Theses and Dissertations

Issuing Body

Mississippi State University

Advisor

Chambers, Janice E.

Committee Member

Kaplan, Barbara L.F.

Committee Member

Olivier, Alicia K.

Committee Member

Howell, George E.

Committee Member

Carr, Russell L.

Date of Degree

8-8-2023

Document Type

Dissertation - Campus Access Only

Major

Environmental Toxicology

Degree Name

Doctor of Philosophy (Ph.D)

College

College of Veterinary Medicine

Department

College of Veterinary Medicine

Abstract

Organophosphorus compounds (OPs), both nerve agents and insecticides, may induce damage leading to long-term neurological deficits. Oxime 20, the lead compound from a platform of substituted phenoxyalkyl pyridinium oximes (US Patent 9,227,937), is an oxime that reactivates OP-inhibited acetylcholinesterase (AChE) and has displayed neuroprotection within the brain of rats in in vivo tests where the currently approved treatment, pralidoxime (2-PAM), has not. This research investigated the neuroprotective effect of novel oxime therapy. Gene expression in rat piriform cortex was analyzed to determine if neurotoxicity, stress, and synaptic plasticity-associated genes were down-regulated by Oxime 20 following a sublethal dose of sarin surrogate 4-nitrophenyl isopropyl methylphosphonate (NIMP). Significant therapeutic changes from the NIMP+Oxime20 group relate to cell viability and attenuation of neuroinflammation, while networks formed by Ingenuity Pathway Analysis (IPA) emphasize neuroinflammatory and cell death pathways. Neuropathology cell biomarkers glial fibrillary acidic protein (GFAP), neuronal nuclear antigen (NeuN), ionized calcium-binding adapter molecule 1 (IBA-1), and cyclooxygenase-2 (COX-2) were measured immunohistochemically in rat CA1 region of the hippocampus following a lethal dose of NIMP plus Oxime 20 or 2-PAM therapy. For GFAP and IBA-1, an expected trend of NIMP activation and Oxime 20 recovery was seen and was more pronounced in the apex CA1 region. Loss of neurons were observed most often in the NIMP experimental group. A platform of novel oximes was selected based on percent brain AChE reactivation (24–35% and 10–17%) following exposure of rats to NIMP to determine if interactions between ATP-binding cassette efflux transporters of the blood-brain barrier, p-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), contribute to oxime in vivo efficacy. In vitro human P-gp and BCRP membrane assays determined activation and inhibition measurements of total ATPase activity. Human P-gp transport was variable among oximes. Oxime 55 was the only oxime transported by BCRP. Therefore, the lower efficacy of 10-17% in the reactivation oxime group was not due to greater P-gp or BCRP efflux. The explanation might lie with different transporter or mechanism. These tests support our laboratory testing OP inhibited AChE reactivators to understand their efficacy and evaluate neuroprotection from damage caused by OP exposure

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