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dc.contributor.authorKadriu, Bashkim
dc.contributor.authorGocel, James
dc.contributor.authorLarson, John
dc.contributor.authorGuidotti, Alessandro
dc.contributor.authorDavis, John M
dc.contributor.authorNambiar, Madhusoodana P.
dc.contributor.authorAuta, James
dc.date.accessioned2012-04-30T01:12:05Z
dc.date.available2012-04-30T01:12:05Z
dc.date.issued2011-12
dc.identifier.bibliographicCitationKadriu, B., Gocel, J., Larson, J., Guidotti, A., Davis, J. M., Nambiar, M. P., & Auta, J. 2011. Absence of tolerance to the anticonvulsant and neuroprotective effects of imidazenil against DFP-induced seizure and neuronal damage. Neuropharmacology. doi.org/10.1016/j.neuropharm.2011.08.043en
dc.identifier.issn0028-3908
dc.identifier.otherdoi.org/10.1016/j.neuropharm.2011.08.043
dc.identifier.urihttp://hdl.handle.net/10027/8294
dc.descriptionNOTICE: this is the author’s version of a work that was accepted for publication in Neuropharmacology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Neuropharmacology, Vol 61, Issue 8, (December 2011) doi.org/10.1016/j.neuropharm.2011.08.043en
dc.description.abstractThe clinical use of diazepam or midazolam to control organophosphate (OP) nerve agent-induced seizure activity is limited by their unwanted effects including sedation, amnesia, withdrawal, and anticonvulsant tolerance. Imidazenil is an imidazobenzodiazepine derivative with high intrinsic efficacy and selectivity for α2-, α3-, and α5- but low intrinsic efficacy for α1-containing GABAA receptors. We have previously shown that imidazenil is more efficacious than diazepam at protecting rats and mice from diisopropyl fluorophosphate (DFP)-induced seizures and neuronal damage without producing sedation. In the present study, we compared the tolerance liability of imidazenil and diazepam to attenuate the seizure activity and neurotoxic effects of DFP. Rats received protracted (14 days) oral treatment with increasing doses of imidazenil (1 to 4 mg/kg), diazepam (5 to 20 mg/kg), or vehicle. Eighteen hours after the last dose of the protracted treatment schedule, rats were tested for anticonvulsant tolerance after a 30 min pretreatment with a single test dose of imidazenil (0.5 mg/kg) or diazepam (5 mg/kg) prior to a DFP challenge (1.5 mg/kg). The anticonvulsant (modified Racine score scale) and neuroprotective (fluoro-jade B staining) effects of diazepam were significantly reduced in protracted diazepam-treated animals whereas the effects of imidazenil were not altered in protracted imidazenil-treated animals. The present findings indicate that protracted imidazenil treatment does not produce tolerance to its protective action against the neurotoxic effects of OP exposure.en
dc.description.sponsorshipThis work was supported by SBIR grant: [W81XWH-05-C-0125] to Neupharm Inc. (513 Central Avenue, Chicago IL) subcontracted to the Board of Trustees of the University of Illinois (Department of Psychiatry).en
dc.language.isoen_USen
dc.publisherElsevieren
dc.titleAbsence of Tolerance to the Anticonvulsant and Neuroprotective Effects of Imidazenil against DFP-Induced Seizure and Neuronal Damageen
dc.title.alternativeRunning Title: Imidazenil is devoid of anticonvulsant tolerance against DFPen
dc.typeArticleen


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