPubMedGoogle Scholar
- Haglund L, Kohler C, Haaparanta T, Goldstein M, Gustafsson JA (1984) Presence of NADPH-cytochrome P-450 reductase in central catecholaminergic neurons. Nature 107: 259–262Google Scholar
- Knoll J (1983) Deprenyl (selegiline): the history of its development and pharmacological action. Acta Neurol Scand 95: 57–80Google Scholar
- Kopin IJ, Burns SR, Chiueh CC, Markey SP (1986) MPTP induced Parkinsonian syndromes in humans and animals. In: Fisher A, Hanin I, Lachman CH (eds) Alzheimer and Parkinson's disease. Strategies for research and development. Plenum Press, New York (Adv Behav Biol, vol 29, pp 519–530)Google Scholar
- Lichtensteiger W, Felix D, Lienhart R, Hefti F (1976) A quantitative correlation between single unit activity and fluorescence intensity of dopamine neurons in zona compacta of substantia nigra, as demonstrated under the influence of nicotine and physostigmine. Brain Res 117: 85–103CrossRefPubMedGoogle Scholar
- Lyden A, Bondesson V, Larsson BS, Lindquist NG (1983) Melanin affinity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, an inducer of chronic parkinsonism in humans. Acta Pharmacol Toxicol (Copenh) 53: 429–432Google Scholar
- Marsden CD (1983) Neuromelanin and Parkinson's disease. J Neural Transm 19: 121–141Google Scholar
- Mayer SE, Melmon KL, Gilman AG (1980) The dynamics of drug absorption, distribution and elimination. In: Goodman Gilman A, Goodman LS, Gilman A (eds) The pharmacological basis of therapeutics. McMillan, New York, pp 1–27Google Scholar