AN ENDOGENOUS DOPAMINERGIC NEUROTOXIN - IMPLICATION FOR PARKINSONS-DISEASE

Oxidation of dopamine by monoamine oxidase results in the endogenous m etabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL). The toxicity of DOP AL for dopaminergic neurons was investigated using rat neostriatal syn aptosomes, PC-12 cells and cultures of fetal rat dissociated mesenceph alon. The Na+-dependent uptake of [H-3]DOPAL in synaptosomes was inhib ited by mazindol. DOPAL selectively inhibited dopamine uptake but not [C-14]GABA uptake, induced membrane damage and liberation of dopamine into the medium. Incubation of PC-12 cells with 6.5 mu M of DOPAL for 24 h caused degeneration of the neuritic process, and the number of vi able cells were reduced by 25% of control. There were practically no s urviving cells after 24 h of incubation with 33 mu M of DOPAL. After 8 h of treatment with 33 mu M of DOPAL, dopamine and 3,4-dihydroxypheny lacetic acid content in the cells were reduced by 38% and 53% of contr ol. DOPAL-induced cell damage released lactic acid dehydrogenase into the incubation media. This toxic effect of DOPAL was time- and concent ration-dependent. In mesencephalic cultures, after exposure to 33 mu M of DOPAL, the surviving TH+ cells showed rounded cell body, and fibre network was highly reduced. These results indicate DOPAL is a neuroto xin and may be involved in the degeneration of dopaminergic neurons. ( C) 1995 Academic Press Limited