| Autor: |
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 |
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| Zdroj: |
Epilepsia (Series 4); Mar2017, Vol. 58 Issue 3, p484-493, 10p |
| Abstrakt: |
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. [ABSTRACT FROM AUTHOR] |
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