Evaluation of the Therapeutic Potential of Synthetic Growth Hormone-Releasing Hormone Antagonist MIA-690 as a Cognitive Modulator in a Mouse Model of Gulf War Illness

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Abstract
Gulf War illness (GWI) is a multi-symptom disorder affecting veterans of the Persian Gulf operations. Persistent neuroendocrine dysregulation contributes to impairing cognitive capacity and generates anxiety-like behavior. Effective treatments for this illness are challenging due to compromised metabolism, increased oxidative stress and neuroinflammation, perpetuated by chronic stress and hypothalamic–pituitary–adrenal (HPA) axis dysfunction. This neuroinflammation can be alleviated with synthetic antagonistic analogs of the growth hormone-releasing hormone (GHRH) through modulation of the HPA axis. We evaluated the efficacy of the GHRH antagonist analog, MIA-690, against cognitive impairment and anxiety-like behavior in GWI. Mice exposed to an experimental GWI model involving corticosterone (CORT) and diisopropylfluorophosphate (DFP), followed by CORT and lipopolysaccharide (LPS), received a daily subcutaneous dose of 10 μg of MIA-690 for 10 days. Assessments of spatial memory, recognition capacity, somatic health, anxiety and innate survival were carried out, combining the Morris water maze (MWM), novel object recognition (NORT), grip strength (GST), and open field (OFT) tests. Learning efficiency was selectively enhanced in females using the MWM. There were no significant differences in the recall capacity and performance on the OFT, NOR, and GST tasks. Our findings suggest that the MIA-690 dosage is sufficient to improve learning deficits in experimental GWI exposures.
Funding Information
  • U.S. Department of War (W81XWH-17-2-0063)
  • the resources of the Institute for Neuro-Immune Medicine at Nova Southeastern University (W81XWH-17-2-0063)
  • the Research Services at the Veterans Affairs Department (W81XWH-17-2-0063)
  • the Miami VA Healthcare System (W81XWH-17-2-0063)
  • the South Florida Veterans Affairs Foundation for Research and Education Inc. (W81XWH-17-2-0063)

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