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.
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.
Tang
Feng Ru
FR
Epilepsy Research Lab, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore. feng_ru_tang@nni.com.sg
Chen
Peng Min
PM
Tang
Yong Cheng
YC
Tsai
Mui Chiung
MC
Lee
Wei Ling
WL
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003975:Diazepam / Q000627:therapeutic use*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004569:Electroencephalography / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D018757:GABA Modulators / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D010078:Oxazines; D010862:Pilocarpine; D011725:Pyridines / Q000097:blood / Q000627:therapeutic use*; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology
D018691:Excitatory Amino Acid Antagonists; D018757:GABA Modulators; D010078:Oxazines; D011725:Pyridines; D010862:Pilocarpine; C008619:Nile Blue; D016291:Dizocilpine Maleate; C121465:6-methyl-2-(phenylethynyl)pyridine; D003975:Diazepam