Paradoxical effects of adenosine receptor ligands on hydroxyl radical generation by L-DOPA in the rat striatum.
Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with selective loss of dopaminergic neurons in substantia nigra pars compacta. Among the proposed mechanisms of dopaminergic degeneration, oxidative stress is believed to play an important role. On the other hand, L-DOPA used as the main medication in PD and overproduction of dopamine (DA) in striatal neurons could elicit toxic effects due to formation of free radicals (FRs). Adenosine, an endogenous neuromodulator was shown in various experimental models to have neuroprotective properties. In our study, we investigated the role of adenosine A(1) and A(2A) receptor ligands in hydroxyl radical generation by L-DOPA in the rat striatum. The hydroxyl radical was assayed by HPLC-ED as a product of its reaction with p-hydroxybenzoic acid (PBA). Intrastriatal infusion of L-DOPA(50 microM) markedly increased dialysate level of DA and 3,4-dihydroxybenzoic acid (3,4-DHBA). An adenosine A(1) receptor agonist N(6)-cyclopentyladenosine (CPA, 25-50 microM), nonselectiveA(1)/A(2A) receptor agonist 2-chloroadenosine (2-CADO, 50-100 microM), and selective A(2A) receptor agonist CGS 21680 (25-50 microM) decreased the level of 3,4-DHBA. A non-selective A(1)/A(2A) adenosine receptor antagonist caffeine (100 microM) produced similar effect on 3,4-DHBA level. At the same time, CPA and 2-CADO, but not CGS 21680 or caffeine, decreased L-DOPA-induced DA release. The adenosine receptor ligands alone only weakly changed extracellular DA level and did not influence hydroxyl radical production. However, they showed scavenging activity in Fenton reaction in vitro. The primary caffeine metabolite in rodents, 1,3,7-trimethyl uric acid (1,3,7-mUA) decreased both, DA synthesis and 3,4-DHBA level. Thus, paradoxically, both agonists of A(1) receptor and agonist of A(2A) receptor as well as antagonist of A(1) and A(2A) receptors (caffeine), all decreased generation of FRs. Our study suggests that a decrease in hydroxyl radical generation caused by adenosine receptor ligands results from attenuation of L-DOPA-induced DA release or from their scavenging activity.
Gołembiowska
Krystyna
K
Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Kraków, Poland. nfgolemb@cyf-kr.edu.pl
Dziubina
Anna
A
Kowalska
Magdalena
M
Kamińska
Katarzyna
K
D015762:2-Chloroadenosine / Q000494:pharmacology; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D001545:Benserazide / Q000494:pharmacology; D002110:Caffeine / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006719:Homovanillic Acid / Q000378:metabolism; D062385:Hydroxybenzoates / Q000037:antagonists & inhibitors / Q000378:metabolism; D017665:Hydroxyl Radical / Q000378:metabolism*; D007980:Levodopa / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D010627:Phenethylamines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012642:Selegiline / Q000494:pharmacology; D014527:Uric Acid / Q000031:analogs & derivatives / Q000494:pharmacology
D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D015259:Dopamine Agents; D062385:Hydroxybenzoates; D008024:Ligands; D010627:Phenethylamines; D015102:3,4-Dihydroxyphenylacetic Acid; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D015762:2-Chloroadenosine; D014527:Uric Acid; D012642:Selegiline; D017665:Hydroxyl Radical; C009091:protocatechuic acid; D002110:Caffeine; C048599:N(6)-cyclopentyladenosine; D007980:Levodopa; C039222:1,3,7-trimethyluric acid; D001545:Benserazide; D000241:Adenosine; D004298:Dopamine; D006719:Homovanillic Acid