Information on primers and probes used in the study.

<p>Information on primers and probes used in the study.</p

Administration with (−)-phenserine but not posiphen thirty minutes prior to soman exposure reduces neuronal cell death in the vulnerable piriform cortex.

<p>Representative photomicrographs of the piriform cortex stained with Fluorojade C staining (A–D, magnification 200×). Animals were injected with saline (A), a single dose of posiphen (1 mg/kg iv) [C] or (−)-pheserine (1 mg/kg iv) [D] thirty min prior to injection of soman (B). Animals were euthanized 24 hours after soman exposure. The piriform cortex (Pir) is outlined in the coronal section. Fluorojade C-positive degenerating neurons are indicated by the arrowheads. There was no statistically significant difference between groups of animals injected with saline and administration of either posiphen or (−)-phenserine in the absence of soman and are not shown.</p

Administration of (−)-phenserine thirty minutes prior to soman differentially modulates gene expression in the piriform cortex three hours after soman.

<p>NS: not significant.</p

Effect of pretreatment time of (−)-phenserine on movement after soman.

<p>*p<0.05.</p><p>**p<0.01.</p

Administration of (−)-phenserine injected intravenously 30 min after soman protects neurons against soman-induced neuronal cell death.

<p>Rats were post-treated with (−)-phenserine, posiphen or saline thirty minutes after soman. Images from three representative fields were acquired for each of the four brain regions/animal. The number of fluorescein-positive neurons was counted by an investigator that was blinded to the treatment. The bar represents the average percent neuronal cell death ± SD in the pirform cortex (A), hippocampus (B), basolateral amygdala (C), cingulate cortex (D). n = 6/group. *p<0.001 <i>vs</i> soman/saline by ANOVA+Tukey <i>post hoc</i> analysis.</p

Administration of (−)-phenserine prior to but not after soman protects against soman-induced mortality.

<p>Rats were administered (−)-phenserine, posiphen or saline 4 hr (A), or 30 min (B) prior to or 5 min (C) or 30 min (D) after soman. In the 4 hr pretreatment groups of animals, 12 rats died in the posiphen group and 11 rats died in the control group. There were no deaths in the (−)-phenserine group. In the 30 min pretreatment groups of animals, 2 animals died in the (−)-phenserine group. The bar represents the percent of surviving rats 24 hr after soman exposure calculated as: number of surviving rats 24 hr after soman/total number of rats ×100. n = 17–20. *p<0.026 <i>vs</i> saline/soman by Fisher exact test.</p

Evaluating mice lacking serum carboxylesterase as a behavioral model for nerve agent intoxication

<p>Mice and other rodents are typically utilized for chemical warfare nerve agent research. Rodents have large amounts of carboxylesterase in their blood, while humans do not. Carboxylesterase nonspecifically binds to and detoxifies nerve agent. The presence of this natural bioscavenger makes mice and other rodents poor models for studies identifying therapeutics to treat humans exposed to nerve agents. To obviate this problem, a serum carboxylesterase knockout (Es1 KO) mouse was created. In this study, Es1 KO and wild type (WT) mice were assessed for differences in gene expression, nerve agent (soman; GD) median lethal dose (MLD) values, and behavior prior to and following nerve agent exposure. No expression differences were detected between Es1 KO and WT mice in more than 34 000 mouse genes tested. There was a significant difference between Es1 KO and WT mice in MLD values, as the MLD for GD-exposed WT mice was significantly higher than the MLD for GD-exposed Es1 KO mice. Behavioral assessments of Es1 KO and WT mice included an open field test, a zero maze, a Barnes maze, and a sucrose preference test (SPT). While sex differences were observed in various measures of these tests, overall, Es1 KO mice behaved similarly to WT mice. The two genotypes also showed virtually identical neuropathological changes following GD exposure. Es1 KO mice appear to have an enhanced susceptibility to GD toxicity while retaining all other behavioral and physiological responses to this nerve agent, making the Es1 KO mouse a more human-like model for nerve agent research.</p