Dopamine and adenosine receptor interaction as basis for the treatment of Parkinson's disease.
Preclinical evidence strongly indicate that adenosine A(2A) receptor antagonists represent a promising class of drugs for the treatment of motor deficits associated to Parkinson's disease. The effects of adenosine A(2A) receptor antagonists were here assessed in a rat model of parkinsonian tremor induced by cholinomimetic drugs by evaluating the counteraction of tremulous jaw movements. Systemic administration of the A(2A) antagonist SCH 58261 dose-dependently reduced the magnitude of perioral tremor induced by the acetylcholinesterase inhibitor tacrine (2.5 mg/kg). Furthermore, intrastriatal infusion of SCH BT2 (5 microg/microl), a water-soluble analogue of SCH 58261, antagonized tacrine-induced jaw movements with a maximal effect in the ventrolateral striatum. On the other hand, SCH 58261 (5 mg/kg) was ineffective in blocking tremulous jaw movements stimulated by the direct muscarinic agonist pilocarpine (1 mg/kg). Taken together, these results indicate that A(2A) antagonists reduce parkinsonian tremor stimulated in rats by tacrine and that the striatum is deeply involved in the observed effect. Moreover, the ineffectiveness of SCH 58261 in blocking pilocarpine-stimulated perioral tremor suggests that the antitremorigenic effects of A(2A) antagonists described here are not related to a direct action on muscarinic receptor. The prospective of providing additional antitremor benefits considerably enhances the therapeutic potential of A(2A) antagonists.
Simola
Nicola
N
Department of Toxicology and Centre of Excellence for Neurobiology of Dependence, University of Cagliari, 09124 Cagliari, Italy.
Fenu
Sandro
S
Baraldi
Pier G
PG
Tabrizi
Mojgan Aghazadeh
MA
Morelli
Micaela
M
D000704:Analysis of Variance; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004347:Drug Interactions; D007568:Jaw / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D009068:Movement / Q000187:drug effects / Q000502:physiology; D010300:Parkinson Disease / Q000503:physiopathology* / Q000628:therapy; D010862:Pilocarpine; D010879:Piperazines / Q000008:administration & dosage; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D013619:Tacrine; D014202:Tremor / Q000139:chemically induced / Q000188:drug therapy; D014230:Triazoles / Q000008:administration & dosage
C492656:2-furan-2-yl-7-3-(4-(4-(4-methylpiperazine-1-sulfonyl)phenylethyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo-(1,5-c)pyrimdin-5-ylamine); C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D010879:Piperazines; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines; D018047:Receptors, Purinergic P1; D014230:Triazoles; D010862:Pilocarpine; D013619:Tacrine; D004298:Dopamine