thioinosine and Epilepsy--Temporal-Lobe

Type 1 equilibrative nucleoside transporter (ENT1) promotes glutamate release by inhibition of adenosine signaling. However, whether ENT1 plays a role in epileptic seizure that involves elevated glutamatergic neurotransmission is unknown. Here, we report that both seizure rats and patients show increased expression of ENT1. Intrahippocampal injection of a specific inhibitor of ENT1, nitrobenzylthioinosine (NBTI), attenuates seizure severity and prolongs onset latency. In order to examine whether NBTI would be effective as antiepileptic after peripheral application, we injected NBTI intraperitoneally, and the results were similar to those obtained after intrahippocampal injection. NBTI administration leads to suppressed neuronal firing in seizure rats. In addition, increased mEPSC in seizure are inhibited by NBTI. Finally, NBTI results in deactivation of phosphorylated cAMP-response element-binding protein in the seizure rats. These results indicate that ENT1 plays an important role in the development of seizure. Inhibition of ENT1 might provide a novel therapeutic approach toward the control of epileptic seizure.

Topics: Action Potentials; Adenosine; Adolescent; Adult; Animals; Anterior Temporal Lobectomy; Anticonvulsants; CA1 Region, Hippocampal; Carrier Proteins; Child, Preschool; Convulsants; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Drug Resistance; Epilepsy, Temporal Lobe; Equilibrative Nucleoside Transporter 1; Glutamates; Humans; Male; Middle Aged; Nerve Tissue Proteins; Phosphorylation; Pilocarpine; Protein Processing, Post-Translational; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Seizures; Thioinosine; Young Adult

Using quantitative receptor autoradiographic methods we have examined A1 adenosine receptors, adenosine uptake sites, benzodiazepine receptors, NMDA, AMPA, and kainic acid receptors in temporal lobes removed from patients suffering from complex partial seizures and in normal control post-mortem temporal cortex. Binding to A1 adenosine receptors and NMDA receptors was reduced in epileptic temporal cortex, while the other neurochemical parameters were unchanged. The reason for this A1 receptor loss is unclear as it occurred in both idiopathic and symptomatic cases and thus may be a consequence rather than an initial cause of seizures. However, because adenosine is a powerful anticonvulsant substance, loss of anticonvulsant A1 receptors may contribute to the human epileptic condition. It is also possible that the observed differences in A1 binding are due to autopsy vs. biopsy changes in the levels of A1 adenosine receptors.

Topics: Adolescent; Adult; Aged; Autoradiography; Cell Count; Epilepsy, Temporal Lobe; Female; Hippocampus; Humans; Male; Middle Aged; Receptors, Amino Acid; Receptors, GABA; Receptors, Purinergic P1; Reference Values; Temporal Lobe; Thioinosine