Organophosphates (OPs), including nerve agents, target the cholinergic system via inhibition of acetylcholinesterase (AChE), with subsequent overstimulation resulting in neural damage and potential detrimental long-term effects. The efficacy of novel pyridinium oxime reactivators, created with moieties to increase blood-brain barrier penetration, was tested using highly relevant sarin and VX surrogates. Glial fibrillary acidic protein (GFAP; an indicator of neural damage) and monoamines (dopamine, serotonin, and their metabolites) were measured in select brain regions via immunohistochemistry and HPLC, respectively. Adult male rats were treated ip with high, sub-lethal doses of surrogates for sarin or VX, nitrophenyl isopropyl methylphosphonate (NIMP) or nitrophenyl ethyl methylphosphonate (NEMP), respectively. Surrogate treatment was followed after 1 hr by im administration of novel oxime. Seizure activity was monitored, and kainic acid (KA) served as a positive control. Administration of KA or surrogate (NIMP or NEMP) significantly increased GFAP expression compared to control animals. Two different formulations of one particular oxime (bromide vs. mesylate salt) attenuated seizures and reduced GFAP levels over NIMP or NEMP treatments alone to levels near those of controls in both the piriform cortex and dentate gyrus region of the hippocampus, while 2-PAM did not provide protection. Serotonergic activity was increased in several brain regions, including the piriform cortex, one hr after NIMP treatment. Markers of oxidative stress (isoprostanes) were also tested. Overall, these results indicate the potential therapeutic efficacy of these oximes and suggest this innovative chemistry may protect against neural damage induced by OP.
| Identifer | oai:union.ndltd.org:MSSTATE/oai:scholarsjunction.msstate.edu:td-4279 |
| Date | 11 May 2013 |
| Creators | Pringle, Ronald B |
| Publisher | Scholars Junction |
| Source Sets | Mississippi State University |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations |
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