Two-methyl-6-phenylethynyl-pyridine (MPEP), a metabotropic glutamate receptor 5 antagonist, with low doses of MK801 and diazepam: a novel approach for controlling status epilepticus.

Abstract

By intravenous administration of group I metabotropic glutamate receptor antagonists at 1 or 2h during pilocarpine induced status epilepticus (PISE), we showed that mGluR1 antagonists AIDA or LY367385 (at dosages ranging from 25 to 200mg/kg), mGluR5 antagonists SIB1757 (at dosages ranging from 25 to 200mg/kg), SIB1893 (from 25 to 100mg/kg), MPEP (from 25 to 100mg/kg) injected at 1 or 2h during PISE were ineffective in controlling status epilepticus (SE). However, when administered at 1h during PISE, MPEP at 200mg/kg, combination of MPEP (200mg/kg) with MK801 (0.1mg/kg) or with MK801 (0.1mg/kg) and diazepam (0.5mg/kg), combination of SIB1893 (200mg/kg) with MK801 (0.1mg/kg) could effectively control behavioral SE, and were neuroprotective. In particular, the combination of MPEP with MK801 and diazepam could stop both behavioral SE and electrical SE (under EEG monitoring) within a few minutes after the administration. HPLC study showed that a high level of MPEP was maintained in the blood and its metabolism rate was slow in experimental mice with PISE. We therefore concluded that the combination of MPEP (200mg/kg) with MK801 (0.1mg/kg) and diazepam (0.5mg/kg) could effectively stop SE and its subsequent neuronal loss in the hippocampus when administered 1h during PISE. It may provide a new approach to effectively control intractable SE.

• Authors: Feng Ru Tang, Peng Min Chen, Yong Cheng Tang, Mui Chiung Tsai, Wei Ling Lee
• Journal: Neuropharmacology (Neuropharmacology) Vol. 53 Issue 7 Pg. 821-31 (Dec 2007) ISSN: 0028-3908 [Print] England
• PMID: 17904168 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Excitatory Amino Acid Antagonists
• GABA Modulators
• Oxazines
• Pyridines
• Pilocarpine
• Nile Blue
• Dizocilpine Maleate
• 6-methyl-2-(phenylethynyl)pyridine
• Diazepam

Topics

• Animals
• Behavior, Animal (drug effects)
• Chromatography, High Pressure Liquid (methods)
• Diazepam (therapeutic use)
• Disease Models, Animal
• Dizocilpine Maleate (therapeutic use)
• Dose-Response Relationship, Drug
• Drug Therapy, Combination
• Electroencephalography (methods)
• Excitatory Amino Acid Antagonists (therapeutic use)
• GABA Modulators (therapeutic use)
• Male
• Mice
• Oxazines
• Pilocarpine
• Pyridines (blood, therapeutic use)
• Status Epilepticus (chemically induced, drug therapy, physiopathology)