The effects of L-3,4-dihydroxyphenylalanine and dopamine agonists on dopamine neurons in the progressive hemiparkinsonian rat models

Abstract

Objectives: 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.

Discussion: 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.

Keywords:

• DOPAMINE AGONISTS
• HEMIPARKINSONIAN RAT MODELS
• L-DOPA
• NEUROPROTECTION
• NEUROTOXICITY