Melanotan 2 Peptide
Melanotan 2 peptide is a synthetic analog of alpha-MSH. MSH 2 is similar to MSH 1 in terms of potency, range of receptors, and effect but possesses greater in vivo stability, blood-brain permeability, and longer half-life.
The melanocortin system consists of melanocyte-stimulating hormone (MSH), ACTH, five G-protein coupled receptors (MR1R-MR5R), and endogenous antagonists (Agouti & Agouti-related proteins). The central melanocortin system consists of alpha-MSH, agouti-related proteins, and MC3R and MC4R. Studies have established the roles of these melanocortins in various complex biological pathways.
Research Implications
1. Melanogenesis
Melanin is the compound that imparts pigment to skin, hair, and eyes. It is produced by skin cells called melanocytes in cell structures called melanosomes. It has a pivotal role in photoprotection and prevents the development of melanoma.
The mechanism involves a Signaling cascade by activation of MC1R.
● MC1R is activated by binding of Melanotan 1 or 2. This activates adenylate cyclase AC leading to cAMP stimulation.
● cAMP causes phosphorylation of cAMP response-element-binding CREB through activation of protein kinase A PKA.
● This phosphorylated CREB, after binding to CRE on the microphthalmia-associated transcription factor MTIF gene, causes the production of MTIF protein.
All this leads to an increased quantity of melanogenic enzymes in melanocytes.
MC1R polymorphism is responsible for the ethnic variability in skin color in response relative to ultraviolet radiation exposure.
2. Sexual and Erectile Dysfunction
Melanocortins have been studied to treat erectile function and female sexual dysfunction. Studies have suggested a significant role of MC3R in peripheral and central receptors. In some studies, the administration of bremelanotide (PT-141) – acting on MC4R – has a profound aphrodisiac effect in female rats, promoting pre-copulatory behavior.
Some preliminary clinical studies have also been shown to enhance sexual drive in women.
Studies have also established the role of melanocortin peptides in sexuality through dopaminergic transmission.
3. Melanotan 2 Peptide Role in Immunity
Inflammation is a natural host protective phenomenon, but unchecked and prolonged inflammation can deteriorate the host immune system. We see this in chronic inflammatory diseases such as inflammatory bowel disease. A study has shown the significant role of receptors MC1R, MC3R, MC4R, and MC5R in regulating host inflammatory response.
The inflammatory cells express melanocortin receptors. Monocytes, macrophages, lymphocytes, and microglia possess MC1R, MC3R, and MC5R. By modulating these receptors, we can downregulate inflammatory pathways even in the presence of proinflammatory mediators such as cytokine interferon-gamma, TNF-alpha, IL-1, IL-6, IL-8, and growth regulated oncogene-alpha.
Alpha-MSH plays its anti-inflammatory role through several ways such as:
● Downregulating IL-8 receptors and non-cytokine mediators, e.g., NO2 and iNOS.
● Reduction in migration of inflammatory cells and cell-adhesion molecule expression.
● Enhancing the activity of anti-inflammatory cytokine IL-10.
● Inhibition of NF_kB proinflammatory pathway.
● Reduction in chemotaxis of neutrophils by inhibiting superoxide radical production.
MC1R plays a significant role in various chronic inflammatory diseases by regulating the immune system to combat proinflammatory mediators. MC1R agonists improve blood-brain barrier efficiency and prevent penetration of inflammatory cells into the CNS. This is of great value in neuroinflammatory diseases such as multiple sclerosis.
Another mechanism by which melanocortin receptors (mainly MC3R and MC4R) express anti-inflammatory effects is a cholinergic anti-inflammatory pathway through the vagus nerve and alpha-7 receptors. This plays its role in ischemic brain and heart conditions and autoimmune regulation.
5. Role in Metabolism
Melanotan 2 peptide body metabolism via MC4R binding and improves cholesterol and glucose metabolism. MC4R activated by alpha-MSH comprises the brain melanocortin system’s efferent limb and maintains body weight homeostasis.
The pharmacological antagonists of MC4R led to weight gain while the agonist led to the contrary in laboratory experiments. It was reported that chronic activation of MC4R leads to persistent high BP despite weight loss, and this BP can be controlled by adrenoceptor blockade.
Melanin is present in excess in the adipose tissue of obese individuals owing to its anti-inflammatory and anti-oxidative properties. The body of these individuals is under oxidative stress.
6. Melanotan 2 Peptide & Role in Brain Inflammation
The melanocortin receptors help resolve inflammation in brain tissue by modulating NF-kappaB-mediated transcription following brain injury. Alpha-MSH has neuroprotective properties. The melanocortins accelerate neuro-physical recovery after spinal cord injury and repair.
MC1R and MC4R modulation have many beneficial effects in treating Alzheimer’s disease, depression, autism spectrum disorder, and schizophrenia.
7. Alcohol and Drug Abuse
A large number of researches have provided evidence for the role of Melanotan 2 peptide in opioid and alcohol addiction. The Melanocortin system promotes tolerance to the antinociceptive property of morphine through MC4R. MC4R and opioid receptors’ distribution show a significant overlap in various brain and spinal cord areas, thus providing the neuroanatomical basis for this effect.
There is laboratory evidence for the effect of Melanotan 2 peptide in enhancing the impact of naltrexone to blunt the intake of ethanol. The melanocortin system also plays its part by regulating mesostriatal and mesolimbic dopamine systems in reward-based addiction phenomenon.
8. Role in Cardiovascular System
Alpha and gamma-MSH raise heart rate and blood pressure through sympathetic system stimulation by activating alpha-MSH by MC4R and gamma-MSH by sodium channels in CNS.
Studies have suggested the role of melanocortin peptides in resolving inflammation and preventing reperfusion injury following ischemia through MC3R in association with the cholinergic anti-inflammatory pathway.
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Dr. Marinov (MD, Ph.D.) is a researcher and chief assistant professor in Preventative Medicine & Public Health. Prior to his professorship, Dr. Marinov practiced preventative, evidence-based medicine with an emphasis on Nutrition and Dietetics. He is widely published in international peer-reviewed scientific journals and specializes in peptide therapy research.