Excitotoxicity of L-dopa and 6-OH-dopa: implications for Parkinson's and Huntington's diseases.
Despite several decades of research aimed at elucidating the mechanisms underlying neuronal degeneration in Parkinson's and Huntington's diseases, these mysteries remain unfathomed. The brain contains high concentrations of the putative transmitters, glutamate and aspartate, which have neurotoxic (excitotoxic) potential and are thought to cause neuronal degeneration in certain acute neurological disorders. However, no mechanism has been identified by which these diffusely distributed agents might cause the regionally selective patterns of neuronal degeneration characterizing Parkinson's and Huntington's diseases. Here we report that L-DOPA, the natural precursor to dopamine, is a weak excitotoxin and its ortho-hydroxylated derivative, 6-OH-DOPA, is a powerful excitotoxin. We propose that an excitotoxic process mediated by L-DOPA or an acidic derivative such as 6-OH-DOPA might be responsible for degeneration of nigral neurons in Parkinson's disease or striatal neurons in Huntington's disease.
Olney
J W
JW
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110.
Zorumski
C F
CF
Stewart
G R
GR
Price
M T
MT
Wang
G J
GJ
Labruyere
J
J
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000818:Animals; D002642:Chick Embryo; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives* / Q000633:toxicity; D016291:Dizocilpine Maleate; D006624:Hippocampus / Q000166:cytology; D006816:Huntington Disease / Q000378:metabolism*; D007980:Levodopa / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects; D010300:Parkinson Disease / Q000378:metabolism*; D011810:Quinoxalines / Q000494:pharmacology; D017981:Receptors, Neurotransmitter / Q000187:drug effects* / Q000378:metabolism; D012160:Retina / Q000187:drug effects
D003986:Dibenzocycloheptenes; D011810:Quinoxalines; D017981:Receptors, Neurotransmitter; C001388:6-hydroxydopa; D007980:Levodopa; D004295:Dihydroxyphenylalanine; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D015763:2-Amino-5-phosphonovalerate