Neuroprotective effect of L-DOPA co-administered with the adenosine A2A receptor agonist CGS 21680 in an animal model of Parkinson's disease.
Adenosine A2A receptors are a new target for drug development in Parkinson's disease. Some experimental and clinical data suggest that A2A receptor antagonists can provide symptomatic improvement by potentiating the effects of L-DOPA as well as a decrease in secondary effects such as L-DOPA-induced dyskinesia. L-DOPA-induced behavioral sensitization in unilateral 6-hydroxydopamine-lesioned rats is frequently used as an experimental model of L-DOPA-induced dyskinesia. In the present work this model was used to evaluate the effect of the A2A receptor agonist CGS 21680 and the A2A receptor antagonist MSX-3 on L-DOPA-induced behavioral sensitization and 6-hydroxydopamine-induced striatal dopamine denervation. L-DOPA-induced behavioral sensitization was determined as an increase in L-DOPA-induced abnormal involuntary movements and enhancement of apomorphine-induced turning behavior. Striatal dopamine innervation was determined by measuring tyrosine-hydroxylase immunoreactivity. Chronic administration of MSX-3 was not found to be effective at counteracting L-DOPA-induced behavioral sensitization. On the other hand, CGS 21680 completely avoided the development of L-DOPA-induced behavioral sensitization. The analysis of the striatal dopamine innervation showed that L-DOPA-CGS 21680 co-treatment conferred neuroprotection to the toxic effects of 6-hydroxydopamine. This neuroprotective effect was dependent on A2A and D2 receptor stimulation, since it was counteracted by MSX-3 and by the D2 receptor antagonist haloperidol. These results open new therapeutic avenues in early events in Parkinson's disease.
Agnati
Luigi F
LF
Department of Biomedial Sciences, University of Modena and Reggio Emilia, Modena, Italy. luigiagnati@tin.it
Leo
Giuseppina
G
Vergoni
Anna-Valeria
AV
Martínez
Emili
E
Hockemeyer
Jörg
J
Lluis
Carme
C
Franco
Rafael
R
Fuxe
Kjell
K
Ferré
Sergi
S
D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D058908:Adenosine A2 Receptor Agonists; D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001058:Apomorphine / Q000633:toxicity; D002452:Cell Count / Q000379:methods; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D018491:Dopamine Agonists; D004359:Drug Therapy, Combination; D020820:Dyskinesias / Q000209:etiology / Q000517:prevention & control; D007150:Immunohistochemistry / Q000379:methods; D007980:Levodopa / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000209:etiology / Q000517:prevention & control*; D010627:Phenethylamines / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013239:Stereotyped Behavior / Q000187:drug effects / Q000502:physiology; D013565:Sympatholytics / Q000633:toxicity; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D058908:Adenosine A2 Receptor Agonists; D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D010627:Phenethylamines; D013565:Sympatholytics; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D007980:Levodopa; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D000241:Adenosine; D001058:Apomorphine