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

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• 作者：De Sarro ; Giovambattista ; De Sarro ; Angela ; Di Paola ; Eugenio Donato ; Bertorelli ; Rosalia
• 关键词：Epilepsy ; Adenosine ; Adenosine receptor subtype ; Adenosine receptor agonist ; Adenosine receptor antagonist ; Seizure audiogenic ; DBA/2 mice
• 刊名：European Journal of Pharmacology
• 出版年：1999
• 出版时间：April 29, 1999
• 年：1999
• 卷：371
• 期：2-3
• 页码：137-145
• 全文大小：204 K

文摘

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 A₃ receptor agonist, N⁶-(3-iodobenzyl)-5′-N-methylcarboxamidoadenosine (IB-MECA), all the agonists studied prevented the development of audiogenic seizures in a dose-dependent manner. The ED₅₀ values against the clonic phase of the audiogenic seizures were low, that is: 0.06 mg/kg, i.p., for the adenosine A₁ receptor agonist, 2-chloro-N⁶-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 A₁/A₃ receptor agonist, N⁶-2-(4-aminophenyl)ethyladenosine (APNEA). Conversely, the non-selective agonist, N-ethyl-carboxamidoadenosine (NECA), was highly potent, the ED₅₀ 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 ED₅₀ values were: for caffeine, 207.5 mg/kg, i.p., for the adenosine A₁ 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 ED₅₀ values for such proconvulsant effects were: for caffeine 0.04 mg/kg, i.p., for the adenosine A₁ 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 A₁ and A_2A receptors is involved in the suppression of seizures.