Novel Therapeutic Approaches for the Treatment of Depression and Cognitive Deficits in a Rodent Model of Gulf War Veterans' Illness
Technical Report,29 Sep 2016,28 Sep 2017
Virginia Commonwealth University Richmond United States
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About 13rd 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 Casup 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 Casup 2 levels Casup 2i. This study is aimed at identifying mechanisms underlying elevated Ca sup 2i and investigating whether their therapeutic targeting could improve GWI neurological morbidities. Sustained Casup 2 elevations in GWI neurons had their origin in Casup 2 release from intracellular Casup 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 Casup 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 Casup 2 release could be effective therapies for GWI.
- Medicine and Medical Research