Anticonvulsant treatment of sarin-induced seizures with nasal midazolam: an electrographic, behavioral, and histological study in freely moving rats.

Centrally mediated seizures and convulsions are common consequences of exposure to organophosphates (OPs). These seizures rapidly progress to status epilepticus (SE) and contribute to profound brain injury. Effective management of these seizures is critical for minimization of brain damage. Nasal application of midazolam (1.5 mg/kg) after 5 min of sarin-induced electrographic seizure activity (EGSA) ameliorated EGSA and convulsive behavior (238 +/- 90 s). Identical treatment after 30 min was not sufficient to ameliorate ECoG paradoxical activity and convulsive behavior. Nasal midazolam (1.5 mg/kg), together with scopolamine (1 mg/kg, im) after 5 min of EGSA, exerted a powerful and rapid anticonvulsant effect (53 +/- 10 s). Delaying the same treatment to 30 min of EGSA leads to attenuation of paroxysmal ECoG activity in all cases but total cessation of paroxysmal activity was not observed in most animals tested. Cognitive tests utilizing the Morris Water Maze demonstrated that nasal midazolam alone or together with scopolamine (im), administered after 5 min of convulsions, abolished the effect of sarin on learning. Both these treatments, when given after 30 min of convulsions, only decreased the sarin-induced learning impairments. Whereas rats which were not subject to the anticonvulsant agents did not show any memory for the platform location, both treatments (at 5 min as well as at 30 min) completely abolished the memory deficits. Both treatments equally blocked the impairment of reversal learning when given at 5 min. However, when administered after 30 min, midazolam alone reversed the impairments in reversal learning, while midazolam with scopolamine did not. Rats exposed to sarin and treated with the therapeutic regimen with the exclusion of midazolam exhibited severe brain lesions that encountered the hippocampus, pyriform cortex, and thalamus. Nasal midazolam at 5 min prevented brain damage, while delaying the midazolam treatment to 30 min of EGSA resulted in brain damage. The addition of scopolamine to midazolam did not alter the above observation. In summary, nasal midazolam treatment briefly after initiation of OP-induced seizure leads to cessation of EGSA and prevented brain lesions and behavioral deficiencies in the rat model.

Protection and inflammatory markers following exposure of guinea pigs to sarin vapour: comparative efficacy of three oximes.

The purpose of the present study was to compare the antidotal efficacy and the combined effects on inflammatory markers of three oximes--toxogonine, TMB4 and 2-PAM--in combination with anticholinergic drugs following exposure to sarin vapour by inhalation. Guinea pigs restrained in plethysmographs were exposed to various doses of sarin vapour (in the range of 1.4-4.4LD50). The antidotal mixture was injected immediately (5-20 s) following exposure (3 mg kg(-1) atropine and 1 mg kg(-1) benactyzine in combination with 6 mg kg(-1) toxogonine, 2 mg kg(-1) TMB4 or 12 mg kg(-1) 2-PAM). Bronchoalveolar lavage (BAL) samples were taken from surviving animals 24 h after exposure to determine the levels of inflammatory markers. A differential cell count was performed in BAL samples on Giemsa-stained slides. The inflammatory markers--histamine and prostaglandins (PGE)--were measured in BAL using radioimmunoassay (RIA) techniques. The survival rate in the various treatment groups and analysis of BAL samples showed that: (i) Toxogonine, TMB4 and 2-PAM, without pyridostigmine pretreatment, at doses that were proportional to their doses in the respective auto-injectors, exhibited similar antidotal efficacy against sarin exposure. (ii) The results demonstrated that a centrally acting anticholinergic drug is essential in the antidotal mixture to ensure survival. (iii) Histamine release and eosinophilia following sarin inhalation might require additional intervention, aimed at reducing the symptoms of allergic reaction and possibly expediting recovery.

Wistar-Kyoto rats in the Morris water maze: impaired working memory and hyper-reactivity to stress.

Wistar-Kyoto (WKY) rats were tested as a potential animal model for memory dysfunction. These animals were reported to be highly reactive to stress and this was associated with findings of alterations in their hippocampal cholinergic activity. Since hippocampal cholinergic hypofunction is often associated with deficits in memory processes, untreated WKY rats were tested here in a working memory task in the Morris water maze. Animals were tested for five daily sessions, with two identical trials per day, and their performance was compared to that of Sprague-Dawley (SD) rats. Results show that WKY rats failed to improve their performance both from day to day and within the two trials each day. This suggests impaired memory capabilities of WKY rats and may support their use as an animal model of memory dysfunction. However, because of their increased tendency to float, speed of performance was also reduced in WKY compared to SD rats. This difference may be associated with their increased reactivity to stress. The combination of memory dysfunction and stress hyper-reactivity seen in WKY rats may be used to study the association between these two functions, particularly the possible interaction between memory and depression.

Visual and spatial trials paired in a new behavioral procedure: effects of benactyzine.

A paired discrimination (PD) task in which visual and spatial discrimination trials were combined is offered as a method for the evaluation of drug effects on various behavioral parameters. Acquisition of the PD task is characterized by six different parameters simultaneously recorded each session. Analysis of memory requirements suggest that intact reference memory is involved in the performance of both types of trials while working memory is involved only in the performance of the spatial trial. Benactyzine (1-4 mg/kg), an anticholinergic drug, was tested for its effects on visual and spatial tasks presented either separately or in the PD combination. Benactyzine-induced mydriasis was also determined for its possible role in photophobic-induced errors. Benactyzine was found to differentially increase the number of errors performed during the spatial but not during the visual trials. The data are in accord with earlier finding of specific cholinergic involvement in working memory processes. Thus, low doses of benactyzine, and the PD task, can prove useful in the cognitive analysis of cholinergic hypofunction and its reversal by memory-enhancing drugs.

Improvement of cognitive function by MAO-B inhibitor L-deprenyl in aged rats.

This study evaluated the ability of the selective MAO-B inhibitor, L-deprenyl, to reverse cognitive impairments appearing in aged rats, using the reference memory, Morris Water Maze paradigm. L-Deprenyl significantly improved learning and memory deficits associated with old age in doses of 1.25 and 5 mg/kg PO (escape latency measure) and doses of 1.25, 2.5 and 5 mg/kg PO (path length measure). L-Deprenyl also improved reversal learning impairments in doses of 1.25, 2.5 and 5 mg/kg PO, as expressed by the escape latency measure. The data suggest that L-deprenyl possesses potential cognitive enhancement abilities probably due to an increase in dopaminergic activity.