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

Epilepsia. 2017 Mar;58(3):484-493. doi: 10.1111/epi.13659. Epub 2017 Feb 6.

Abstract

Objective: The metabotropic glutamate receptor subtype 2 (mGlu2 ) possesses both orthosteric and allosteric modulatory sites, are expressed in the frontal cortex and limbic structures, and can affect excitatory synaptic transmission. Therefore, mGlu2 is a potential therapeutic target in the treatment of epilepsy. The present study seeks to evaluate the anticonvulsant potential of mGlu2 -acting compounds.

Methods: The anticonvulsant efficacy of two selective mGlu2 -positive allosteric modulators (PAMs) (JNJ-42153605 and JNJ-40411813/ADX71149) and one mGlu2/3 receptor agonist (LY404039) were evaluated alone and in combination with the antiseizure drug levetiracetam (LEV) in the mouse 6 Hz model.

Results: In the 6 Hz (32 mA stimulus intensity) model, median effective dose (ED50 ) values were determined for JNJ-42153605 (3.8 mg/kg), JNJ-40411813 (12.2 mg/kg), and LY404039 (10.9 mg/kg). At the 44 mA stimulus intensity, ED50 values were determined for JNJ-42153605 (5.9 mg/kg), JNJ-40411813 (21.0 mg/kg), LY404039 (14.1 mg/kg), and LEV (345 mg/kg). In addition, subprotective doses of each mGlu2 -acting compound, administered in combination with various doses of LEV, were able to shift the 6 Hz 44 mA ED50 for LEV by >25-fold. When JNJ-42153605 was administered at varying doses in combination with a single dose of LEV (10 mg/kg), the potency of JNJ-42153605 was increased 3.7-fold. Similarly, when a moderately effective dose of LEV (350 mg/kg) was administered in combination with varying doses of JNJ-40411813, the potency of JNJ-40411813 was increased approximately 14-fold. Plasma levels of JNJ-40411813 and LEV were not different when administered alone or in combination, suggesting that increases in potency are not due to pharmacokinetic effects.

Significance: These studies suggest a potential positive pharmacodynamic effect of mGlu2 -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.

Keywords: Animal models; Combination studies; Levetiracetam; Metabotropic glutamate receptors; Psychomotor seizures.

MeSH terms

  • Animals
  • Anticonvulsants / therapeutic use*
  • Biophysics
  • Bridged Bicyclo Compounds, Heterocyclic / therapeutic use
  • Cyclic S-Oxides / therapeutic use
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Electroshock / adverse effects
  • Epilepsy, Complex Partial / drug therapy*
  • Epilepsy, Complex Partial / etiology
  • Excitatory Amino Acid Agents / therapeutic use*
  • Levetiracetam
  • Male
  • Mice
  • Piracetam / analogs & derivatives*
  • Piracetam / therapeutic use
  • Pyridines / therapeutic use
  • Receptors, Metabotropic Glutamate / metabolism*
  • Rotarod Performance Test
  • Stereotyped Behavior / physiology
  • Triazines / therapeutic use

Substances

  • 3-cyclopropylmethyl-7-(4-phenylpiperidin-1-yl)-8-trifluoromethyl(1,2,4)triazolo(4,3-a)pyridine
  • 4-aminho-2-thiabicyclo(3.1.0)hexane-4,6-dicarboxylic acid
  • Anticonvulsants
  • Bridged Bicyclo Compounds, Heterocyclic
  • Cyclic S-Oxides
  • Excitatory Amino Acid Agents
  • Pyridines
  • Receptors, Metabotropic Glutamate
  • Triazines
  • metabotropic glutamate receptor 2
  • Levetiracetam
  • Piracetam