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New insights on the mechanisms for Gulf War Illness

The effects of chronic low-dose exposure to organophosphate category of chemicals which include pesticides and nerve gas on neurobehavioral outcomes are well documented in both civilian and military populations.

Coalition Veterans from the First Gulf War were exposed to organophosphate compounds in the Iraqi War theater and approximately 33% of them exhibit a chronic multi-symptom illness that includes mood imbalances and cognitive deficits. Neuronal calcium imbalances are reported in many neurological disorders in Gulf War Illness. However, no studies have investigated: (1) mechanisms for sustained neuronal calcium levels in Gulf War Illness; and (2) pharmacologically target neuronal calcium release pathways for therapeutic amelioration of Gulf War Illness neurobehavioral morbidities.

In a recent study published in Toxicological Sciences, it was shown that hippocampal neurons isolated from a rat model of Gulf War Illness exhibited chronic calcium elevations. The source for this calcium was calcium stores in the endoplasmic reticulum since blockade of ryanodine receptors that guard these stores significantly lowered elevated cytoplasmic calcium levels. In addition, a decrease in ryanodine stabilizing protein Calstabin2 were also noted. Such a possible post-transcriptional remodeling of ryanodine receptor characterized by decreased Calstabin-2 binding could render ryanodine receptors “leaky” and could contribute to the sustained calcium elevations in Gulf War Illness neurons. Finally, it was demonstrated that therapeutic targeting of calcium stores with an FDA approved drug levetiracetam (trade name: keppra) significantly improved symptoms of depression, anxiety, and memory impairment in Gulf War Illness exhibiting rats.

The implications here are that: (1) “leaky” ryanodine receptors could contribute to maintenance of neurological disorders that include calcium disturbances; (2) ER calcium release pathways are druggable targets; and (3) levetiracetam therapy may offer important alternative for therapeutic management of GWI neurological symptoms

Keywords: Gulf War Illness, Keppra, levetiracetam, depression, calcium

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