Publication Date

2012

Document Type

Thesis

Committee Members

David R. Cool (Committee Member), Michael B. Hennessy (Committee Member), James B. Lucot (Advisor)

Degree Name

Master of Science (MS)

Abstract

Exposure to the chemical warfare agent sarin produces long term neurological deficits. The long term medical consequences could be averted with the development of neuroprotectants to preserve brain function. In our mouse model, the combination of the carboxylesterase inhibitor 2-(o-cresyl)-4H-1:3:2-benzodioxaphosphorin-2-oxide (CBDP) with the organophosphorus (OP) nerve agent sarin was used to render mice more sensitive to poisoning and reduce the amount of hydrogen fluoride cleaved from sarin during binding to esterases. Since carboxylesterase acts as a scavenger, reducing the levels causes sarin to have a greater inhibition effect on acetylcholinesterase. These smaller doses permitted the use of doses similar to those producing symptoms in humans. Prior work demonstrated that 8-OH-DPAT (DPAT) was neuroprotective when given up to two hours after sarin administration through its secondary pharmacology. The aim of this study was to explore the efficacy of CM-2,525, which acts on part of that secondary pharmacology, as a neuroprotectant and to directly compare its effects with DPAT. Male C57BL/6 mice were administered a toxic challenge of 1.5 mg/kg of CBDP plus the dose of sarin needed to achieve 35% mortality. A dose-response curve for CM-2,535 was determined by administration one minute after the toxic challenge. Male C57BL/6 mice also were administered a toxic challenge followed in one minute by saline or DPAT (1 mg/kg). Functional Observational Battery (FOB) data were collected for each mouse and weight data were collected pre- and post-exposure for 3 days. Treatment with DPAT revealed no benefit on FOB scores and had no effect on weight loss. Low doses of CM-2,525 reduced the FOB scores and the higher doses decreased weight loss. Immunohistological analysis was performed using Glial Fibrillary Associated Protein (GFAP) which increases in sarin treated animals and Neuronal Nuclei (NeuN), a stain for mature neurons that decreases after toxic challenge. Previously we found that treatment with DPAT resulted in a significant decrease in GFAP-labeled cells in the dentate gyrus (DG) and is effective when given two hours after the toxic challenge. In this study it both reduced GFAP and increased NeuN. The higher doses of CM-2,525 significantly decreased GFAP-labeled cells in the amygdala (Amy) and DG regions and increased NeuN-labeled cells in the Amy, piriform cortex, and DG regions. CM-2,525 has efficacy superior to DPAT with effects on weight loss and FOB scores as well as providing neuroprotection and would likely be neuroprotective as long after sarin exposure as DPAT.

Page Count

74

Department or Program

Department of Pharmacology and Toxicology

Year Degree Awarded

2012

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