title: Prevention of organophosphate-induced chronic epilepsy by early benzodiazepine treatment.
abstract: Poisoning with organophosphates (OPs) may induce status epilepticus (SE), leading to severe brain damage. Our objectives were to investigate whether OP-induced SE leads to the emergence of spontaneous recurrent seizures (SRSs), the hallmark of chronic epilepsy, and if so, to assess the efficacy of benzodiazepine therapy following SE onset in preventing the epileptogenesis. We also explored early changes in hippocampal pyramidal cells excitability in this model. Adult rats were poisoned with the paraoxon (450μg/kg) and immediately treated with atropine (3mg/kg) and obidoxime (20mg/kg) to reduce acute mortality due to peripheral acetylcholinesterase inhibition. Electrical brain activity was assessed for two weeks during weeks 4-6 after poisoning using telemetric electrocorticographic intracranial recordings. All OP-poisoned animals developed SE, which could be suppressed by midazolam. Most (88%) rats which were not treated with midazolam developed SRSs, indicating that they have become chronically epileptic. Application of midazolam 1min following SE onset had a significant antiepileptogenic effect (only 11% of the rats became epileptic; p=0.001 compared to non-midazolam-treated rats). Applying midazolam 30min after SE onset did not significantly prevent chronic epilepsy. The electrophysiological properties of CA1 pyramidal cells, assessed electrophysiologically in hippocampal slices, were not altered by OP-induced SE. Thus we show for the first time that a single episode of OP-induced SE in rats leads to the acquisition of chronic epilepsy, and that this epileptogenic outcome can be largely prevented by immediate, but not delayed, administration of midazolam. Extrapolating these results to humans would suggest that midazolam should be provided together with atropine and an oxime in the immediate pharmacological treatment of OP poisoning.
authors.affiliation: Medical Corps HQ, IDF, Israel, PO Box 02149, Tel-Hashomer Base, Ramat-Gan, Israel; Sheba Medical Center, Tel Hashomer, affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, 2 Sheba Road, Ramat-Gan 52621, Israel. Electronic address: shaishrot@gmail.com.
authors.forename: Shai
authors.initials: S
authors.lastname: Shrot
authors.affiliation: Medical Corps HQ, IDF, Israel, PO Box 02149, Tel-Hashomer Base, Ramat-Gan, Israel; Sheba Medical Center, Tel Hashomer, affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, 2 Sheba Road, Ramat-Gan 52621, Israel. Electronic address: eramaty@gmail.com.
authors.forename: Erez
authors.initials: E
authors.lastname: Ramaty
authors.affiliation: Department of Medical Neurobiology, Institute for Medical Research Israel - Canada, Hebrew University-Hadassah Faculty of Medicine, PO Box 12272, Jerusalem 91121, Israel. Electronic address: yoavbiala@gmail.com.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Biala
authors.affiliation: Departments of Physiology and Biomedical Engineering, Faculty of Health Sciences, Ben-Gurion University of the Negev, PO Box 653, Beer-Sheva 8410501, Israel. Electronic address: guy.bar@gmail.com.
authors.forename: Guy
authors.initials: G
authors.lastname: Bar-Klein
authors.affiliation: Department of Medical Neurobiology, Institute for Medical Research Israel - Canada, Hebrew University-Hadassah Faculty of Medicine, PO Box 12272, Jerusalem 91121, Israel. Electronic address: moshe.daninos@mail.huji.ac.il.
authors.forename: Moshe
authors.initials: M
authors.lastname: Daninos
authors.affiliation: Departments of Physiology and Biomedical Engineering, Faculty of Health Sciences, Ben-Gurion University of the Negev, PO Box 653, Beer-Sheva 8410501, Israel. Electronic address: lyn2307@gmail.com.
authors.forename: Lyn
authors.initials: L
authors.lastname: Kamintsky
authors.affiliation: Medical Corps HQ, IDF, Israel, PO Box 02149, Tel-Hashomer Base, Ramat-Gan, Israel. Electronic address: igmak28@gmail.com.
authors.forename: Igor
authors.initials: I
authors.lastname: Makarovsky
authors.affiliation: Medical Corps HQ, IDF, Israel, PO Box 02149, Tel-Hashomer Base, Ramat-Gan, Israel. Electronic address: lir1n@yahoo.com.
authors.forename: Liran
authors.initials: L
authors.lastname: Statlender
authors.affiliation: Medical Corps HQ, IDF, Israel, PO Box 02149, Tel-Hashomer Base, Ramat-Gan, Israel; Sheba Medical Center, Tel Hashomer, affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, 2 Sheba Road, Ramat-Gan 52621, Israel. Electronic address: rosmanyossi@gmail.com.
authors.forename: Yossi
authors.initials: Y
authors.lastname: Rosman
authors.affiliation: Medical Corps HQ, IDF, Israel, PO Box 02149, Tel-Hashomer Base, Ramat-Gan, Israel; Sackler Faculty of Medicine, Tel-Aviv University, PO Box 39040, Tel-Aviv 69978, Israel. Electronic address: amir.krivoy@gmail.com.
authors.forename: Amir
authors.initials: A
authors.lastname: Krivoy
authors.affiliation: Medical Corps HQ, IDF, Israel, PO Box 02149, Tel-Hashomer Base, Ramat-Gan, Israel. Electronic address: ophir.lavon@gmail.com.
authors.forename: Ophir
authors.initials: O
authors.lastname: Lavon
authors.affiliation: Medical Corps HQ, IDF, Israel, PO Box 02149, Tel-Hashomer Base, Ramat-Gan, Israel. Electronic address: nmde@014.net.il.
authors.forename: Michael
authors.initials: M
authors.lastname: Kassirer
authors.affiliation: Departments of Physiology and Biomedical Engineering, Faculty of Health Sciences, Ben-Gurion University of the Negev, PO Box 653, Beer-Sheva 8410501, Israel. Electronic address: alonf@bgu.ac.il.
authors.forename: Alon
authors.initials: A
authors.lastname: Friedman
authors.affiliation: Department of Medical Neurobiology, Institute for Medical Research Israel - Canada, Hebrew University-Hadassah Faculty of Medicine, PO Box 12272, Jerusalem 91121, Israel. Electronic address: yoely@ekmd.huji.ac.il.
authors.forename: Yoel
authors.initials: Y
authors.lastname: Yaari
mesh_terms: D000818:Animals; D000931:Antidotes / Q000627:therapeutic use*; D001285:Atropine / Q000627:therapeutic use; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000627:therapeutic use; D002908:Chronic Disease; D004827:Epilepsy / Q000139:chemically induced / Q000517:prevention & control*; D008874:Midazolam / Q000627:therapeutic use*; D018721:Muscarinic Agonists; D009768:Obidoxime Chloride / Q000627:therapeutic use; D010261:Paraoxon / Q000633:toxicity*; D010575:Pesticides / Q000633:toxicity; D010862:Pilocarpine; D051381:Rats; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000139:chemically induced* / Q000503:physiopathology
chemical_list: D000931:Antidotes; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D018721:Muscarinic Agonists; D010575:Pesticides; D010862:Pilocarpine; D009768:Obidoxime Chloride; D001285:Atropine; D010261:Paraoxon; D008874:Midazolam
keywords: Epileptogenesis; Midazolam; Neurotoxicity; Paraoxon; Pesticide; Poisoning