Summary
The amino acid, 6-hydroxydopa (6-OHDOPA), found at the active site of amine oxidases, exists as a keto-enol. Exogenously administered 6-OHDOPA is an excitotoxin likeβ-N-oxalylamino-L-alanine (BOAA) andβ-N-methylamino-L-alanine (BMAA), acting at the non-N-methyl-D-aspartate (non-NMDA)α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor. BMAA and BOAA are causal factors of neurolathyrism in humans. Much exogenously administered 6-OHDOPA is biotransformed by aminoacid decarboxylase (AADC) to the highly potent and catecholamine (CA) selective neurotoxin, 6-hydroxydopamine (6-OHDA). 6-OHDOPA destroys locus coeruleus noradrenergic perikarya and produces associated denervation of brain by norepinephrine-(NE) containing fibers. Opiopeptides and opioids enhance neurotoxic effects of 6-OHDOPA on noradrenergic nerves, by a naloxone-reversible process. An understanding of mechanisms underlying neurotoxic effects of 6-OHDOPA can be helpful in defining actions of known and newfound amino acids and for investigating their potential neurotoxic properties.
Similar content being viewed by others
Abbreviations
- AADC:
-
aminoacid decarboxylase
- AMPA:
-
α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid
- BOAA:
-
β-N-oxalylamino-Lalanine
- CA:
-
catecholamine
- L-DOPA:
-
L-dihydroxyphenylalanine
- DA:
-
dopamine
- EAA:
-
excitatory amino acid
- 6-OHDOPA:
-
6-hydroxydopa
- 6-OHDA:
-
6-hydroxydopamine
- NE:
-
norepinephrine
- BMAA:
-
β-N-methylamino-L-alanine
- NMDA:
-
N-methyl-D-aspartate
- S.E.M.:
-
standard error of the mean
References
Cha JH, Dure LS, Sakurai SY, Penney JB, Young AB (1991) 2,4,5-Trihydroxyphenylalanine (6-hydroxy-dopa) displaces [3H]AMPA binding in rat striatum. Neurosci Lett 132: 55–58
Clark MB, King JC, Kostrzewa RM (1979) Loss of nerve cell bodies in caudal locus coeruleus following treatment of neonates with 6-hydroxydopa. Neurosci Lett 13: 331–336
Harston CT, Clark MB, Hardin JC, Kostrzewa RM (1981) Opiate-enhanced toxicity and noradrenergic sprouting in rats treated with 6-hydroxydopa. Eur J Pharm 71: 365–373
Jacobowitz D, Kostrzewa R (1971) Selective action of 6-hydroxydopa on noradrenergic terminals: mapping of preterminal axons of the brain. Life Sci 10: 1329–1341
Janes SM, Mu D, Wemmer D, Smith AJ, Kaur S, Maltby D, Burlingame AL (1990) A new redox cofactor in eukaryotic enzymes: 6-hydroxydopa at the active site of bovine serum amine oxidase. Science 248: 981–987
Kostrzewa RM (1998) 6-Hydroxydopa, a catecholamine neurotoxin and endogenous excitotoxin at non-NMDA receptors. In: Kostrzewa RM (ed) Highly selective neurotoxins: basic and clinical applications. Humana Press, Totowa, NJ (in press)
Kostrzewa RM, Garey RE (1977) Sprouting of noradrenergic terminals in rat cerebellum following neonatal treatment with 6-hydroxydopa. Brain Res 124: 385–391
Kostrzewa RM, Harper JW (1974) Effects of 6-hydroxydopa on catecholamine-containing neurons in brains of newborn rats. Brain Res 69: 174–181
Kunig G, Hartmann J, Niedermeyer G, Deckert J, Ransmayr G, Heinsen H, Beckmann H, Riederer P (1994) Excitotoxins L-beta-oxalyl-amino-alanine (L-BOAA) and 3,4,6-trihydroxyphenylalanine (6-OH-DOPA) inhibit [3H]alpha-amino-3-hydroxy-5-me thyl-4-isoxazole-propionic acid (AMPA) binding in human hippocampus. Neurosci Lett 169: 219–222
Metodiewa D, Reszka K, Dunford HB (1989) Oxidation of the substituted catechols dihydroxyphenylalanine methyl ester and trihydroxyphenylalanine by lactoperoxidase and its compounds. Arch Biochem Biophys 274: 601–608
Morrison ME, Yagi MJ, Cohen G (1985) In vitro studies of 2,4-dihydroxyphenylalanine, a prodrug targeted against malignant melanoma cells. Proc Natl Acad Sci 82: 2960–2964
Olney JW, Zorumski CF, Stewart GR, Price MT, Wang GH, Labruyere J (1990) Excitotoxicity of L-dopa and 6-OH-dopa: implications for Parkinson's and Huntington's diseases. Exp Neurol 108: 269–272
Ong HH, Creveling CR, Daly JW (1969) The synthesis of 2,4,5-trihydroxyphenylalanine (6-hydroxydopa). A centrally active norepinephrine-depleting agent. J Med Chem 12: 458–462
Pedersen JZ, el-Sherbini S, Finazzi-Agro A, Rotilio G (1992) A substrate-cofactor free radical intermediate in the reaction mechanism of copper amine oxidase. Biochemistry 31: 8–12
Pichorner H, Metodiewa D, Winterbourn CC (1995) Generation of superoxide and tyrosine peroxide as a result of tyrosyl radical scavenging by glutathione. Arch Biochem Biophys 323: 429–437
Rosenberg PA, Loring R, Xie Y, Zaleskas V, Aizenman E (1991) 2,4,5-trihydroxyphenylalanine in solution forms a non-N-methyl-D-aspartate glutamatergic agonist and neurotoxin. Proc Natl Acad Sci 88: 4865–4869
Sachs C, Jonsson G (1972) Selective 6-hydroxy-DOPA induced degeneration of central and peripheral noradrenaline neurons. Brain Res 40: 563–568
Thoenen H, Tranzer JP (1968) Chemical sympathectomy by selective destruction of adrenergic nerve endings with 6-hydroxydopamine. Naunyn-Schmiedebergs Arch Pharmacol Exp Pathol 261: 271–288
Weiss JH, Koh JY, Choi DW (1989) Neurotoxicity of beta-N-methylamino-L-alanine (BMAA) and beta-N-oxalylamino-L-alanine (BOAA) on cultured cortical neurons. Brain Res 497: 64–71
Wick MM, Byers L, Ratliff J (1979) Selective toxicity of 6-hydroxydopa for melanoma cells. J Invest Dermatol 72: 67–69
Zieher LM, Jaim-Etcheverry G (1975) Different alterations in the development of the noradrenergic innervation of the cerebellum and the brain stem produced by neonatal 6-hydroxydopa. Life Sci 17: 987–991
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kostrzewa, R.M., Brus, R. Destruction of catecholamine-containing neurons by 6-hydroxydopa, an endogenous amine oxidase cofactor. Amino Acids 14, 175–179 (1998). https://doi.org/10.1007/BF01345259
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01345259