title: Anticonvulsant activity of B2, an adenosine analog, on chemical convulsant-induced seizures.
abstract: Epilepsy is a chronic neurological disorder characterized by recurrent seizures. However, approximately one-third of epilepsy patients still suffer from uncontrolled seizures. Effective treatments for epilepsy are yet to be developed. N (6)-(3-methoxyl-4-hydroxybenzyl) adenine riboside (B2) is a N(6)-substitued adenosine analog. Here we describe an investigation of the effects and mechanisms of B2 on chemical convulsant-induced seizures. Seizures were induced in mice by administration of 4-aminopyridine (4-AP), pentylenetetrazol (PTZ), picrotoxin, kainite acid (KA), or strychnine. B2 has a dose-related anticonvulsant effect in these chemical-induced seizure models. The protective effects of B2 include increased latency of seizure onset, decreased seizure occurrence, shorter seizure duration and reduced mortality rate. Radioligand binding and cAMP accumulation assays indicated that B2 might be a functional ligand for both adenosine A1 and A2A receptors. Furthermore, DPCPX, a selective A1 receptor antagonist, but not SCH58261, a selective A2A receptor antagonist, blocked the anticonvulsant effect of B2 on PTZ-induced seizure. c-Fos is a cellular marker for neuronal activity. Immunohistochemical and western blot analyses indicated that B2 significantly reversed PTZ-induced c-Fos expression in the hippocampus. Together, these results indicate that B2 has significant anticonvulsant effects. The anticonvulsant effects of B2 may be attributed to adenosine A1 receptor activation and reduced neuronal excitability in the hippocampus. These observations also support that the use of adenosine receptor agonist may be a promising approach for the treatment of epilepsy.
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Ruixia
authors.initials: R
authors.lastname: Kang
authors.forename: Jiangong
authors.initials: J
authors.lastname: Shi
authors.forename: Gengtao
authors.initials: G
authors.lastname: Liu
authors.forename: Jianjun
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D058916:Adenosine A1 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D003292:Convulsants / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D000927:Anticonvulsants; D003292:Convulsants; C586155:N6-(3-methoxyl-4-hydroxybenzyl) adenine riboside; D016760:Proto-Oncogene Proteins c-fos; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D000242:Cyclic AMP; D000241:Adenosine