Theses and Dissertations

ORCID

https://orcid.org/0000-0001-8677-539X

Issuing Body

Mississippi State University

Advisor

Chambers, Janice E.

Committee Member

Kaplan, Barbara L.

Committee Member

Carr, Russel L.

Committee Member

Howell, George E., III

Committee Member

Ross, Matthew K.

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

Our laboratory has invented a series of oxime acetylcholinesterase (AChE) reactivators (US Patent 9,227,937) that enter the brain, reduce time to cessation of seizure-like activities, and prevent organophosphorus compound (OP) neuropathology, not seen with the current U.S. approved AChE reactivator, pralidoxime (2-PAM). Thus, 2-PAM fails to protect the brain against damage and long-term cognitive and behavioral deficits seen in humans after OP exposure. However, the mechanisms by which these novel oximes provide central neuroprotection through preservation of neuronal cell structures from damage in a rat model are not fully understood by AChE reactivation alone. This dissertation investigated neurotoxic mechanisms of NIMP as potential targets for additional direct and indirect neuroprotection by our lead in vivo AChE reactivator, Oxime 20.

Male Sprague Dawley rats exposed to NIMP experienced neurotoxic effects in areas critical to OP-induced seizure generation (e.g., hippocampus and piriform cortex) such as the inhibition of multiple serine hydrolases (i.e., fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL)), necrotic cell death evident by increased necrotic receptor-interacting serine/threonine-protein kinase 1 (RIPK1) levels and no apoptotic caspase-3 activity, and increased levels of neuroinflammation via elevated levels of pro-inflammatory oxylipins 4 days post lethal exposure. However, due to the lack of statistical significance, NIMP exposure did not definitively affect the subcellular location of either phosphorylated excitatory N-methyl-D-aspartate (NMDA) receptor or inhibitory γ-aminobutyric acid (GABA) receptor subunits.

Results suggested that Oxime 20 therapy provided neuroprotection after NIMP exposure, such as limited reactivation of other serine hydrolase targets, significantly decreased RIPK1 levels (i.e., necrotic environment) in the hippocampus, and significantly decreased inflammatory oxylipins 4 days post-NIMP exposure. Thus, reducing OP-induced neuroinflammation might be the main contributor to the neuroprotection (i.e., neuronal cell structure preservation) previously observed in our laboratory.

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