Targeting the sphingosine-1-phosphate system in a mouse model of Gulf War Veterans' Illness

点击翻译按钮获取中文摘要

The pathophysiology of Gulf War Veterans’ Illness (GWVI) remains poorly understood, and treatments are lack- ing. Neurological symptoms including cognitive impairment, attention deficits, depression, and anxiety are a top complaint among GWVI patients. GWVI may be the result of exposure to drugs designed to protect military personnel from a chemical attack and from insects. These include: 1) pyridostigmine bromide (PB), 2) permethrin (PER), and 3) diethyltoluamide (DEET). Although these drugs are considered safe at the doses administered to GW personnel, it has been hypothesized that their combination together with the stress of war may have con- tributed synergistically to generate the GWVI. We have used an animal model of GWVI based on this hypothesis by exposing mice to relevant doses of PB, PER, DEET and stress and found anxiety, brain neuroinflammation, cholinergic, GABAergic and neurotrophic factor abnormalities as latent post-exposure markers of this disease. Some changes were sexually dimorphic indicating that the pathophysiology of GWVI and responses to potential treatments may be different in men and women. Our data provide evidence for a neuroinflammatory process in brains of GWVI-model animals, which is characterized by astrocyte and microglia activation in the hippocampus that correlates with the increased level of anxiety and memory abnormalities seen in the model and can be related to reports indicating aberrant immune function and chronic inflammation in GWVI patients. Therefore, we propose to use our mouse model of GWVI to test the hypothesis that GWVI may be ameliorated by targeting neuroinflammation using fingolimod, a drug that targets the sphingosine-1-phosphate receptor and is used for the treatment of relapsing remitting multiple sclerosis (RRMS). In RRMS it prevents the infiltration of lymphocytes into the CNS, promotes remyelination, and exerts neuroprotective effects on astrocytes. We propose to deter- mine the efficacy of fingolimod on ameliorating the delayed and persistent GWVI-related behavioral, cellular and molecular CNS abnormalities in male and female mice. Based on our preliminary data, the use of a high and low dose of fingolimod will allow us to differentiate the drug’s peripheral versus central action. We will assess the treatment effect on: a) behavior using specific animal paradigms for assessing anxiety, locomotion, memory, and depression; b) neuroinflammation measured with multiplexed proteomic immunoassays of cytokine panels and by immunohistochemical determinations of cells expressing Iba1 and GFAP; c) BDNF levels and signaling by ELISA and immunohistochemical assays; d) indices of cholinergic and GABAergic function by Western blot; e) peripheral measures of inflammation by complete blood count and serum cytokine panel assays. This study incorporates rational pharmacology with state-of-the-art neuropathological and neurochemical techniques to- gether with cognitive and affective behavioral assessment to advance therapeutic strategies for GWVI.