Preclinical Treatment of an Organophosphate Model of Gulf War Illness
Abstract
Objective: This study aims to validate a new form of treatment for cognitive impairment associated with Gulf War Illness (GWI) using a safe, easy to use remedy already approved for use in adults and children by the Food and Drug Administration (FDA) for other neurological disorders. This is a preclinical trial, performed in a mouse model of GWI that will evaluate the effectiveness of a human growth factor IGF-1, at the maximum clinical dose, on cell-to-cell communication between individual neurons -- a level of resolution that cannot be achieved in humans. Rationale: Our mouse model of GWI is based on the repeated, low-dose exposure of military personnel to strong pesticides, such as chlorpyrifos, during the 1990-1991 Gulf War. Chlorpyrifos, and other pesticides like it, have been restricted in their use in the United States in the past decade due to their neurotoxic effects on farm workers and children, and are believed to contribute to the delayed onset of cognitive problems in GWI patients (along with subclinical exposure to nerve agents such as Sarin nerve gas that work through a similar mechanism of action). Most importantly, GWI cognitive problems did not develop until after some delay, and the types and severity of these symptoms can be highly variable between patients. Our mouse model faithfully recapitulates delayed onset neurological damage without any signs of acute neurotoxicity or illness during repeated exposure to low doses of pesticide. Therefore, our model provides a relevant, non-human system for evaluating the effectiveness and safety of new GWI therapies ahead of clinical trials. The main neurons in the brain, called principal neurons, have two types of long processes that are used to communicate with one another: axons and dendrites. Axons transmit information to other neurons and dendrites receive information from other neurons. Dendrites have specialized protrusions called "spines" that are the site of cell-to-cell communication, so that the strength of cellular communication is directly related to the number of dendritic spines. Changes in the shape of the dendritic spines or in the spine number have been implicated in autism spectrum disorders, Down syndrome, Alzheimer s disease, and Rett syndrome. Similarly, we observe a 50% decrease in the number of spines in the brains of our GWI mouse model. This corresponds with a 50% decrease in the strength of cell-to-cell communication in the same region. Loss of dendritic spines is reversible with IGF-1 treatment in cells from patients with autism spectrum disorders, and in mouse models of autism and Rett syndrome. Therefore, we hope to translate IGF-1 treatment from our GWI mouse model to GWI patients with the same efficiency via this research proposal. Applicability: This study is designed as a tool for evaluating the effectiveness of IGF-1 therapy on cell-to-cell communication, relevant to cognitive symptoms reported by GWI patients. These symptoms include learning and memory problems, particularly short-term memory, working memory, and associative memory. This strategy of testing IGF-1 therapy in mouse models of human disorders has led to rapid establishment of clinical trials testing IGF-1 therapy in autism spectrum disorders and Rett syndrome. If IGF-1 is successful in restoring normal cell-to-cell communication in our GWI mouse model, the ground is set for IGF-1 clinical trials in GWI patients with impaired cognition. There are other treatments on the market to increase cognitive ability, particularly for Alzheimer s disease, but they rely on a similar mechanism of action as that of OP pesticides. In addition, these treatments have a limited window of effectiveness, declining with continued treatment. Conversely IGF-1 is a human growth factor that has no adverse side effects and has been approved by the FDA for other neurological disorders with no notable side effects. Furthermore, in humans, IGF-1 can be administered vi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510713
Entities
People
- Haley Speed
Organizations
- United States Army
- University of Texas Southwestern Medical Center