Pramipexole has ameliorating effects on levodopa-induced abnormal dopamine turnover in parkinsonian striatum and quenching effects on dopamine-semiquinone generated in vitro.
OBJECTIVE
To clarify the effects of a non-ergot dopamine agonist pramipexole on levodopa-induced abnormal dopamine metabolism in the parkinsonian model, we examined striatal changes in dopamine and its metabolites after repeated administration of pramipexole and/or levodopa using 6-hydroxydopamine-lesioned hemi-parkinsonian mice. Moreover, the effects of pramipexole on dopamine-semiquinones were also accessed using an in vitro dopamine-semiquinone generating system to elucidate its neuroprotective property against dopamine quinone-induced neurotoxicity that appears as dopamine neuron-specific oxidative stress.


RESULTS
Combined administration of pramipexole (0.5 or 1 mg/kg/day, 7 days) selectively suppressed the levodopa-induced (50 mg/kg/day) increase of striatal dopamine turnover in the parkinsonian side, but not in the non-lesioned side. In addition to the antioxidant properties previously reported, it was clarified that pramipexole scavenged dopamine-semiquinones generated in a dose-dependent manner either in simultaneous incubation or post-incubation.


CONCLUSIONS
The neurotoxicity of dopamine quinones that appear as dopaminergic neuron-specific oxidative stress has recently been known to play a role in the pathogenesis of Parkinson's disease and neurotoxin-induced parkinsonism. Therefore, the present results revealed that pramipexole possesses neuroprotective effects against abnormal dopamine metabolism in excessively levodopa-administered parkinsonian brains and against cytotoxic dopamine quinones generated from excess dopamine, preventing consequently dopaminergic neuronal damage induced by excess dopamine or levodopa.
Asanuma
Masato
M
Department of Brain Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. asachan@cc.okayama-u.ac.jp
Miyazaki
Ikuko
I
Diaz-Corrales
Francisco J
FJ
Shimizu
Masako
M
Tanaka
Ken-ichi
K
Ogawa
Norio
N
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000009:adverse effects; D016227:Benzoquinones / Q000378:metabolism*; D052160:Benzothiazoles; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004578:Electron Spin Resonance Spectroscopy / Q000379:methods; D007839:Functional Laterality / Q000187:drug effects; D006719:Homovanillic Acid / Q000378:metabolism; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D000077487:Pramipexole; D013844:Thiazoles / Q000494:pharmacology*; D013997:Time Factors
D000978:Antiparkinson Agents; D016227:Benzoquinones; D052160:Benzothiazoles; D013844:Thiazoles; D015102:3,4-Dihydroxyphenylacetic Acid; C025232:semiquinone radicals; D007980:Levodopa; D000077487:Pramipexole; D016627:Oxidopamine; D004298:Dopamine; D006719:Homovanillic Acid