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

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.

Effects of Levetiracetam in Acute and Kindling Model of Epilepsy Through Adenosinergic Pathway in Mice: Possible Involvement of Adenosine A1 Receptor

“…It has also been revealed that the expression of ENT1 increased in patients suffering from epilepsy and also in animal models of epilepsy and pharmacological inhibition of ENT1 transporters in epileptic animal models decreased the severity of seizures (Ho et al 2020). Data of the present study revealed that the increased expression of the ENT1 mRNA seen in the kindling model of epilepsy is ameliorated by levetiracetam.…”

Emerging roles of dysregulated adenosine homeostasis in brain disorders with a specific focus on neurodegenerative diseases

“…Adenosine is an inhibitory neuromodulator and has been proposed as an endogenous anticonvulsant molecule [ 73 , 78 ]. An increase in extracellular adenosine and sustained enhancement in adenosine metabolites (including hypoxanthine, xanthine, and inosine) were observed in the brains of epileptic animal models, suggesting a compensatory protective mechanism in response to seizures [ 1 , 111 ]. On the other hand, since A 1 R activation mediates presynaptic inhibition and stabilization of excitatory membrane potential, it has been logically speculated that dysregulation of A 1 R signaling may contribute to epileptogenesis.…”

“…Direct injection of a specific ENT1 inhibitor, nitrobenzylthioinosine, into the hippocampus ameliorated the severity of seizures and prolonged the onset latency of pilocarpine-induced seizures in rats [ 248 ]. Recently, systemic administration of BBB-permeable ENT1 inhibitors (JMF1907 and J4) produced beneficial effects in various seizure models that represent generalized tonic–clonic seizures, generalized myoclonic seizures, and focal seizure conditions [ 111 ] (Table 2 ). The anti-epileptic effects were associated with the suppression of excitatory neuronal activities by reducing the action potential-dependent release of neurotransmitters [ 111 ].…”

“…Recently, systemic administration of BBB-permeable ENT1 inhibitors (JMF1907 and J4) produced beneficial effects in various seizure models that represent generalized tonic–clonic seizures, generalized myoclonic seizures, and focal seizure conditions [ 111 ] (Table 2 ). The anti-epileptic effects were associated with the suppression of excitatory neuronal activities by reducing the action potential-dependent release of neurotransmitters [ 111 ]. There was no direct evidence showing that specific adenosine receptors are involved in the protective effects of ENT1 inhibition in epilepsy.…”

Equilibrative nucleoside transporter 1 inhibition rescues energy dysfunction and pathology in a model of tauopathy

“…An interesting study recently reported that Tau22 mice are more susceptible to pentylenetetrazol (PTZ) for seizure and mortality than WT mice, probably due to the enhanced expression of ADK [ 65 ]. This is of great interest because J4 is an anti-epileptic agent in a PTZ-induced kindling model [ 66 ]. Given that J4 treatment reduced the level of ADK in Tau22 mice (Table 1 ), it is plausible that modulation of ADK may contribute to the beneficial effect of J4 in Tau22 mice.…”