Elsevier

NeuroToxicology

Volume 26, Issue 1, January 2005, Pages 39-48
NeuroToxicology

Soman-induced Convulsions in Rats Terminated with Pharmacological Agents after 45 min: Neuropathology and Cognitive Performance

https://doi.org/10.1016/j.neuro.2004.07.011Get rights and content

Abstract

It has been demonstrated that a triple regimen consisting of procyclidine (6 mg/kg), diazepam (10 mg/kg) and pentobarbital (30 mg/kg) can effectively terminate soman-induced (1 × LD50) seizures/convulsions in rats when administered 30–40 min following onset. However, convulsive activity lasting for only 45 min can result in marked neuronal pathology. The purpose of the present study was to examine potential cognitive impairments of such brain lesions. The results showed that the neuronal pathology (assessed with Fluoro-Jade B) varied from none at all to 30% damage in the index areas (hippocampus, amygdala, piriform cortex). Cognitive deficits were seen in a novelty test (11 days post-exposure) and retention of a brightness discrimination task (28 days post-exposure) among the rats with neuropathology. Furthermore, significant correlations between neuropathology scores and behavioral measures were found for the animals that convulsed. Among these rats, the mortality rate was relatively high (60%) compared with rats in a previous study that had undergone implantation of hippocampal electrodes (17%). Neither the soman poisoning in the absence of convulsions nor the triple regimen alone affected behavior. It is concluded that early management of soman-induced convulsions is of major importance in preventing neuropathology and accompanying cognitive impairments.

Section snippets

INTRODUCTION

Exposure to the organophosphorus nerve agent soman causes a progression of toxic signs including hypersecretion, respiratory distress, tremor, seizures/convulsions, coma, and death (Taylor, 1985). These toxic effects are due to irreversible inhibition of acetylcholinesterase, the enzyme that hydrolyzes acetylcholine. Excessive amounts of acetylcholine lead to over-stimulation of muscarinic and nicotinic receptors. Increased cholinergic activity in the brain can induce the first phase of

Subjects

Sixty-six male Wistar rats from a commercial supplier (Møllegaard Breeding Laboratories, Denmark) weighing 280–330 g served as subjects. The experiments were approved by the National Animal Research Authority. The animals were housed individually and had free access to commercial rat pellets and water, unless otherwise described for behavioral testing. The rats were handled individually 5 days before treatment and 2–5 days following treatment, being allowed to explore a table top (80 × 60 cm) for

Histology

In the Fluoro-Jade stained sections, the background contrast was adjusted to enhance the distinctness of cell elements. For this reason, a brighter background color was convenient for intact tissue, whereas a darker background color made the fluorescent, degenerating cell bodies more evident.

Among the convulsing rats (n = 14), tremendous individual differences were seen in terms of neuropathology: from none to severe degeneration (Fig. 1). In five rats, the neuropathology score was 0, whereas

DISCUSSION

The results from the present study showed that the triple regimen consisting of procyclidine, diazepam and pentobarbital was able to terminate soman-induced convulsions 45 min after onset. The neuropathology caused by soman plus convulsions varied enormously from none in 36% of the rats to as much as 30% damage in the index areas (hippocampus, amygdala, and piriform cortex). The brain lesions in the neuropathology group resulted in cognitive impairment in the novelty test and the discrimination

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