Efficacy of mGlu 2 -positive allosteric modulators alone and in combination with levetiracetam in the mouse 6 Hz model of psychomotor seizures

The metabotropic glutamate receptor subtype 2 (mGlu ) possesses both orthosteric and allosteric modulatory sites, are expressed in the frontal cortex and limbic structures, and can affect excitatory synaptic transmission. Therefore, mGlu is a potential therapeutic target in the treatment of epilepsy...

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Published in:Epilepsia (Copenhagen) 2017-03, Vol.58 (3), p.484-493
Main Authors: Metcalf, Cameron S, Klein, Brian D, Smith, Misty D, Pruess, Tim, Ceusters, Marc, Lavreysen, Hilde, Pype, Stefan, Van Osselaer, Nancy, Twyman, Roy, White, H Steve
Format: Article
Language:English
Subjects:
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
Male
Mice
Piracetam - analogs & derivatives
Piracetam - therapeutic use
Pyridines - therapeutic use
Receptors, Metabotropic Glutamate - metabolism
Rotarod Performance Test
Stereotyped Behavior - physiology
Triazines - therapeutic use
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Summary:The metabotropic glutamate receptor subtype 2 (mGlu ) possesses both orthosteric and allosteric modulatory sites, are expressed in the frontal cortex and limbic structures, and can affect excitatory synaptic transmission. Therefore, mGlu is a potential therapeutic target in the treatment of epilepsy. The present study seeks to evaluate the anticonvulsant potential of mGlu -acting compounds. The anticonvulsant efficacy of two selective mGlu -positive allosteric modulators (PAMs) (JNJ-42153605 and JNJ-40411813/ADX71149) and one mGlu receptor agonist (LY404039) were evaluated alone and in combination with the antiseizure drug levetiracetam (LEV) in the mouse 6 Hz model. In the 6 Hz (32 mA stimulus intensity) model, median effective dose (ED ) 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, ED 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 mGlu -acting compound, administered in combination with various doses of LEV, were able to shift the 6 Hz 44 mA ED 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. 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.
ISSN:0013-9580
1528-1167
DOI:10.1111/epi.13659