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

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

doi:10.3389/fnins.2020.610898

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

Front Neurosci. 2020 Dec 17:14:610898. doi: 10.3389/fnins.2020.610898. eCollection 2020.

Authors

Shih-Yin Ho^{1

2}, I-Chun Chen², Kai-Chieh Chang^{1

3}, Hsiao-Ru Lin⁴, Che-Wen Tsai², Chun-Jung Lin⁴, Horng-Huei Liou^{1

2

3}

Affiliations

¹ Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
² Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
³ National Taiwan University Hospital Yunlin Branch, Douliu, Taiwan.
⁴ School of Pharmacy, National Taiwan University, Taipei, Taiwan.

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.

Keywords: ENT-1; adenosine; maximal electroshock seizure; pentylenetetrazol-induced seizure; whole-cell patch-clamp recording.