title: Protection against sarin-induced seizures in rats by direct brain microinjection of scopolamine, midazolam or MK-801.
abstract: 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.
authors.affiliation: Pharmacology Branch, Research Division, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5400, USA.
authors.forename: Jacob W
authors.initials: JW
authors.lastname: Skovira
authors.forename: John H
authors.initials: JH
authors.lastname: McDonough
authors.forename: Tsung-Ming
authors.initials: TM
authors.lastname: Shih
mesh_terms: 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
chemical_list: 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
references.citation: Brain Res. 1987 Dec 1;435(1-2):123-37
references.pmid: 3427447
references.citation: Neurosci Biobehav Rev. 1993 Summer;17(2):203-15
references.pmid: 8515903
references.citation: Neurotoxicology. 1995 Spring;16(1):123-32
references.pmid: 7603632
references.citation: Electroencephalogr Clin Neurophysiol. 1973 Nov;35(5):487-94
references.pmid: 4126454
references.citation: Epilepsy Res. 1998 Sep;32(1-2):194-205
references.pmid: 9761320
references.citation: Nature. 1985 Oct 17-23;317(6038):623-5
references.pmid: 4058572
references.citation: Neurosci Biobehav Rev. 1997 Sep;21(5):559-79
references.pmid: 9353792
references.citation: J Pharmacol Exp Ther. 2007 Jan;320(1):154-61
references.pmid: 17015638
references.citation: Brain Res Bull. 1989 Jul-Aug;23(1-2):145-8
references.pmid: 2553217
references.citation: Neurosci Biobehav Rev. 1991 Fall;15(3):349-62
references.pmid: 1683477
references.citation: Prog Neurobiol. 1996 Dec;50(5-6):427-81
references.pmid: 9015822
references.citation: Arch Toxicol. 2006 Aug;80(8):502-7
references.pmid: 16525814
references.citation: Ital J Neurol Sci. 1995 Feb-Mar;16(1-2):17-25
references.pmid: 7642347
references.citation: Neurochem Res. 2008 Feb;33(2):348-54
references.pmid: 17710542
references.citation: Toxicol Appl Pharmacol. 2003 Apr 15;188(2):69-80
references.pmid: 12691725
references.citation: Eur J Pharmacol. 2001 Oct 12;428(3):323-30
references.pmid: 11689190
references.citation: Eur J Neurosci. 2000 Dec;12(12):4195-205
references.pmid: 11122331
references.citation: Neuroreport. 1994 May 9;5(9):1113-7
references.pmid: 8080968
references.citation: Chem Biol Interact. 2005 Dec 15;157-158:293-303
references.pmid: 16256093