ABSTRACT
Although 6-hydroxydopamine-induced (6-OHDA-induced) rats are a well-known Parkinson's disease model, the effects of dopamine D2 agonists in mice with 6-OHDA-induced lesions are not completely understood. We produced mice with 6-OHDA-induced lesions and measured their total locomotion counts following administration of several dopamine D2 agonists (pramipexole, ropinirole, cabergoline, rotigotine, apomorphine, talipexole, and quinelorane). Cabergoline showed the longest duration of drug action, which was in agreement with its long-lived anti-Parkinson effects in rats and humans. In contrast, pramipexole and ropinirole had notably short durations of drug action. We demonstrated that mice with 6-OHDA-induced lesions accompanied with significant lesions in the striatum may be reasonable models to predict the action duration of anti-Parkinson drug candidates in humans.
Subject(s)
Antiparkinson Agents/pharmacokinetics , Corpus Striatum/pathology , Dopamine Agonists/pharmacokinetics , Motor Activity/drug effects , Parkinsonian Disorders/chemically induced , Receptors, Dopamine D2/agonists , Animals , Apomorphine/pharmacokinetics , Azepines/pharmacokinetics , Benzothiazoles/pharmacokinetics , Cabergoline , Corpus Striatum/drug effects , Disease Models, Animal , Ergolines/pharmacokinetics , Indoles/pharmacokinetics , Injections, Intraventricular , Male , Mice , Oxidopamine/pharmacology , Parkinsonian Disorders/pathology , Parkinsonian Disorders/psychology , Pramipexole , Quinolines/pharmacokinetics , Tetrahydronaphthalenes/pharmacokinetics , Thiophenes/pharmacokineticsABSTRACT
BACKGROUND AND AIM OF THE STUDY: The symptoms of Parkinson's disease are alleviated by dopamine D2 agonists, which are classified as ergot dopamine D2 agonists and non-ergot D2 agonists. Among the former, pergolide has been associated with valvular heart disease, since it has both potent D2 receptor and serotonin 5-HT(2B) receptor agonistic properties. Among the latter, pramipexole has few incidences of heart valve disease onset, since it has an absence of 5-HT(2B) receptor agonism. METHOD: A [3H]thymidine incorporation assay was performed to monitor function, and microarray global analysis to monitor gene expression, on porcine heart valve interstitial cells (VICs) treated with pergolide or pramipexole. RESULTS: The 5-HT(2B) receptor was abundantly expressed in porcine VICs. The 5-HT(2B) receptor agonist pergolide induced an increase in [3H]thymidine incorporation, accompanied by a decrease in 5-HT(2B) receptor mRNA expression. [3H]thymidine incorporation was blocked by lisuride, a 5-HT(2B) receptor antagonist, and also by LY-294002, a specific inhibitor of PI3K and Akt. Moreover, type 2 iodothyronine deiodinase (Dio2) expression in porcine VICs treated with pergolide was shown, by a global analysis of mRNA, to be markedly increased compared to that induced by pramipexole. Such changes in VICs may correlate with the mechanism of heart valve disease pathogenesis. CONCLUSION: There were substantial differences (increased [3H]thymidine incorporation, and Dio2 expression) between pergolide and pramipexole, which might correlate with the mechanism of heart valve disease onset.
Subject(s)
Benzothiazoles/toxicity , Dopamine Agonists/toxicity , Mitral Valve/drug effects , Pergolide/toxicity , Receptors, Dopamine D2/agonists , Animals , Cell Proliferation/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Gene Expression Profiling/methods , Gene Expression Regulation/drug effects , Mitral Valve/metabolism , Mitral Valve/pathology , Oligonucleotide Array Sequence Analysis , Pramipexole , Protein Kinase Inhibitors/pharmacology , RNA, Messenger/metabolism , Real-Time Polymerase Chain Reaction , Receptor, Serotonin, 5-HT2B/drug effects , Receptor, Serotonin, 5-HT2B/genetics , Receptor, Serotonin, 5-HT2B/metabolism , Receptors, Dopamine D2/metabolism , Reproducibility of Results , Serotonin 5-HT2 Receptor Agonists/toxicity , Serotonin 5-HT2 Receptor Antagonists/pharmacology , Signal Transduction/drug effectsABSTRACT
The stable ascorbic acid derivative 2-O-alpha-D-glucopyranosyl-L-ascorbic acid (AA-2G) was used to investigate the role of ascorbic acid (AA) in B cell differentiation in vitro. AA-2G is stable in a solution unlike AA but is hydrolyzed by cellular alpha-glucosidase to release AA. Mouse spleen B cells were primed for 2 days with an anti-mu antibody in the presence of interleukin (IL)-4 and IL-5 and then washed and recultured with AA-2G in the presence of IL-4 and IL-5. AA-2G, but not AA, dose-dependently increased IgM production, the greatest enhancement being 150% at concentrations of more than 0.5mM. In the absence of IL-4 and IL-5, primed B cells produced a negligible amount of IgM, and AA-2G had no effect. AA-2G-induced IgM production in the presence of IL-4 and IL-5 was inhibited by the alpha-glucosidase inhibitor castanospermine. Intracellular AA content, depleted during the priming period, increased by adding AA-2G at the start of reculture. Treatment of B cells with AA-2G resulted in an increase in the number of IgM-secreting cells, CD138-positive cells and CD45R/B220-negative cells. The number of viable cells in untreated cultures decreased gradually, but the decrease was significantly attenuated by AA-2G, resulting in about 70% more viable cells in AA-2G-treated cultures. AA-2G caused a slight but reproducible enhancement of DNA synthesis and a slight decrease in the number of cells with a sub-G1 DNA content. These results demonstrated that AA released from AA-2G enhanced cytokine-dependent IgM production in anti-mu-primed B cells and suggest that its effect is caused through promoting the differentiation of B cells to plasma cells and attenuating the gradual decrease in the number of viable cells.
