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Effects of growth hormone-releasing hormone receptor antagonist MIA-602 in mice with emotional disorders: a potential treatment for PTSD

Abstract

Anxiety and depression have been suggested to increase the risk for post-traumatic stress disorders (PTSD). A link between all these mental illnesses, inflammation and oxidative stress is also well established. Recent behavior studies by our group clearly demonstrate a powerful anxiolytic and antidepressant-like effects of a novel growth hormone releasing hormone (GHRH) antagonist of MIAMI class, MIA-690, probably related to modulatory effects on the inflammatory and oxidative status. In the present work we investigated the potential beneficial effects of MIA-602, another recently developed GHRH antagonist, in mood disorders, as anxiety and depression, and the possible brain pathways involved in its protective activity, in adult mice. MIA-602 exhibited antinflammatory and antioxidant effects in ex vivo and in vivo experimental models, inducing anxiolytic and antidepressant-like behavior in mice subcutaneously treated for 4 weeks. The beneficial effect of MIA-602 on inflammatory and oxidative status and synaptogenesis resulting in anxiolytic and antidepressant-like effects could be related by increases of nuclear factor erythroid 2-related factor 2 (Nrf2) and of brain-derived neurotrophic factor (BDNF) signaling pathways in the hippocampus and prefrontal cortex. These results strongly suggest that GHRH analogs should be tried clinically for the treatment of mood disorders including PTSD.

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Fig. 1: Evaluation of PGE2 and 8-iso-PGF levels and gene expression of COX-2, NF-kB and iNOS in mouse hippocampal and prefrontal cortex specimens following LPS treatment (n = 5 for each group of treatment).
Fig. 2: Analysis of anxiety-related behavior and behavioral despair in mice treated with MIA-690 (5 μg/d) or MIA-602 (5 μg/d) (n = 18 for each group of treatment).
Fig. 3: Haematoxylin-eosin staining and immunohistochemical analysis of Nrf2 and BDNF expression in brain of mice exposed to daily subcutaneous treatment for 4 weeks (n = 9 for each group of treatment).
Fig. 4: Evaluation of PGE2 and 8-iso-PGF levels and gene expression of COX-2, iNOS,  TNF-α and IL-6 in hippocampus and prefrontal cortex regions of mice exposed to daily subcutaneous treatment for 4 weeks (n = 9 for each group of treatment).
Fig. 5: Potential mechanisms of GHRH‐R antagonist in hippocampus and prefrontal cortex.

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Acknowledgements

This work was supported by the University G. d’Annunzio of Chieti FAR 2020 (to Sheila Leone) and FAR 2020 (to Lucia Recinella). Work in Miami was supported by the Medical Research Service of the Department of Veterans Affairs and by the University of Miami Miller School of Medicine (to Andrew V. Schally).

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LR, AVS, LB and SL conceived and coordinated the study and wrote the paper; AC (Annalisa Chiavaroli) performed ex vivo studies, in vivo studies and gene expression analysis and analyzed the data; GO, CF, IG and RG analyzed the data; SV and AC (Alessandro Cama) performed western blot analysis and analyzed the data; GDM and FD performed haematoxylin-eosin staining/light microscopy analysis and immunohistochemistry; RC, WS and AVS contributed new reagents. All authors revised and approved the final version of manuscript.

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Correspondence to Luigi Brunetti or Sheila Leone.

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AVS and RC are listed as co-inventors on patents for GHRH antagonists, assigned to the University of Miami, Miami, FL, and the Veterans Affairs Medical Center, Miami, FL. LR, AC, GO, CF, SV, AC, GDM, FD, IG, RG, WS, LB, and SL declare no potential conflict of interest.

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Recinella, L., Chiavaroli, A., Orlando, G. et al. Effects of growth hormone-releasing hormone receptor antagonist MIA-602 in mice with emotional disorders: a potential treatment for PTSD. Mol Psychiatry (2021). https://doi.org/10.1038/s41380-021-01228-5

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