Novel Therapeutic Approaches for the Treatment of Depression and Cognitive Deficits in a Rodent Model of Gulf War Veterans' Illness
Abstract
About 1/3rd of the Persian Gulf War veterans exhibit Gulf War Illness (GWI) symptoms, particularly depression, and memory deficits. Chronic exposure to organophosphates (OP) is among multiple causes for GWI, yet its pathobiology remains ill understood. The role of calcium (Ca(sup 2+)) signaling in memory and mood is well established. In an OP- diisopropyl fluorophosphates (DFP) based rat model of GWI, we observed disruptions in neuronal Ca(sup 2+) levels ([Ca(sup 2+)]i). This study is aimed at identifying mechanisms underlying elevated [Ca( sup 2+)]i and investigating whether their therapeutic targeting could improve GWI neurological morbidities. Sustained Ca(sup 2+) elevations in GWI neurons had their origin in Ca(sup 2+) release from intracellular Ca(sup 2+) stores, since the application of ryanodine/ IP3 receptor antagonist dantrolene or levetiracetam produced greater than 50 percent reduction in their levels. Treatment with levetiracetam significantly improved symptoms of depression and anxiety in GWI rats. Since Ca(sup 2+) is a majorsecond messenger molecule, such chronic increases in its levels could produce pathological synaptic plasticity that expresses itself as GWI morbidities. Our studies show that treatment with drugs targeted at blocking intracellular Ca(sup 2+) release could be effective therapies for GWI.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2017
- Accession Number
- AD1042930
Entities
People
- Laxmikant S. Deshpande
Organizations
- Virginia Commonwealth University