title: Anticonvulsant efficacy of antihistamine cyproheptadine in rats exposed to the chemical warfare nerve agent soman.
abstract: Organophosphate compounds, such as soman and sarin, are highly toxic chemical warfare nerve agents that cause a build-up of acetylcholine in synapses and neuromuscular junctions. Current therapies aim to prevent seizures and protect against brain injury following exposure. The present study was designed to evaluate the effectiveness of the antihistamine cyproheptadine in improving survival and controlling seizures in rats exposed to soman. Rats were pretreated with the oxime reactivator HI-6 (125mg/kg, ip) 30min prior to soman exposure (225μg/kg, sc) and then treated with atropine methylnitrate (AMN, 2.0mg/kg, im) 1min after soman. Cyproheptadine (10, 13, 16 or 20mg/kg, ip) was given at one of three time points: 1min after soman intoxication, at the onset of soman-induced seizures or 5min after seizure onset. Control animals were exposed to soman and given an equivalent volume of sterile water instead of cyproheptadine. The incidence of seizures, mortality, neuron counts, neuropathology and apoptosis in specific regions of the brain were evaluated. In animals given HI-6 and AMN the incidence of soman-induced seizure and mortality rate within the first 24h were 100%. When cyproheptadine was given at a dose of 13 or 20mg/kg 1min after soman exposure, the incidence of seizures was reduced from 100% to 13% and 30%, respectively. In addition, cyproheptadine given at 1min after soman exposure increased the survival rate to 100% regardless of dose. When cyproheptadine was administered at seizure onset, seizures were terminated in 100% of the animals at doses above 10mg/kg. The survival rate with cyproheptadine treatment at the onset of seizure was ≥83%. Seizures terminated in ≥75% of the animals that received cyproheptadine 5min after soman-induced seizure onset. When given at 5min after seizure onset the survival rate was 100% at all tested doses of cyproheptadine. The neuropathology scores and the number of TUNEL positive cells in the brain regions examined decreased at all time points and cyproheptadine doses tested. These observations indicate that cyproheptadine treatment can effectively control seizures, improve survival, reduce seizure duration and reduce the number of dying cells in the brain following soman exposure.
authors.affiliation: Pharmacology Division, U.S. Army Medical Research Institute of Chemical Defense, 21010-5400 Ricketts Point Road, Aberdeen Proving Ground, MD 54141-5400, USA. Electronic address: jennifer.l.winkler9.ctr@mail.mil.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Winkler
authors.affiliation: Pharmacology Division, U.S. Army Medical Research Institute of Chemical Defense, 21010-5400 Ricketts Point Road, Aberdeen Proving Ground, MD 54141-5400, USA. Electronic address: jacob.w.skovira.civ@mail.mil.
authors.forename: Jacob W
authors.initials: JW
authors.lastname: Skovira
authors.affiliation: Pharmacology Division, U.S. Army Medical Research Institute of Chemical Defense, 21010-5400 Ricketts Point Road, Aberdeen Proving Ground, MD 54141-5400, USA. Electronic address: kwailude1@yahoo.com.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Kan
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology; D003292:Convulsants / Q000633:toxicity*; D003533:Cyproheptadine / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D004827:Epilepsy / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology; D020287:In Situ Nick-End Labeling; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012999:Soman / Q000633:toxicity*; D013997:Time Factors
chemical_list: D000927:Anticonvulsants; D003292:Convulsants; D003533:Cyproheptadine; D012999:Soman
keywords: Anticholinergic; Cyproheptadine; Nerve agent; Neuropathology; Seizure; Soman