Effects of adenosine receptor agonists and antagonists on audiogenic seizure-sensible DBA/2 mice

Abstract

We have studied the effects of selective and non-selective adenosine receptor agonists and antagonists in audiogenic-seizure-sensitive DBA/2 mice, an animal model of generalized reflex epilepsy. With the exception of the adenosine A 3 receptor agonist, N 6-(3-iodobenzyl)-5′- N-methylcarboxamidoadenosine (IB-MECA), all the agonists studied prevented the development of audiogenic seizures in a dose-dependent manner. The ED 50 values against the clonic phase of the audiogenic seizures were low, that is: 0.06 mg/kg, i.p., for the adenosine A 1 receptor agonist, 2-chloro- N 6-cyclopentyladenosine (CCPA), 0.02 and 0.03 mg/kg, i.p., for the adenosine A 2A receptor agonists, 2-(4-(2-carboxyethyl)-phenylamino)-5′- N-ethylcarboxamidoadenosine (CGS 21680) and 2-hexynyl-5′- N-ethyl-carboxamidoadenosine (2-HE-NECA), and 0.7 mg/kg, i.p., for the adenosine A 1/A 3 receptor agonist, N 6-2-(4-aminophenyl)ethyladenosine (APNEA). Conversely, the non-selective agonist, N-ethyl-carboxamidoadenosine (NECA), was highly potent, the ED 50 being 0.0005 mg/kg, i.p. In the absence of auditory stimulation, the adenosine receptor antagonists increased the incidence of both clonic and tonic seizures in DBA/2 mice. The ED 50 values were: for caffeine, 207.5 mg/kg, i.p., for the adenosine A 1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), 327.8 mg/kg i.p., for the adenosine A 2A receptor antagonists, 3,7-dimethyl-1-propylxanthine (DPMX), 86.7 mg/kg i.p., for the ( E,18%– Z,82%)7-methyl-8-(3,4-dimethoxystyryl)-1,3-dipropylxanthine (KF 17837), 69.1 mg/kg i.p., and 5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo-(4,3- c)1,2,4-triazolo(1,5- c)-pyrimidine (SCH 58261), 321.8 mg/kg i.p. The rank order of convulsant potency in our epileptic model, following intracerebroventricular administration, was DPCPX>DMPX>1,3,7-trimethyl-8-(3-chlorostyryl)xanthine (CSC)>KF 17837>Caffeine>SCH 58261>5-amino-9-chloro-2-(2-furyl)-1,2,4-triazolo(1,5- c)quinazoline (CGS 15943). Following a subconvulsant audiogenic stimulus of 83 dB, all adenosine receptor antagonists induced both tonic and clonic seizures. The ED 50 values for such proconvulsant effects were: for caffeine 0.04 mg/kg, i.p., for the adenosine A 1 receptor antagonist, DPCPX, 5.84 mg/kg, i.p., for the adenosine A 2A receptor antagonists, DMPX, 0.02 mg/kg, i.p., CGS 15943, 0.29 mg/kg i.p., KF 17837, 0.57 mg/kg, i.p., CSC 0.12 mg/kg, i.p. and SCH 58261 0.07 mg/kg, i.p., respectively. These data suggest that stimulation of adenosine A 1 and A 2A receptors is involved in the suppression of seizures.