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

Article

Author: Myasoedov, Nikolai F. ; Levitskaya, Natalia G ; Dolotov, Oleg V. ; Glazova, Natalya Yu ; Kamensky, Andrey A. ; Yatsenko, Ksenia A. ; Yatsenko, Ksenia A ; Kamensky, Andrey A ; Levitskaya, Natalia G. ; Inozemtseva, Ludmila S. ; Inozemtseva, Ludmila S ; Myasoedov, Nikolai F ; Dolotov, Oleg V ; Glazova, Natalya Yu. ; Grivennikov, Igor A ; Grivennikov, Igor A.

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.

01 Nov 2024·Journal of Forensic Sciences

Barbie drug identification: Not a child's play

Article

Author: Charlier, Corinne ; Deville, Marine

AbstractVarious samples—including two vials with a pharmaceutical appearance—were submitted to the laboratory for identification. The aim of this work was to describe the unique characteristics observed during the analysis of the powder contained in the vial. Samples were submitted to HPLC‐DAD, UHPLC‐TOF‐MS, and/or UPLC‐MS–MS analysis. The majority of the samples were easily identified as standard drugs of abuse. The main difficulty lay in identifying the powder in the vials. No match was found in the library through HPLC‐DAD analysis. Fortunately, the vials were labeled as “Melanotan II”, although the UV spectrum was not available. Mass spectrometric analysis of melanotan II was challenging, as it is a small peptide with a molecular weight of 1024 Da, which is significantly heavier than classical drugs that the laboratory usually handles. As a result, mass spectrometer's parameters can be limited to detect masses up to 1000 Da. Additionally, melanotan II is multi‐charged which is also unusual for compounds typically targeted in our daily work. Finally, the reference standard allowed us to confirm the identification with both instruments, and determine the purity of 30%. Melanotan II is not approved on the market due to safety concerns. It is used illegally mainly for tanning, explaining its nickname “Barbie drug”. To conclude, analysis of melanotan II was challenging as it is heavy and doubly charged. Moreover, its UV spectrum was initially not available in the literature. The difficulties faced by forensic scientists in detecting this drug may explain its popularity on the illicit market.

27 May 2024·Endocrinology

Therapeutic Strategies Against Metabolic Imbalance in a Male Mouse Model With 5-HT2CR Loss-of-Function

Article

Author: Xu, Nathan ; Han, Junying ; Jossy, Sanika V ; Wong, HueyXian Kelly ; Wong, HueyZhong ; Liu, Hailan ; Burt, Megan E ; Liu, Qingzhuo ; He, Yang ; Liu, Zhaoxun ; Liu, Yao ; Li, Yongxiang

AbstractThe serotonin 2C receptor (5-HT2CR)-melanocortin pathway plays well-established roles in the regulation of feeding behavior and body weight homeostasis. Dysfunctions in this system, such as loss-of-function mutations in the Htr2c gene, can lead to hyperphagia and obesity. In this study, we aimed to investigate the potential therapeutic strategies for ameliorating hyperphagia, hyperglycemia, and obesity associated with a loss-of-function mutation in the Htr2c gene (Htr2cF327L/Y). We demonstrated that reexpressing functional 5-HT2CR solely in hypothalamic pro-opiomelanocortin (POMC) neurons is sufficient to reduce food intake and body weight in Htr2cF327L/Y mice subjected to a high-fat diet (HFD). In addition, 5-HT2CR expression restores the responsiveness of POMC neurons to lorcaserin, a selective agonist for 5-HT2CR. Similarly, administration of melanotan II, an agonist of the melanocortin receptor 4 (MC4R), effectively suppresses feeding and weight gain in Htr2cF327L/Y mice. Strikingly, promoting wheel-running activity in Htr2cF327L/Y mice results in a decrease in HFD consumption and improved glucose homeostasis. Together, our findings underscore the crucial role of the melanocortin system in alleviating hyperphagia and obesity related to dysfunctions of the 5-HT2CR, and further suggest that MC4R agonists and lifestyle interventions might hold promise in counteracting hyperphagia, hyperglycemia, and obesity in individuals carrying rare variants of the Htr2c gene.

100 Deals associated with Melanotan II

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Indication	Highest Phase	Country/Location	Organization	Date
Erectile Dysfunction	Phase 2	-	Palatin Technologies, Inc.	-
Erectile Dysfunction	Phase 2	US	University of Arizona	-
Erectile Dysfunction	Phase 2	-	The University of Arizona Health Network	-
Male sexual dysfunction	Phase 2	US	University of Arizona	-

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