Journal Article

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

Sha, Wei, O’Callaghan, James, Schally, Andrew Victor, Cai, Renzhi, Klimas, Nancy, Jayakumar, Arumugam Radhakrishnan, Kochen, William, Johnson, Erik, Jászberényi, Miklós, Salgueiro-Tosta, Luis Manuel

2025

Overview

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.

• Publisher: MDPI AG,Multidisciplinary Digital Publishing Institute (MDPI)
• Subject: Analysis / Animals / Anxiety - chemically induced / Anxiety - drug therapy / Anxiety - physiopathology / Chronic illnesses / Cognition - drug effects / Cognition - physiology / Cognitive ability / Cognitive Dysfunction - chemically induced / Cognitive Dysfunction - drug therapy / Cognitive Dysfunction - physiopathology / Corticosterone / Corticosterone - toxicity / Disease Models, Animal / Enzyme inhibitors / Female / Females / Growth Hormone-Releasing Hormone - antagonists & inhibitors / Growth hormones / Health aspects / Hormone antagonists / Insulin-like growth factors / Isoflurophate - toxicity / Lipopolysaccharides - toxicity / Male / Males / Maze Learning - drug effects / Maze Learning - physiology / Memory / Mental disorders / Metabolism / Mice / Mice, Inbred C57BL / Peptides / Peptides - pharmacology / Peptides - therapeutic use / Persian Gulf Syndrome - chemically induced / Persian Gulf Syndrome - drug therapy / Persian Gulf Syndrome - physiopathology / Persian Gulf War / Post traumatic stress disorder / Somatotropin / Somatotropin releasing hormone / Spatial Memory - drug effects / Spatial Memory - physiology / Synthetic Drugs - pharmacology / Synthetic Drugs - therapeutic use