Novel Therapeutic Approaches for the Treatment of Depression and CognitiveDeficits in a Rodent Model of Gulf War Veterans' Illness
Technical Report,29 Sep 2015,28 Sep 2016
Virginia Commonwealth University Richmond United States
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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.
- Medicine and Medical Research