Equilibrative Nucleoside Transporters-1 Inhibitors Act as Anti-epileptic Agents by Inhibiting Glutamatergic Transmission.

I-Chun Chen,Chun-Jung Lin,Kai-Chieh Chang,Shih-Yin Ho,Che-Wen Tsai,Horng-Huei Liou,Hsiao-Ru Lin

doi:10.3389/fnins.2020.610898

Abstract

Background and Purpose: Adenosine dysregulation is associated with the occurrence of the epilepsy and equilibrative nucleoside transporters-1 (ENT-1) functions as an important regulator of extracellular adenosine in the brain. This study was aimed to prove the anti-epileptic effect of BBB permeable ENT-1 inhibitors, JMF1907 and J4, on animal models of various epilepsy, and the mechanisms that are involved.Experimental Approach: Maximal electroshock seizure (MES), pentylenetetrazol (PTZ)-induced seizure and kindling models were used as mouse models of generalized tonic-clonic epilepsy, generalized myoclonic epilepsy, and partial epilepsy, respectively. The epilepsy frequency, duration, and Racine score were evaluated. Whole-cell recordings were made from the hippocampal dentate granule cells by using a patch-clamp technique in the brain slice of the mice.Key Results: In MES, JMF1907 at a dose of 5 mg kg–1 was efficacious in decreasing hindlimb extension, while J4 did not decrease hindlimb extension until a higher dose (10 mg kg–1). Both JMF1907 and J4 were more potent in lengthening onset latency than ethosuximide (ETH) in PTZ-induced myoclonic epilepsy model, whereas ETH had better effects on the Racine score. In kindling model, JMF1907 and J4 at a dose of 1 mg kg–1 had effects on seizure frequency and duration, and the effects of JMF1907 were comparable with those of carbamazepine. Both JMF1907 and J4 can reduce the glutamatergic spontaneous excitatory post-synaptic currents (sEPSCs) frequency. The maximal inhibition was about 50% for JMF1907 at a concentration of 1 μg L–1, whereas J4 only inhibited 40% of sEPSCs frequency at a dose of 10 μg L–1.Conclusion and Implications: ENT-1 inhibitors, JMF1907 and J4, showed anti-epileptic effects in different epilepsy models and the effects involved pre-synaptic neuronal modulation.

Highlights

Epilepsy is a neurological disease characterized by the occurrence of transient paroxysms of excessive or uncontrolled discharges of neurons that leads to clinical manifestation of seizure
Adenosine dysregulation is associated with the occurrence of the epilepsy and equilibrative nucleoside transporters-1 (ENT-1) functions as an important regulator of extracellular adenosine in the brain
Maladaptive changes in adenosine homeostasis were considered to occur during the pathogenesis of temporal lobe epilepsy (TLE) (Boison and Aronica, 2015)

Summary

Introduction

Epilepsy is a neurological disease characterized by the occurrence of transient paroxysms of excessive or uncontrolled discharges of neurons that leads to clinical manifestation of seizure. An aberrant expression of adenosine A1 receptor whose activation is important for seizure suppression was identified in humans with epilepsy (Angelatou et al, 1993; Glass et al, 1996). In this regard, the dysregulation of adenosine-based neuromodulation may be associated with epileptogenesis and the augmentation of adenosine levels has been considered as a potentially therapeutic approach in epilepsy (Boison, 2012). Adenosine dysregulation is associated with the occurrence of the epilepsy and equilibrative nucleoside transporters-1 (ENT-1) functions as an important regulator of extracellular adenosine in the brain. Whole-cell recordings were made from the hippocampal dentate granule cells by using a patchclamp technique in the brain slice of the mice

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