Bromocriptine protects dopaminergic neurons from levodopa-induced toxicity by stimulating D(2)receptors.
Neuroprotective properties of bromocriptine, a D(2) receptor agonist, were investigated using the in vitro neurotoxicity of levodopa for dopaminergic neurons from rat embryonic ventral mesencephalon. Levodopa, when added to the culture medium, showed toxicity which was specific for dopaminergic neurons. Bromocriptine was found to protect dopaminergic neurons from levodopa toxicity. Another D(2) agonist, 2-(N-phenethyl-N-propyl-amino-5-hydroxytetralin, showed similar protective effects. The neuroprotective effect of bromocriptine was inhibited by supplementation of the culture medium with sulpiride, a D(2) antagonist, or by D(2) receptor knockdown with an antisense oligonucleotide. Dopaminergic neurons treated with levodopa showed an increase in free radicals. These data suggest that neuroprotective properties of bromocriptine seen in this cellular model of neurotoxicity are dependent on dopamine D(2) autoreceptor binding and that levodopa toxicity may be related to increased free radical generation in dopaminergic neurons.
Takashima
H
H
Section of Neurology, Nagasaki Kita Hospital, Nagasaki, 852-8061, Japan.
Tsujihata
M
M
Kishikawa
M
M
Freed
W J
WJ
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D000818:Animals; D000978:Antiparkinson Agents / Q000633:toxicity*; D016375:Antisense Elements (Genetics) / Q000494:pharmacology; D017660:Autoreceptors / Q000235:genetics; D001971:Bromocriptine / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004298:Dopamine / Q000502:physiology; D015259:Dopamine Agents / Q000633:toxicity; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D005260:Female; D005333:Fetus / Q000166:cytology; D005452:Fluoresceins / Q000494:pharmacology; D005609:Free Radicals / Q000032:analysis; D015870:Gene Expression / Q000502:physiology; D007980:Levodopa / Q000633:toxicity*; D008636:Mesencephalon / Q000166:cytology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy; D009474:Neurons / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000633:toxicity; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000235:genetics*; D013469:Sulpiride / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis
C077797:2-(N-phenylethyl-N-propyl)amino-5-hydroxytetralin fluorescein; D000978:Antiparkinson Agents; D016375:Antisense Elements (Genetics); D017660:Autoreceptors; D015259:Dopamine Agents; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D005452:Fluoresceins; D005609:Free Radicals; D018696:Neuroprotective Agents; D009498:Neurotoxins; D017448:Receptors, Dopamine D2; D001971:Bromocriptine; D007980:Levodopa; D013469:Sulpiride; D014446:Tyrosine 3-Monooxygenase; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine