Effect of adenosine A(2A) receptor antagonists on L-DOPA-induced hydroxyl radical formation in rat striatum.
A(2A) adenosine receptor antagonists have been proposed as a new therapy for Parkinson's disease (PD). Since oxidative stress plays an important role in the pathogenesis of PD, we studied the effect of the selective A(2A) adenosine receptor antagonists 8-(3-chlorostyryl)caffeine (CSC) and 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385) on L: -3,4-dihydroxyphenylalanine (L: -DOPA)-induced hydroxyl radical generation using in vivo microdialysis in the striatum of freely moving rats. L: -DOPA (100 mg/kg; in the presence of benserazide, 50 mg/kg) given acutely or repeatedly for 14 days generated a high level of hydroxyl radicals, measured by HPLC with electrochemical detection, as the product of their reaction with p-hydroxybenzoic acid (PBA). CSC (1 mg/kg) and ZM 241385 (3 mg/kg) decreased haloperidol (0.5 mg/kg)-induced catalepsy, while at low doses of 0.1 and 0.3 mg/kg, respectively, they did not display an effect. CSC (1 and 5 mg/kg) and ZM 241385 (3 and 9 mg/kg) given acutely, or CSC (1 mg/kg) and ZM 241385 (3 mg/kg) given repeatedly, increased the production of hydroxyl radicals in dialysates from rat striatum. Both acute and repeated administration of CSC (0.1 and 1 mg/kg) and ZM 241385 (3 mg/kg) decreased L: -DOPA-induced generation of hydroxyl radicals. However, a high single dose of either CSC (5 mg/kg) and ZM 241385 (9 mg/kg) markedly potentiated the effect of L: -DOPA on hydroxyl radical production. The increase in hydroxyl radical production by acute and chronic injection of CSC and ZM 241385 may be related to the increased release of dopamine (DA) and its metabolism in striatal dialysates. Similarly, increased DA release following a single high dose of CSC or ZM 241385 appears to be responsible for augmentation of L: -DOPA-induced hydroxyl radical formation. Conversely, the inhibition of L: -DOPA-induced production of hydroxyl radical by single and repeated low doses of CSC or repeated low doses of ZM 241385 may be related to reduced DA metabolism. Summing up, A(2A) antagonists, used as a supplement of L: -DOPA therapy, depending on the dose used, may have a beneficial or adverse effect on ongoing neurodegenerative processes and accompanying oxidative stress.
Gołembiowska
Krystyna
K
Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, Kraków 31-343, Poland. nfgolemb@cyf-kr.edu.pl
Dziubina
Anna
A
Kowalska
Magdalena
M
Kamińska
Katarzyna
K
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D019540:Area Under Curve; D001545:Benserazide / Q000494:pharmacology; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006220:Haloperidol; D006719:Homovanillic Acid / Q000378:metabolism; D017665:Hydroxyl Radical / Q000378:metabolism*; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014227:Triazines / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*; D014970:Xanthines / Q000494:pharmacology*
C515416:8-(3-Chlorostyryl)-1,3,7-trimethylxanthine; D058917:Adenosine A2 Receptor Antagonists; D015259:Dopamine Agents; D014227:Triazines; D014230:Triazoles; D014970:Xanthines; C097270:ZM 241385; D015102:3,4-Dihydroxyphenylacetic Acid; D017665:Hydroxyl Radical; D007980:Levodopa; D001545:Benserazide; D006220:Haloperidol; D004298:Dopamine; D006719:Homovanillic Acid