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Melanotan-II Overview
Melanotan-II (MT-II) is a synthetic α-melanocyte-stimulating hormone (α-MSH) analog belonging to the class of melanocortin agonists. MT-II is not solely used for tanning-related purposes; in the field of medical research, it is being explored for potential applications in treating conditions such as erectile dysfunction.
Figure 1 The structure of Melanotan-II.
Melanotan-II Mechanism of Action
MT-II primarily exerts its effects by interacting with melanocortin receptors (MCRs). The melanocortin receptor family includes multiple subtypes such as MC1R, MC2R, MC3R, MC4R, and MC5R. MT-II is a non-selective melanocortin receptor agonist that can bind to and activate multiple MCRs.
In the skin, MT-II binds to MC1R on the surface of melanocytes, activating adenylate cyclase, which increases cyclic AMP (cAMP) levels, thereby activating protein kinase A (PKA). PKA activates the microphthalmia-associated transcription factor (MITF) through phosphorylation. MITF is a key transcription factor in melanin synthesis, It upregulates the expression of genes such as tyrosinase, tyrosinase-related protein-1 (TRP-1), and tyrosinase-related protein-2 (TRP-2), which are enzymes involved in melanin synthesis, ultimately leading to increased skin pigmentation and achieving a tanning effect.
In the nervous system, MT-II also influences certain neuroendocrine systems. It can stimulate the central oxytocin system. Studies have shown that intravenous injection of MT-II significantly induces the expression of Fos in large neurons of the suprachiasmatic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus, a response that can be attenuated by prior intracerebroventricular injection of the melanocortin antagonist SHU-9119. Electrophysiological recordings show that intravenous injection of MT-II increases the firing frequency of oxytocin neurons in the SON but does not trigger dendritic oxytocin release within the SON. Due to previous studies showing that direct application of melanocortin agonists inhibits supraoptic nucleus (SON) oxytocin neurons, the effects of intravenous MT-II may be at least partially mediated indirectly, potentially through activating inputs from the caudal brainstem, where MT-II also increases Fos expression.
Additionally, MT-II has certain mechanisms of action on energy metabolism and thermoregulation. In mouse experiments, intraperitoneal injection of MT-II induces significant and transient hypometabolism/hypothermia. This hypothermic phenomenon disappears in Kit<sup>W-sh/W-sh</sup> mice lacking mast cells, indicating that mast cells are essential for MT-II-induced hypothermia. MT-II can stimulate mast cells through both MRGPRB2-dependent and -independent mechanisms to release histamine, which produces hypothermia via histamine H<sub>1</sub> receptors, as the selective antagonist pyrilamine or ablation of H<sub>1</sub> receptors significantly attenuates this hypothermic effect.
Effects of Melanotan-II
Role in Skin Pigmentation
One of the most notable effects of MT-II is inducing increased skin pigmentation, i.e., achieving a tanning effect. Feedback from users shows that nearly all participants who attempted tanning with MT-II exhibited skin darkening. This indicates that MT-II has a certain degree of autonomy in inducing skin pigmentation, not fully dependent on ultraviolet radiation to initiate the melanogenesis machinery.In some studies, observations from animal models and in vitro cell experiments have shown that MT-II directly stimulates melanocytes, upregulating the expression of enzymes related to melanin synthesis, thereby promoting melanin production and darkening skin color. This effect offers a potential alternative for those seeking a bronze complexion while concerned about UV-induced skin damage.
Effects on Neurobehavior
In terms of neurobehavioral effects, MT-II exhibits multifaceted actions. In studies using zebrafish as a model, it was found that even short-term high-fat (HF) diets (lasting only approximately 1% of a zebrafish's lifespan, or three weeks) can lead to impaired recognition memory, elevated anxiety levels, and reduced exploratory tendencies in zebrafish. MT-II can reverse these abnormalities induced by a high-fat diet, restoring the zebrafish's recognition memory, anxiety, and exploratory behavior to levels similar to those of the normal diet group.
In autism-related research, using a maternal immune activation (MIA) mouse model to simulate autism, male MIA mice exhibit autism-like characteristics, such as impaired social behavior indicators, reduced vocal communication, and increased repetitive behavior. After seven days of MT-II treatment, social behavior indicators in male MIA mice improved, while social behavior indicators in C57 mice with a normal background showed no significant changes after MT-II treatment. This suggests that MT-II has potential therapeutic effects in improving autism-like behavioral deficits, providing new directions for autism treatment research.
Figure 2 Adult male MIA mice demonstrated an increase in oxytocin receptor expression in the anterior cingulate cortex.
