Novel Therapeutic Approaches for the Treatment of Depression and CognitiveDeficits in a Rodent Model of Gulf War Veterans' Illness
Abstract
Around 35 of Persian Gulf War soldiers suffer from the Gulf War Illness (GWI). Exposure to organophosphates (OP) is thought to underlie GWI. Disruptions in Ca2 homeostasis are found in many neurological conditions, but has not been studied in GWI. Male Sprague-Dawley rats were exposed to various diisopropyl fluorophosphate (DFP) dose to approximate GW OP exposures. We observed depressive symptoms and cognitive deficits at 3-mos post DFP exposures. At this time-point, acutely isolated CA1neurons from GWI rats manifested [Ca2 ]i, that were significantly higher than [Ca2 ]i in neurons from age-matched control rats. Analysis of the population distributions of [Ca2 ]i revealed a significant right-ward population shift towards higher Ca2 level in DFP rats. Analysis of protein expression for the components of Ca2 -induced Ca2 -release (CICR) machinery revealed a significantupregulation in the levels of phosphorylated ryanodine receptor, and signaling enzymes PKA and PLC. Treatment with CICR antagonists significantly dropped elevated [Ca2 ]i in DFP neurons and also improved performance on neurobehavioral tests. SinceCa2 is a major second messenger molecule, sustained increase in its levels could activate multiple signaling cascades, and alter expression of proteins involved in synaptic plasticity, which could underlie the chronic morbidity following DFP exposures.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2016
- Accession Number
- AD1047218
Entities
People
- Laxmikant S. Deshpande
Organizations
- Virginia Commonwealth University