Protective effects of pergolide on dopamine levels in the 6-hydroxydopamine-lesioned mouse brain.
Pergolide, along with bromocriptine and lisuride, is one of the most active dopamine receptor agonists. To determine whether or not pergolide protects against dopaminergic neuronal damage, via its activity on monoamine metabolism, we studied the effects of pergolide pretreatment on changes in monomaines and their metabolites in the mouse striatum after intracerebroventricular injection of 6-hydroxydopamine with pretreatment of desipramine. After intracerebroventricular administration of 6-hydroxydopamine (40 micrograms) in mice, the levels of dopamine and its metabolites (DOPAC, HVA) in the striatum rapidly decreased to 49%, 29% and 68%, respectively, of the naive controls at week 1 but then gradually recovered to control levels at weeks 2 and 4. Repeated pretreatment with pergolide (0.5 mg/kg, i.p.) for 7 days before administration of 6-hydroxydopamine, almost completely protected against reduction in striatal dopamine and its metabolites 1 week after injection of 6-hydroxydopamine. Therefore, pergolide could normalize the decreased dopamine synthesis or storage, and has a neuroprotective effect against dopaminergic dysfunction induced by the neurotoxin, 6-hydroxydopamine. Although we found that pergolide did not show radical scavenging activity in an in vitro system that generated hydroxyl radicals, it has been reported in vivo that pergolide treatment may induce Cu/Zn superoxide dismutase in the rat striatum. Considering these findings, pergolide may well be protective to dopaminergic neurons, largely because of its effects on presynaptic autoreceptors and on its induction of Cu/Zn superoxide dismutase. Further research on the neuroprotective effects of pergolide in Parkinson disease models, by injection of 6-hydroxydopamine, is needed to clarify its mechanism of action on dopaminergic indices.
Department of Neuroscience, Okayama University Medical School, Japan.
M
M
Asanuma
N
N
Ogawa
S
S
Nishibayashi
M
M
Kawai
Y
Y
Kondo
E
E
Iwata
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004347:Drug Interactions; D005609:Free Radicals; D006719:Homovanillic Acid / Q000378:metabolism; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009498:Neurotoxins / Q000008:administration & dosage / Q000633:toxicity*; D016627:Oxidopamine / Q000008:administration & dosage / Q000633:toxicity*; D010479:Pergolide / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D012640:Seizures / Q000188:drug therapy
D000978:Antiparkinson Agents; D005609:Free Radicals; D009498:Neurotoxins; D015102:3,4-Dihydroxyphenylacetic Acid; D010479:Pergolide; D016627:Oxidopamine; D004298:Dopamine; D006719:Homovanillic Acid