title: Sarin-induced brain damage in rats is attenuated by delayed administration of midazolam.
abstract: Sarin poisoned rats display a hyper-cholinergic activity including hypersalivation, tremors, seizures and death. Here we studied the time and dose effects of midazolam treatment following nerve agent exposure. Rats were exposed to sarin (1.2 LD50, 108 μg/kg, im), and treated 1 min later with TMB4 and atropine (TA 7.5 and 5 mg/kg, im, respectively). Midazolam was injected either at 1 min (1 mg/kg, im), or 1 h later (1 or 5 mg/kg i.m.). Cortical seizures were monitored by electrocorticogram (ECoG). At 5 weeks, rats were assessed in a water maze task, and then their brains were extracted for biochemical analysis and histological evaluation. Results revealed a time and dose dependent effects of midazolam treatment. Rats treated with TA only displayed acute signs of sarin intoxication, 29% died within 24h and the ECoG showed seizures for several hours. Animals that received midazolam within 1 min survived with only minor clinical signs but with no biochemical, behavioral, or histological sequel. Animals that lived to receive midazolam at 1h (87%) survived and the effects of the delayed administration were dose dependent. Midazolam 5 mg/kg significantly counteracted the acute signs of intoxication and the impaired behavioral performance, attenuated some of the inflammatory response with no effect on morphological damage. Midazolam 1mg/kg showed only a slight tendency to modulate the cognitive function. In addition, the delayed administration of both midazolam doses significantly attenuated ECoG compared to TA treatment only. These results suggest that following prolonged seizure, high dose midazolam is beneficial in counteracting adverse effects of sarin poisoning.
authors.affiliation: Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, Israel.
authors.forename: Shira
authors.initials: S
authors.lastname: Chapman
authors.affiliation: Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, Israel.
authors.forename: Guy
authors.initials: G
authors.lastname: Yaakov
authors.affiliation: Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, Israel.
authors.forename: Inbal
authors.initials: I
authors.lastname: Egoz
authors.affiliation: Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, Israel.
authors.forename: Ishai
authors.initials: I
authors.lastname: Rabinovitz
authors.affiliation: Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, Israel.
authors.forename: Lily
authors.initials: L
authors.lastname: Raveh
authors.affiliation: Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Kadar
authors.affiliation: Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Gilat
authors.affiliation: Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, Israel. Electronic address: ettieg@iibr.gov.il.
authors.forename: Ettie
authors.initials: E
authors.lastname: Grauer
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001930:Brain Injuries / Q000139:chemically induced* / Q000188:drug therapy* / Q000503:physiopathology; D002352:Carrier Proteins / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004334:Drug Administration Schedule; D004569:Electroencephalography; D004797:Enzyme-Linked Immunosorbent Assay; D006993:Hypnotics and Sedatives / Q000008:administration & dosage*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008874:Midazolam / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D012524:Sarin / Q000633:toxicity*; D012720:Severity of Illness Index; D013997:Time Factors
chemical_list: D002352:Carrier Proteins; D002800:Cholinesterase Inhibitors; D016207:Cytokines; D006993:Hypnotics and Sedatives; D011963:Receptors, GABA-A; C069997:Tspo protein, rat; D012524:Sarin; D015232:Dinoprostone; D008874:Midazolam
keywords: Anticonvulsants; Nerve agents; Neuroinflammation; Seizures