Studies on the formation of 6-hydroxydopamine in mouse brain after administration of 2,4,5-trihydroxyphenylalanine (6-hydroxyDOPA).
2,4,5-Trihydroxyphenylalanine (6-OH-DOPA) destroys central and peripheral noradrenergic neurons, while sparing dopaminergic neurons. Previous studies indicate that 6-OH-DOPA toxicity is mediated by the formation of 6-hydroxydopamine. However, levels of 6-hydroxydopamine in brain following peripheral administration of 6-OH-DOPA have not been documented. In the current study, 6-OH-DOPA and 6-hydroxydopamine were measured in brain by HPLC with electrochemical detection after intraperitoneal injection of 6-OH-DOPA. When mice were injected with 100 mg 6-OH-DOPA/kg, 6-hydroxydopamine levels in the striatum were highest (1.9 microgram/g) at 15 min and fell slowly to 24% of the peak value at 4 h. Experiments with reserpine indicated that the relatively stability of 6-hydroxydopamine was largely dependent upon storage in synaptic vesicles. Reserpine (10 mg/kg) lowered striatal 6-hydroxydopamine levels to 21.6% of control (non-reserpine-treated) values at 1 h, and to 8.9% of control values at 4 h. Levels of 6-hydroxydopamine in the striatum at 1 h were increased 113% by pargyline (100 mg/kg), 145% by alpha-methyldopahydrazine (carbidopa; 25 mg/kg), and 261% by pargyline and carbidopa together. Levels of dopamine in the striatum were unchanged at 2.5 h after 200 mg 6-OH-DOPA/kg (with pargyline and 50 mg carbidopa/kg), whereas levels of norepinephrine in the frontal cortex fell by 77%. At the same time, 6-hydroxydopamine levels were 8.8-fold higher in the striatum (5.54 micrograms/g) than in the cortex (0.63 micrograms/g).(ABSTRACT TRUNCATED AT 250 WORDS)
Evans
J M
JM
Graduate School of Biomedical Sciences (Neurobiology), Department of Neurology Mount Sinai School of Medicine of the City University of New York, New York 10029.
Cohen
G
G
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002230:Carbidopa / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000378:metabolism; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D005625:Frontal Lobe / Q000378:metabolism; D006892:Hydroxydopamines / Q000378:metabolism*; D008297:Male; D051379:Mice; D009638:Norepinephrine / Q000378:metabolism; D016627:Oxidopamine; D010293:Pargyline / Q000494:pharmacology; D012110:Reserpine / Q000494:pharmacology; D013572:Synaptic Vesicles / Q000378:metabolism
D006892:Hydroxydopamines; C001388:6-hydroxydopa; D004295:Dihydroxyphenylalanine; D012110:Reserpine; D016627:Oxidopamine; D010293:Pargyline; D002230:Carbidopa; D004298:Dopamine; D009638:Norepinephrine