Antidepressant-like and antistress effects of the ACTH(4-10) synthetic analogs Semax and Melanotan II on male rats in a model of chronic unpredictable stress.
This animal study investigated whether two synthetic analogs of the ACTH(4-10) peptide fragment — Semax (ACTH(4-7)-Pro-Gly-Pro) and Melanotan II (MTII), a melanocortin receptor agonist — possess antidepressant-like and antistress properties in a chronic unpredictable stress (CUS) rat model of depression. Male adult Sprague-Dawley rats were subjected to CUS and received daily intraperitoneal injections of either saline or a low dose of Semax or MTII. Outcomes assessed included body weight, hedonic status via the sucrose preference test, adrenal gland weight, hippocampal BDNF levels, and immobility in the forced swim test. The study found that both Semax and MTII reversed or substantially reduced CUS-induced anhedonia, suppressed body weight gain, adrenal hypertrophy, and decreased hippocampal BDNF levels. Neither the CUS procedure nor the peptide treatments produced significant effects on immobility in the forced swim test. The authors concluded that systemically administered ACTH(4-10) analogs may have therapeutic potential for depression and stress-related conditions. Key limitations include the exclusive use of male rats, an animal-only design with no human data, and restriction to a single dose level.
Why this grade: All experiments were conducted exclusively in male Sprague-Dawley rats using a CUS model; no human or clinical data were included.
Current antidepressant therapy shows substantial limitations, and there is an urgent need for the development of new treatment strategies for depression. 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 at several levels including adrenocorticotropic hormone (ACTH)-mediated feedback. Here, we investigated whether noncorticotropic synthetic analogs of the ACTH(4-10) fragment, ACTH(4-7)-Pro-Gly-Pro (Semax) and Ac-Nle4-cyclo[Asp5-His6-D-Phe7-Arg8-Trp9-Lys10]ACTH(4-10)-NH2 (Melanotan II (MTII), a potent agonist of melanocortin receptors), have potential antidepressant activity in a chronic unpredictable stress (CUS) rat model of depression. Stressed and control male adult Sprague-Dawley rats received daily intraperitoneal injections of saline or a low dose (60 nmol/kg of body weight (BW)) of Semax or MTII. Rats were monitored for BW and hedonic status, as measured in the sucrose preference test. We found that chronic treatment with Semax and MTII reversed or substantially attenuated CUS-induced anhedonia, BW gain suppression, adrenal hypertrophy and a decrease in the hippocampal levels of BDNF. In the forced swim test, no effects of the CUS procedure or peptides on the duration of rat immobility were detected. Our findings show that in the CUS paradigm, systemically administered ACTH(4-10) analogs Semax and MTII exert antidepressant-like effects on anhedonia and hippocampal BDNF levels, and attenuate markers of chronic stress load, at least in male rats. The results support the argument that ACTH(4-10) analogs and other noncorticotropic melanocortins may have promising therapeutic potential for the treatment and prevention of depression and other stress-related pathologies.
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