Contrasting effects of adenosine A1 and A2 receptor ligands in different chemoconvulsive rodent models.
The pro- and anticonvulsive properties of selective adenosine A1 and A2 receptor agonists and antagonists were investigated in mice using seizure models involving a specific blockade of adenosine A1 and A2 receptors, modulation of the gamma-aminobutyric acid/benzodiazepine receptor complex or activation with the excitatory amino acid glutamate. The selective adenosine A1 receptor agonists N-cyclopentyladenosine (CPA) and R-N-(phenylisopropyl) adenosine (R-PIA) in doses of 1 and 10 mg/kg i.p. potentiated seizures induced by the selective adenosine A1 receptor antagonist 8-[4-[[[[(2-aminoethyl)amino]carbonyl]methyl]oxy]-phenyl]- 1,3-dipropylxanthine (XAC). Likewise, the selective adenosine A2 receptor agonists N-[(2-methylphenyl)methyl]adenosine (metrifudil) and N-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl]adenosine (DPMA), in doses of 30 and 100 mg/kg i.p., respectively, potentiated seizures induced by the selective adenosine A2 receptor antagonist 3,7-dimethyl-1-propargylxanthine (DMPX). In contrast, the adenosine A1 and A2 receptor agonists both antagonized seizures induced by methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM--an inverse agonist at benzodiazepine receptors) and the adenosine A1 receptor agonists also protected against seizures induced by glutamate. Paradoxically, the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT) antagonized DMCM- and pentylenetetrazole-induced seizures. Thus, it appears that adenosine A1 and A2 receptor agonists can be both pro- and anticonvulsive depending on the mechanism of action of the chemoconvulsant used in the seizure model. The findings with CPT suggest that other types of adenosine analogues than agonists may possess anticonvulsive properties.
Klitgaard
H
H
Pharmaceuticals Research, Novo Nordisk A/S, Måløv, Denmark.
Knutsen
L J
LJ
Thomsen
C
C
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D003292:Convulsants / Q000494:pharmacology*; D004195:Disease Models, Animal; D005971:Glutamates; D018698:Glutamic Acid; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D058915:Purinergic P1 Receptor Antagonists; D011963:Receptors, GABA-A / Q000187:drug effects*; D018047:Receptors, Purinergic P1 / Q000187:drug effects* / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*; D013805:Theobromine / Q000031:analogs & derivatives; D014970:Xanthines
D000927:Anticonvulsants; D003292:Convulsants; D005971:Glutamates; D058915:Purinergic P1 Receptor Antagonists; D011963:Receptors, GABA-A; D018047:Receptors, Purinergic P1; D014970:Xanthines; D018698:Glutamic Acid; C057837:3,7-dimethyl-1-propargylxanthine; C051869:8-(4-((2-aminoethyl)aminocarbonylmethyloxy)phenyl)-1,3-dipropylxanthine; D013805:Theobromine