Effects of growth hormone-releasing hormone receptor antagonist, MIA-602, in mood disorders: a potential treatment for post-traumatic stress disorders (PTSD)
Progetto 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. On the other hand, anxiety and depressive disorders can also occur, both in the setting of endocrine diseases and as events secondary to the pathogenetic mechanisms of the endocrinopathy. The complexity of the topic and the limited availability of relevant scientific literature make understanding the relationship between the endocrine system and emotional disorders even more complicated. Interestingly, the anxiolytic-antidepressant effect of growth hormone releasing hormone (GHRH) analogs, recently reported by our reserch group, suggests that GHRH itself may be involved in behavioral control. The powerful anxiolytic and antidepressant-like effects of GHRH analogs are probably related to modulatory effects on the inflammatory, oxidative status and neuroplasticity. The aim of this project will be to confirm the potential beneficial effect of MIA-602, a recently developed GHRH antagonist, in mood disorders such as PTSD, in both preclinical and clinical studies. Anxiety and depressive disorders belong to the broad category of internal disorders, with an annual incidence in adults of 19.1% and 7.1%, respectively. They represent the most common psychiatric illnesses and are highly comorbid with each other. In particular, 45.7% of individuals with diagnosis of major depressive disorder show one or more anxiety disorders, while as regards the anxiety disorders, the comorbidity with depression can vary based on the diagnosis [20% to 70% for social anxiety disorder, 50% for panic disorder, 48% for post-traumatic stress disorder (PTSD), 43% for generalized anxiety disorder]. Furthermore, anxiety and depression have been suggested to increase the risk for PTSD; in particular, anxiety and depression have been reported to be secondary to PTSD. In addition, is well known that anxiety and depression, as well as PTSD, are characterized by an increased activity of pro-inflammatory and pro-oxidants markers in central and peripheral tissues, including blood. It is important to emphasize that the simultaneous presence of signiflcant anxiety and depression symptoms may predict worse outcomes, such as suicidal ideas tendency, and causes greater difficulty in treating these patients. Anxiety and depressive disorders can also occur, both in the setting of endocrine diseases and as events secondary to the pathogenetic mechanisms of the endocrinopathy. The complexity of the topic and the limited availability of relevant scientific literature make understanding the relationship between the endocrine system and emotional disorders even more complicated. As regards the growth hormone (GH)-insulin-like growth factor (IGF)-l axis, mood dysfunctions have been reported to be specifically related to GH deficiency. Interestingly, the anxiolytic- antidepressant-like effect of GHRH analogs suggests that GHRH itself may be involved in behavioral control. Central administration of somatostatin, which inhibits the release of GH, was also found to exert anxiolytic and antidepressant effects in rats, while GH deficiency, due to knocking out GHRH gene (GHRHKO) in mice was reported to be associated with a decreased anxiety- and depression- related behavior. Confirming the possible role of GHRH in modulating emotional behavior, we recently reported that MIA-690 and MIA-602, two novel GHRH antagonists of the Miami (MLA) series, synthesized by the group of Prof. Andrew V. Schally of University of Miami (Nobel Prize in Physiology or Medicine 1977 "for their discoveries concerning the peptide hormone production of the brain"), have been able to induce anxiolytic and antidepressant effects after chronic treatment in mice, probably because of their ability to modulate inflammatory-oxidative status and neuroplasticity in mouse hippocampal and prefrontal cortex. On the ot