Effects on energy metabolism and thermoregulation
MT-II also has significant effects on energy metabolism and thermoregulation. In mouse experiments, mice with pituitary adenylate cyclase-activating peptide (PACAP) deficiency were administered MT-II via peripheral injection daily for three consecutive weeks during cold adaptation. The results showed that MT-II could partially restore the impaired thermogenesis capacity of the mice. By measuring norepinephrine-induced metabolic rate, it was found that the thermogenic capacity of mice treated with MT-II was partially restored. Additionally, MT-II treatment corrected defects in lipid utilization under adrenergic stimulation, suggesting that MT-II may influence thermogenesis in brown adipose tissue by regulating sympathetic nervous activity, thereby playing a role in maintaining energy metabolic balance.
MT-II can induce hypothermia in mice by activating mast cells and releasing histamine. This process reveals the role of MT-II in temperature regulation mechanisms.
Potential effects on the reproductive system
MT-II also has potential effects on the reproductive system. It has been studied for the treatment of erectile dysfunction, which is related to its stimulatory effects on the reproductive system.
Applications of Melanotan-II
Applications in the beauty industry
In the beauty industry, MT-II is primarily used as a tanning agent. With the growing desire for a healthy, bronze complexion and concerns about the potential skin damage caused by traditional sun exposure (such as sunburn and increased risk of skin cancer), MT-II has garnered attention as a product claimed to achieve tanning without relying on sun exposure. However, since it has not been approved by authoritative agencies such as the FDA and lacks large-scale safety and efficacy studies, its application in the beauty market remains in a gray area. In some countries and regions, illegal online sales of MT-II for cosmetic purposes occasionally occur.
Applications in Medical Research
In the field of medical research, the application of MT-II primarily focuses on exploring its potential therapeutic applications for various diseases. In the context of neurobehavioral disorders, MT-II has demonstrated efficacy in improving neurobehavioral abnormalities induced by a high-fat diet in zebrafish and autism-like behavioral deficits in male MIA mice, offering new research directions for the treatment of related neurological disorders.
In studies of energy metabolism and thermoregulation-related diseases, MT-II's salvage effect on thermogenesis in PACAP-deficient mice suggests its potential value in the treatment of metabolic diseases such as obesity. Further investigation into the regulatory mechanisms of MT-II on energy metabolism-related signaling pathways may lead to the development of novel therapeutic agents for metabolic disorders. Studies on the mechanisms underlying MT-II-induced hypothermia could also deepen our understanding of the physiological processes of thermoregulation, providing a theoretical foundation for the treatment of diseases associated with thermoregulatory abnormalities.
In the field of reproductive system diseases, research on the use of MT-II for the treatment of erectile dysfunction, although still in its preliminary stages, offers a new option for the treatment of male sexual dysfunction.
Conclusion
Melanotan-II, as a synthetic α-melanocyte-stimulating hormone analog, possesses multiple biological functions involving skin pigmentation, neurobehavioral processes, energy metabolism, thermoregulation, and the reproductive system. In terms of skin pigmentation, it can induce skin darkening, offering a potential pathway for tanning. In the field of medical research, MT-II demonstrates broad application prospects. Research into neurobehavioral disorders, energy metabolism and thermoregulation-related diseases, and reproductive system disorders provides new directions for the treatment of these conditions.
Sources
[1] McKenzie N, Gonzalez N, Huang C, et al. Poster presentationsPS09 User experiences of Melanotan II injection for tanning[J]. British Journal of Dermatology, 2024,191(Supplement_1):i179-i180.DOI:10.1093/bjd/ljae090.380.
[2] Wekwejt P, Wojda U, Kiryk A. Melanotan-II reverses memory impairment induced by a short-term HF diet[J]. Biomedicine & Pharmacotherapy, 2023,165:115129.DOI:10.1016/j.biopha.2023.115129.
[3] Tomassi S, Dimmito M P, Cai M, et al. CLIPSing Melanotan-II to Discover Multiple Functionally Selective hMCR Agonists[J]. Journal of Medicinal Chemistry, 2022,65(5):4007-4017.DOI:10.1021/acs.jmedchem.1c01848.
[4] Gilhooley E, Daly S, McKenna D. Melanotan II User Experience: A Qualitative Study of Online Discussion Forums[J]. Dermatology, 2021,237(6):995-999.DOI:10.1159/000514492.
[5] Peters B, Hadimeri H, Wahlberg R, et al. Melanotan II: a possible cause of renal infarction: review of the literature and case report[J]. Cen Case Reports, 2020,9(2):159-161.DOI:10.1007/s13730-020-00447-z.
[6] Paiva L, Sabatier N, Leng G, et al. Effect of Melanotan-II on Brain Fos Immunoreactivity and Oxytocin Neuronal Activity and Secretion in Rats[J]. Journal of Neuroendocrinology, 2017,29(2).DOI:10.1111/jne.12454.
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