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 2 h during pilocarpine induced status epilepticus (PISE), we showed that mGluR1 antagonists AIDA or LY367385 (at dosages ranging from 25 to 200 mg/kg), mGluR5 antagonists SIB1757 (at dosages ranging from 25 to 200 mg/kg), SIB1893 (from 25 to 100 mg/kg), MPEP (from 25 to 100 mg/kg) injected at 1 or 2 h during PISE were ineffective in controlling status epilepticus (SE). However, when administered at 1 h during PISE, MPEP at 200 mg/kg, combination of MPEP (200 mg/kg) with MK801 (0.1 mg/kg) or with MK801 (0.1 mg/kg) and diazepam (0.5 mg/kg), combination of SIB1893 (200 mg/kg) with MK801 (0.1 mg/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 (200 mg/kg) with MK801 (0.1 mg/kg) and diazepam (0.5 mg/kg) could effectively stop SE and its subsequent neuronal loss in the hippocampus when administered 1 h during PISE. It may provide a new approach to effectively control intractable SE.