Peptide ACTH(6-9)-PGP Attenuates the Consequences of Chronic Unpredictable Stress in Male Rats

Current treatments for major depressive disorder (depression) have significant limitations and there is an urgent need to develop new approaches for antidepressant therapy. Stressful events and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis play an important role in the pathogenesis of depression. HPA axis activity is self-regulated by negative feedback loops at several levels, including the negative feedback of the adrenocorticotropic hormone (ACTH). ACTH(6-9) is the amino acid sequence required for activation of ACTH receptors. Here in a chronic unpredictable stress (CUS) model of depression, we investigated the effects of a synthetic PGP-containing analog of this sequence, the peptide ACTH(6-9)-PGP. Adult male Sprague-Dawley rats were daily intraperitoneally injected with saline or ACTH(6-9)-PGP (60 nmol/kg body weight) during the CUS procedure. Administration of ACTH(6-9)-PGP significantly attenuated CUS-induced body weight gain decrease, prevented the decrease in sucrose preference and reduction in hippocampal BDNF levels. The results indicate that in the CUS model, systemically administered ACTH(6-9)-PGP exerts antidepressant-like effects and attenuates the metabolic marker of chronic stress. ACTH(6-9)-PGP can be considered as one of the promising candidates for the development of new pharmacological agents for the treatment and prevention of depression and other stress-related pathologies.