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 N6-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.
Highlights
Epilepsy affects up to 1% of the population [1]
While many drugs have been developed for the treatment of epilepsy, approximately one-third of epilepsy patients still have uncontrolled seizures, with an even larger percent suffering from the side effects of antiepileptic drugs [2]
Given that the anticonvulsant activity of adenosine is primarily mediated though the adenosine A1 receptor [4], adenosine receptor agonists may hold promise for the development of epilepsy drugs [5]
Summary
Epilepsy affects up to 1% of the population [1]. While many drugs have been developed for the treatment of epilepsy, approximately one-third of epilepsy patients still have uncontrolled seizures, with an even larger percent suffering from the side effects of antiepileptic drugs [2].One emerging strategy in the search for new antiepileptic drugs has been to target the adenosine pathway. While many drugs have been developed for the treatment of epilepsy, approximately one-third of epilepsy patients still have uncontrolled seizures, with an even larger percent suffering from the side effects of antiepileptic drugs [2]. It may influence the release of excitatory amino acids and other neurotransmitters or directly inhibit spontaneous neuronal firing and synaptic transmission [3]. Cardiovascular side effects, low brain permeability, and a short time course of action may limit its application in epilepsy treatment. Given that the anticonvulsant activity of adenosine is primarily mediated though the adenosine A1 receptor [4], adenosine receptor agonists may hold promise for the development of epilepsy drugs [5]
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