Neurochemical and Behavioral Effects Following Repeated-Dose Pyridostigmine Bromide and Sublethal Organophosphate Challenge
Abstract
Objectives and Rationale: The main objective of the proposed project is to determine whether prophylactic use of the drug pyridostigmine bromide (PB) exacerbates the toxicity caused by a subsequent exposure to a highly toxic organophosphate (OP) nerve agent. Nerve agents act by potently and persistently inhibiting a critical enzyme in the nervous system, acetylcholinesterase (AChE), which normally acts quickly to prevent inappropriate prolongation of nervous system activity. When this enzyme is inhibited, the nervous system activity is prolonged and excessive and leads to a variety of signs and symptoms of toxicity such as tremors, convulsions, blurred vision, and respiratory distress. Respiratory failure can be lethal. PB is a drug that has been used safely to treat the muscle weakness brought on by the autoimmune disorder myasthenia gravis. In the situation of nerve agent attack, PB inhibits AChE before the nerve agent is encountered, and AChE is protected from inhibition by the nerve agent because it is already inhibited by PB. PB inhibition is transient, so once the nerve agent clears out of the body, the PB dissociates itself from AChE and the enzyme recovers its normal level of activity, thereby saving the Warfighter’s life. This enhancement of survival has been demonstrated in animal experiments with lethal levels of the nerve agent soman, and the PB regimen is approved by the FDA for this purpose. However, one fact that has not been considered is that non-nervous AChE, such as in the red blood cells, can normally act as an important protective scavenger mechanism against nerve agent toxicity, by being available for inhibition by the nerve agent. When blood AChE is inhibited by the OP, the OP molecule is destroyed and cannot cause toxicity. Thus, available blood AChE yields less circulating nerve agent to cause toxicity. With PB pretreatment, however, this protective mechanism will be compromised, and greater toxicity might occur from the nerve agent from a sublethal level of nerve agent. The OP could exert even more severe toxicity that resulted from changes in the brain’s normal biochemistry which would be translated into changes in behaviors. These changes would be short-term and they could become long-term. The hypothesis for this project is: In an animal model, the repeated administration of pyridostigmine bromide will not lead to neurochemical and behavioral changes, but the neurochemical and behavioral changes occurring because of an administration of a high sublethal dosage of a highly toxic OP anticholinesterase will be exacerbated following the repeated dose regimen of PB. Using an animal model with which we have extensive experience, and building on our long background in OP research, we propose a rat model where rats would be treated orally with PB daily for 3 weeks to a level of about 30% blood AChE inhibition (the target level in humans for PB prophylaxis) and are then challenged with a high sublethal dosage of a very toxic nerve agent surrogate. The brains of the rats would be tested for several neurochemical parameters related to expression of genes and proteins important in inflammation, tissue damage, and tissue repair. The animals will be tested for behaviors related to cognition, depression, and anxiety. Relevance to the TERP: The proposed project will address: Program Goal 1. Elucidate mechanisms of how toxic exposures result in adverse effects; Topic Area, Neurotoxin Exposure; Focus Areas 1, Understand the relationship between toxic exposures and long-term neurologic disorders and 2, Elucidate basic mechanisms of neurotoxicity/neurodegeneration resulting from toxic exposures. This project will address mechanisms of toxicity exerted by neurotoxicants important to the military that might lead to long-term neurotoxicity. The proposed project is basic research on mechanisms and toxic responses, and it is not clinical. However, if the hypothesis is supported, the
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310733
Entities
People
- Janice Chambers
Organizations
- Mississippi State University
- United States Army