Protection against sarin-induced seizures in rats by direct brain microinjection of scopolamine, midazolam or MK-801.
Control of seizure activity is critical to survival and neuroprotection following nerve agent exposure. Extensive research has shown that three classes of drugs, muscarinic antagonists, benzodiazepines, and N-methyl-D: -aspartate antagonists, are capable of moderating these seizures. This study began to map the neural areas in rat brain that respond to these three drug classes resulting in anticonvulsant effects. Drugs of each class (scopolamine, midazolam, MK-801) were evaluated for their ability to prevent sarin-induced seizures when injected into specific brain areas (lateral ventricle, anterior piriform cortex, basolateral amygdala, area tempestas). Animals were pretreated by microinjection with saline or a dose of drug from one of the three classes 30 min prior to receiving 150 microg/kg sarin, subcutaneously, followed by 2.0 mg/kg atropine methylnitrate, intramuscularly. Animals were then returned to their cages, where electroencephalographic activity was monitored for seizures. Anticonvulsant effective doses (ED(50)) were determined using an up-down dosing procedure over successive animals. Scopolamine provided anticonvulsant effects in each area tested, while midazolam was effective in each area except the lateral ventricle. MK-801 was only effective at preventing seizures when injected into the basolateral amygdala or area tempestas. The results show a unique neuroanatomical and pharmacological specificity for control of nerve agent-induced seizures.
Skovira
Jacob W
JW
Pharmacology Branch, Research Division, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5400, USA.
McDonough
John H
JH
Shih
Tsung-Ming
TM
D000679:Amygdala / Q000187:drug effects / Q000503:physiopathology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D018680:Cholinergic Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D018757:GABA Modulators / Q000494:pharmacology / Q000627:therapeutic use; D007276:Injections, Intraventricular; D008297:Male; D008874:Midazolam / Q000494:pharmacology / Q000627:therapeutic use; D009833:Olfactory Pathways / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012524:Sarin / Q000633:toxicity*; D012601:Scopolamine / Q000494:pharmacology / Q000627:therapeutic use; D012640:Seizures / Q000139:chemically induced* / Q000188:drug therapy* / Q000517:prevention & control; D016896:Treatment Outcome
D000927:Anticonvulsants; D018680:Cholinergic Antagonists; D002800:Cholinesterase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D018757:GABA Modulators; D016291:Dizocilpine Maleate; D012524:Sarin; D012601:Scopolamine; D008874:Midazolam
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