The effects of L-3,4-dihydroxyphenylalanine and dopamine agonists on dopamine neurons in the progressive hemiparkinsonian rat models.
OBJECTIVE
Dopamine replacement with the precursor L-3,4-dihydroxyphenylalanine (L-DOPA) and dopamine receptor agonists is the standard therapy for the symptomatic treatment of Parkinson's disease (PD). Whether L-DOPA and dopamine agonists may either accelerate or slow the degeneration of dopamine neurons is still controversial with conflicting data from both in vitro and in vivo experiments. We aimed to verify the influence of L-DOPA and receptor-selective dopamine agonists on dopamine neurons in the progressive hemiparkinsonian rat models.


METHODS
We administered different doses of L-DOPA, D1 selective agonist SKF38393, D2 selective agonist quinpirole and D2/D3 agonist pramipexole intraperitoneally for 9 weeks to the rats with progressive nigrostriatal lesions produced by injecting 6-hydroxydopamine (6-OHDA) into the striatum. After 3, 6 and 9 weeks of administration of dopaminergic agents, we performed the behavioral test using the forepaw adjusting step (FAS) test and anatomical analysis using tyrosine hydroxylase (TH) immunohistochemical staining and TH western blots.


RESULTS
Only in the high dose (100 mg/kg/d) L-DOPA treated rats, TH immunoreactive (TH-IR) cells were significantly decreased compared with other groups (p<0.01). We could not detect any influence of dopamine agonists on the behavior or the degeneration of dopaminergic neurons, regardless of their receptor selectivity.


CONCLUSIONS
In conclusion, we demonstrated the potential toxicity of high dose of L-DOPA, but did not observe any protective effect of dopamine agonists in the progressive hemiparkinsonian rat models.
Jeon
Mi Young
MY
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Lee
Won Yong
WY
Kang
Ho Young
HY
Chung
Eun Joo
EJ
D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D007839:Functional Laterality; D007980:Levodopa / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009474:Neurons / Q000187:drug effects*; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D051381:Rats; D011916:Rats, Inbred F344; D013378:Substantia Nigra / Q000166:cytology; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D007980:Levodopa; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine