Dizocilpine (MK-801) arrests status epilepticus and prevents brain damage induced by soman.
The involvement of the NMDA receptor in the neurotoxicity induced by soman, an organophosphorus compound which irreversibly inhibits cholinesterase, was studied in guinea pigs. The drug MK-801 (0.5, 1 or 5 mg/kg, i.p.) was given as a pretreatment before a convulsant dose of soman or as a posttreatment (30, 100 or 300 micrograms/kg, i.m.) 5 min after the development of soman-induced status epilepticus. Pyridostigmine, atropine and pralidoxime chloride were also given to each subject to counteract the lethality of soman. All subjects that were challenged with soman and given the vehicle for MK-801 (saline) exhibited severe convulsions and electrographic seizure activity. Neuronal necrosis was found in the hippocampus, amygdala, thalamus and the pyriform and cerebral cortices of those subjects surviving for 48 hr. Pretreatment with 0.5 or 1 mg/kg doses of MK-801 did not prevent nor delay the onset of seizure activity but did diminish its intensity and led to its early arrest. At the largest dose (5 mg/kg), MK-801 completely prevented the development of seizure activity and brain damage. Posttreatment with MK-801 prevented, arrested or reduced seizure activity, convulsions and neuronal necrosis in a dose-dependent manner. The NMDA receptor may play a more critical role in the spread and maintenance, rather than the initiation of cholinergically-induced seizure activity.
Sparenborg
S
S
Pathophysiology Division, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5425.
Brennecke
L H
LH
Jaax
N K
NK
Braitman
D J
DJ
D000679:Amygdala / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D016291:Dizocilpine Maleate / Q000494:pharmacology* / Q000627:therapeutic use; D004569:Electroencephalography / Q000187:drug effects; D005071:Evoked Potentials / Q000187:drug effects; D006168:Guinea Pigs; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D009336:Necrosis; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D009928:Organ Specificity; D012999:Soman / Q000633:toxicity*; D013226:Status Epilepticus / Q000503:physiopathology* / Q000517:prevention & control; D013788:Thalamus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors
D016291:Dizocilpine Maleate; D012999:Soman