Absence of tolerance to the anticonvulsant and neuroprotective effects of imidazenil against DFP-induced seizure and neuronal damage

Bashkim Kadriu,James Gocel,John Larson,Alessandro Guidotti,John M Davis,Madhusoodana P Nambiar,James Auta

doi:10.1016/j.neuropharm.2011.08.043

Abstract

The 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 imidazo-benzodiazepine 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 (1–4 mg/kg), diazepam (5–20 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.

Highlights

In an era of increased global risk from terrorist attacks, chemical warfare nerve agent (CWNA) exposure is of great concern (Holstage et al, 1997)
We studied neuronal damage in piriform cortex, CA1 hippocampus, and amygdala since we have previously shown that these brain areas are sensitive to the neurotoxic effects of prolonged diisopropyl fluorophosphate (DFP)-induced seizure activity (Kadriu, 2011)
The onset of the behavioral manifestations of DFP-induced seizure activity ranged between five and ten min and was preceded by predictable and consistent behavioral signs including bouts of chewing activity and intermittent head tremors. These initial behavioral signs were followed by whole body tremors, jerky motions, and Straub tail movements that rapidly progressed to explosive tonic-clonic motor convulsions and into status epilepticus

Summary

Introduction

In an era of increased global risk from terrorist attacks, chemical warfare nerve agent (CWNA) exposure is of great concern (Holstage et al, 1997). The preferred anticonvulsant BZs (DZ and MDZ) at the doses needed to prevent CWNA-induced seizures (Newmark, 2007; Shih et al, 2007; Kadriu et al, 2009, 2011), by acting with high intrinsic efficacy at α1-containing GABAA receptors, elicit amnestic, sedative, or hypnotic actions and cardio-respiratory depression effects (Costa and Guidotti., 1996; Costa et al, 2001) These BZs are incapacitating and cannot be given prophylactically to individuals who have an anticipated risk of CWNA exposure (Tashma et al, 2001). These BZs can be administered immediately after CWNA exposure but are less effective anticonvulsants when administered after the instigation of status epilepticus (Mazarati et al, 1998; McDonough 2010)

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Conclusion