Project Title

Growth Hormone Releasing (GHRH) Antagonist:Evaluation of Beneficial Effects for Gulf War Illness

Principal Investigator/Project Director

Luis Salguiero

Colleges / Centers

Dr. Kiran C. Patel College of Osteopathic Medicine

Funder

DOD - U.S. Army Medical Research Acquisition Activity

Start Date

9-30-2017

Abstract

Gulf War Illness (GWI) is a persistent multi-symptom illness that has been implicated in as many as one-third of the 700,000 U.S. troops deployed to the Middle East during the 1990-1991 Gulf War (GW). There is no consensus on the particular agents, combined exposures, or environmental elements contributing to the onset and persistence of the symptoms tied to GWI. In addition, gaining insight into the factors resulting in GWI remains difficult due to the limited monitoring of the wartime environment, insufficient clinical documentation, and the clinical similarity of GWI with other post-war health conditions. Despite the obstacles, evidence from strong clinical and basic science studies has grown, connecting the onset and persistence of symptoms present in GWI to specific underlying biomarkers and signal transduction mechanisms. A published preclinical animal (mouse) model for the study of GWI uses high doses of corticosterone (CORT) to induce experimental stress in combination with sub-lethal exposure to the nerve agent, Diisopropylfluorophosphate (DFP) to generate a priming inflammatory reaction. This response is heightened with the chronic use of CORT in combination with lipopolysaccharides (LPS) as systemic mediators of inflammation. The model is reliable and reproduces the abnormal immune cell responses and the persistent pro-inflammatory cytokine profile responsible for dysfunction. Thus, neuro-inflammation is an important therapeutic target to resolve in GWI. Evidence shows that Gonadotropin Hormone Releasing Hormone (GHRH) analogs have the ability to influence neural activity and function. The GHRH receptor (GHRHr) activates molecular messengers that promote the persistent pro-inflammatory cytokine profile. Moreover, antagonistic GHRH analogs block GHRH receptors and thus inhibit the activation of signaling mediators common to the innate immune system (as shown in cancer cell lines). This strongly supports the merit of further studies with GHRH antagonists using the existing model of GWI. The objective of this proposal is to evaluate new therapeutic alternatives to alleviate Gulf War Illness based on the beneficial effects of highly biologically active analogs (antagonists) of GHRH. For the reasons outlined above we hypothesize that administration of the synthetic GHRH antagonist, MIA-690, will block the activation of regulatory factors associated with the signaling of pro-inflammatory cytokines and the resultantdysfunctional neurons and sickness occurring in animalsin the experimental model of GWI (CORT/DFP-CORT/LPS). We also expect a beneficial effect of the analog in the cognitive capacity of mice affected by the toxic effect of the experimental exposure to warfare agents. Specific Aims: To test this hypothesis we propose to pursue the following aims: • Aim 1: Describe the beneficial effects of the synthetic GHRH antagonist (MIA-690) on the cognitive decline of mice exposed to the experimental model of GWI. • Aim 2: Characterize the pro-inflammatory cytokine profile of plasma and brain section homogenates from mice treated with the synthetic GHRH antagonist (MIA-690). • Aim 3. Describe the effect of the synthetic GHRH antagonist, MIA-690, on the co-localization of specific neuro-inflammation markers in tissue samples of mice exposed to the experimental model of GWI. Study Design: The proposal uses the acute/chronic GWI model which combines sub-lethal exposures to the nerve agent DFP (4 mg/kg,i.p.) with the administration of Corticosterone (200 mg/L, in the drinking water) to simulate combat fear together with LPS(2.5 mg/kg, s.c.) post-exposure as a systemic mediator of inflammation. Animals will be randomly allocated in the following groups: Control (No exposure or treatment); GWI exposure (CORT/DFP-CORT/LPS); Therapy group (Exposure + MIA-690); and the Analog control (MIA-690 alone). Short (5 weeks) or long (12 weeks) term experiments will be performed to describe the effect of the therapy with MIA-690 (10μg/day, s.c.) on the persistent GWI-like toxicity. The in vivo study evaluates behavioral performance with the Morris Water Maze. Complementary studies with quantification of circulating cytokines by chemiluminescence, and co-location studies targeting early inflammatory markers (Translocator protein, TSPO) in combination with glia activation markers (IBa1: Ionized calcium-binding adapter molecule 1 and GFAP: Glial fibrillaryacidic protein) using immunohistochemistry of brain tissue from treated animals. Impact: Both, cytokines together with TSPO, IBA1 and GFAP will be useful in identifying early changes preceding known, major CNS inflammatory events in GWI, thus allowing clarification of early therapeutic interventions meant to prevent health decline due to GWI. Insights from this research will extend in vitro and in vivo investigations of GHRH analogs to allow and encourage clinical development of these agents for GWI therapy.

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