David Cool (Committee Member), Khaled Elased (Committee Member), James Lucot (Advisor)
Master of Science (MS)
Sarin, also known as Sarin (German agent B) is classified as a weapon of mass destruction. Sarin (O-isopropyl methyl phosphonofluoridate) is a highly toxic nerve agent originally produced for chemical warfare and has been used in terrorist activities. Sarin is an extremely potent acetylcholinesterase inhibitor with high specificity and affinity for the enzyme. High sarin doses causes death due to anoxia resulting from airway obstruction, weakness of the muscles of respiration, respiratory failure and convulsions. Current treatments are still not effective at protecting against long term effects following exposure. A current approach aims to counteract the increased glutamatergic and cholinergic neurotransmission occurring in sarin neurotoxicity. In vitro and in vivo, serotonin (5-HT) 1A agonist prevented toxicity from glutamate. We determined the neuroprotective capabilities of serotonin (5-HT) 1A agonists as novel pharmacological countermeasures to chemical warfare agents. Rodents have higher amount of carboxylesterase enzyme and requires higher doses of sarin than other species. To address this issue we administered 1.5 mg/kg of CBDP (2-/o-cresyl/-4 H-1: 3: 2-benzodioxa-phosphorin-2-oxide), which specifically blocks carboxyl esterase and makes mouse model comparable to that of human exposure. We determined 1mg/kg dose of serotonin (5-HT) 1A agonists 8-OH-DPAT from dose response curve based on neuroprotection, with toxic challenge of 1.5 mg/kg CBDP and dose of sarin yielding 25-50 % mortality. This mortality rate gave enough number of survivors with seizures and neurodegeneration for reliable baselines. Measurements were mortality, weight loss AChE activity in blood and CNS, functional observational battery (FOB) and histology compared to control and toxic challenge mice. In addition, a time response curve after toxic challenge was determined with 1mg/kg of 8-OH-DPAT at time points of 1, 15, 30, 45, 60 minutes and 2, 4, 6 hours. We observed neuroprotection by 8-OH-DPAT in the dentate gyrus of the hippocampus when administered up to two hours after Sarin. The ability of the combination of serotonin (5-HT) 1A agonist's dose and time after toxic challenge was tested for its ability to reinstate fear potentiated startle (FPS) response. However this test was invalidated by the response of the control group. DPAT like drugs could be useful in treatment of long term effects produced by sarin induced convulsions.
Department or Program
Department of Pharmacology and Toxicology
Year Degree Awarded
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