An endogenous dopaminergic neurotoxin: implication for Parkinson's disease.
Oxidation of dopamine by monoamine oxidase results in the endogenous metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL). The toxicity of DOPAL for dopaminergic neurons was investigated using rat neostriatal synaptosomes, PC-12 cells and cultures of fetal rat dissociated mesencephalon. The Na(+)-dependent uptake of [3H]DOPAL in synaptosomes was inhibited by mazindol. DOPAL selectively inhibited dopamine uptake but not [14C]GABA uptake, induced membrane damage and liberation of dopamine into the medium. Incubation of PC-12 cells with 6.5 microM of DOPAL for 24 h caused degeneration of the neuritic process, and the number of viable cells were reduced by 25% of control. There were practically no surviving cells after 24 h of incubation with 33 microM of DOPAL. After 8 h of treatment with 33 microM of DOPAL, dopamine and 3,4-dihydroxyphenylacetic acid content in the cells were reduced by 38% and 53% of control. DOPAL-induced cell damage released lactic acid dehydrogenase into the incubation media. This toxic effect of DOPAL was time- and concentration-dependent. In mesencephalic cultures, after exposure to 33 microM of DOPAL, the surviving TH+ cells showed rounded cell body, and fibre network was highly reduced. These results indicate DOPAL is a neurotoxin and may be involved in the degeneration of dopaminergic neurons.
Mattammal
M B
MB
Geriatric Research, Educational and Clinical Center, VA Medical Center, St. Louis, Missouri 63125, USA.
Haring
J H
JH
Chung
H D
HD
Raghu
G
G
Strong
R
R
D015102:3,4-Dihydroxyphenylacetic Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D000818:Animals; D046508:Culture Techniques; D004298:Dopamine / Q000032:analysis; D018765:Dopamine Uptake Inhibitors / Q000633:toxicity*; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism; D009411:Nerve Endings / Q000187:drug effects*; D016716:PC12 Cells; D010300:Parkinson Disease / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018765:Dopamine Uptake Inhibitors; D015102:3,4-Dihydroxyphenylacetic Acid; D005680:gamma-Aminobutyric Acid; C007430:3,4-dihydroxyphenylacetaldehyde; D007770:L-Lactate Dehydrogenase; D004298:Dopamine