Efficacy of mGlu₂‐positive allosteric modulators alone and in combination with levetiracetam in the mouse 6 Hz model of psychomotor seizures

Abstract

These studies suggest a potential positive pharmacodynamic effect of mGlu -acting compounds in combination with LEV. If this effect is translated in a clinical setting, it can support a rational polypharmacy concept in treatment of epilepsy patients.

Progress report on new antiepileptic drugs: A summary of the Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV). I. Drugs in preclinical and early clinical development

“…In the mouse corneal kindling model, tool compound mGlu2 PAMs are active in protecting against seizure expression and in reducing seizure severity in a dose‐dependent and mechanistically specific manner. JNJ‐40411813 (1‐butyl‐3‐chloro‐4‐[4‐phenyl‐1‐piperidinyl]‐2[1H]‐pyridinone), a modestly potent mGlu2 PAM, was not active at 100 mg/kg sc in the corneal kindled mouse and was also inactive in the MES and sc PTZ models, with ED 50 estimates > 100 mg/kg when administered sc.…”

“…The results implicate a potential pharmacodynamic interaction between levetiracetam and mGlu2 PAMs resulting in synergistic seizure‐protecting activity in the 6‐Hz 44‐mA mouse model and in the corneal kindling mouse model, without increasing adverse effects as measured by rotarod performance. Specifically, isobolographic analysis in the 6‐Hz 44‐mA model revealed a strong multifold seizure protection synergy between levetiracetam and mGlu2 PAMs . This positive pharmacodynamic interaction might be especially useful in epilepsy, where increases in glutamate release and extracellular levels associated with increasing excitability in preseizure and active seizure states have been observed, and an mGlu2 PAM could readily downregulate glutamate release on an on‐demand basis.…”

Novel Targets for Developing Antiseizure and, Potentially, Antiepileptogenic Drugs

“…mGlu 2 PAMs (e.g., JNJ-42153605 and JNJ-40411813) have been evaluated both alone and in combination with the ASD levetiracetam (LEV; 65). Both of these compounds are efficacious in the mouse 6 Hz model at both the 32 mA and the more pharmacoresistant 44 mA stimulus intensities (65). Further, in contrast to LEV, which is dramatically less potent at the 44 mA stimulus intensity (at least 18-fold vs 32 mA), mGlu 2 PAMs are effective in this model (44 mA) at doses only 1.5-to 2-fold greater than efficacious doses using the 32 mA stimulus intensity (65).…”

“…This suggests that these compounds present a potentially novel therapy for pharmacoresistant epilepsy. When combined with LEV, mGlu 2 PAMs show a potentially synergistic effect (65), suggesting a combination therapy strategy that may be effective for pharmacoresistant seizures.…”

Potent and selective pharmacodynamic synergy between the metabotropic glutamate receptor subtype 2–positive allosteric modulator JNJ‐46356479 and levetiracetam in the mouse 6‐Hz (44‐mA) model

“…Activation of mGlu 2 receptors decreases glutamate release, [1][2][3] and this receptor subtype is expressed presynaptically in the frontal cortex and in limbic structures. 12 The antiseizure drugs sodium valproate (VPA), lamotrigine (LTG), and levetiracetam (LEV) have been previously evaluated alone and in combination with other agents, in various seizure models. Previously, PAMs have been demonstrated to block seizures in the 6-Hz model of psychomotor seizures using both the 32-mA and 44-mA stimulus intensities.…”