A hypothalamic tripeptide, enzymatic degradation product of oxytocin, that inhibits the release of Melanocyte-Stimulating Hormone.

Marks et al., reported ubiquitous enzyme melanocytc-stimulating hormone release-inhibiting factor (MIF) 1,2. Later William H  et al., in 1973 reported  the hydrolysis of MIF by a  Mn2+-stimulated aminopeptidase of molecular weight 11.7 kDa that cleaves a wide variety of tripeptides and the dipeptide, Leu-Gly 3.

Structural Characteristics
William H  et al., had  used several procedures to isolate the tetrapeptide Tyr- Pro-Leu-Gly-NH2 frombo vine hypothalamus 3. This brain enzyme MIF-I, has physical and enzymic properties distinctly different from rat brain arylamidase.  Two Mn2+ inhibited bovine brain aminopeptidases, which cleave Leu-Gly-Gly in common with the Mn2+ stimulated aminopeptidase, were inactive toward all the peptide hormones tested, including melanocyte-stimulating hormone release inhibiting factor. These brain peptidases capable of acting upon the peptide hormones exhibit a very high degree of substrate specificity 3.

Mode of Action
The pituitary-hypothalamo-pineal complex involving MIF-I and melatonin has been strongly emphasized in the adaptive mechanism of the animal. A series of experiments were conducted to investigate the effects of MIF-I and melatonin on novelty-induced defecation, step-down activity, plasma 11-OHCS levels and whole brain DA and NE concentrations over days of novelty X drug treatment. MIF-I significantly habituated novelty-induced defecation and increased brain norepinephrine (NE) and dopamine (DA) levels over 5 days of drug X novelty treatment. MIF-I did not show any significant effect on the step-down activity of the rats. The results suggest that central catecholamines may be implicated in the behavioral changes observed after MIF-I administration and in the interaction of the pituitary-hypothalamo-pineal complex involving MSH, MIF-I and melatonin 4.

MIF-I a Mn2+ stimulated aminopeptidase was separated from homogenates of bovine cerebrum and was observed to inactivate melanocyte-stimulating hormone release-inhibiting factor (Pro-Leu-Gly-NH2,) in a manner similar to leucine aminopeptidase and arylamidase, by liberating both proline and leucine from the amino end of the tripeptide amide 3.The effect of the factor that inhibits the release of melanocyte stimulating hormone (MSH), i.e., L-prolyl-L-leucyl-glycinamide (MIF), and L-prolyl-N-methyl-D-leucyl-glycinamide, an analog, on brain norepinephrine (NE), dopamine (DA) and serotonin (5-HT) turnover was examined in rats. The analog, like MIF, exerts effects on central catecholamine turnover. The different biochemical profile of the analog compared to MIF may be importance with regard to potential clinical use in the treatment of Parkinson's disease and depression 5. MIF-1, a synthetic tripeptide with MSH-release inhibitory properties, has been reported to improve symptoms of Parkinson's disease, attenuate levodopa-related dyskinesias and diminish the dyskinetic movements of Tardive dyskinesia. More recently, MIF-1 has been reported partially to protect against the nigro-striatal dopamine depleting effects of MPTP in mice, raising the possibility that it may exert protective effects against the development of Parkinson's disease. MIF-1 has been reported to potentiate the melanocyte-lightening effect of melatonin in rats and its effects in patients with Parkinson's disease and Tardive dyskinesia are associated with marked mood elevation. It is, therefore, possible that the effects of MIF-1 in movement disorders are associated with increased melatonin secretion. Thus, hypothalamic MIF may modulate nigro-striatal dopaminergic functions in part via pineal melatonin. Such an interaction represents a novel mechanism by which hypothalamic peptides act to modulate the expression of movement disorders 6. MIF-1 (Tyr-Pro-Leu-Gly- NH2) can exert a number of biological actions in the brain. For example, Tyr-MIF-1 is the first peptide for which a carrier-mediated transport system from brain to blood has been demonstrated 7. It also can act as an anti-opiate in several situations 8 including the immune system and show multiple other extra-endocrine effects such as reversal of “behavioral despair’’ in an animal model of depression and augmented binding of y-aminobutyric acid-stimulated benzodiazepine receptors 9.


1.     Marks N, Walter R (1972). MSH-release-inhibiting factor: inactivation by proteolytic enzymes. Proc Soc Exp Biol Med., 140(2):673-676.

2.     Marks N, Abrash L, Walter R (1973). Degradation of neurohypophyseal hormones by brain extracts and purified brain enzymes. Proc Soc Exp Biol Med., 142(2):  455-460.

3.     William HS, Brecher AS (1973). Inactivation of Melanocyte-stimulating Hormone Releaseinhibiting Factor by a Manganese-stimulated Bovine Brain Aminopeptidase. JBC., 248(16):5780-5784.

4.     Datta PC, King MG (1981). Alpha-MSH, MIF-I and melatonin: effects on novelty-induced defecation, plasma 11-OHCS and central catecholamines in rats. Peptides, 1: 43-54.

5.     Pugsley TA, Lippmann W (1977). Synthetic melanocyte stimulating hormone release-   inhibiting factor (MIF). Part III: effect of L-prolyl-N-methyl-D-leucyl-glycinamide and MIF on biogenic amine turnover. Arzneimittelforschung., 27(12):2293-2296.

6.     Pissios P, Ozcan U, Kokkotou E, Okada T, Liew CW, Liu S, Peters JN, Dahlgren G, Karamchandani J, Kudva YC, Kurpad AJ, Kennedy RT, Maratos-Flier E, Kulkarni RN (2007).  Melanin concentrating hormone is a novel regulator of islet function and growth. Diabetes, 56(2):311-319.

7.     Banks WA, Kastin AJ, Michals, EA (1987).  Tyr-MIF-1 and Met-enkephalin share a saturable blood-brain barrier transport system. Peptides, 8(5):899-903.

8.     Kastin AJ, Stephens E, Ehrensing RH, Fischman AJ (1984). Tyr-MIF-1 acts as an opiate antagonist in the tail-flick test. Pharmacol Biochem Behav., 21(6):937-941.

9.     Miller LG, Kastin AJ, Greenblatt DJ (1987).  Tyr-MIF-1 augments benzodiazepine receptor binding in vivo. Pharmacol Biochem Behav., 28(4):521-524.


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α - MSH, amide
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[D - Phe7] - ACTH, α - MSH (1 - 13), amide
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[Lys0] - γ - 1 - MSH (41 - 58), amide
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Melanin Concentrating Hormone, human, mouse, rat
DFDMLRCMLGRVYRPCWQV (Disulfide bridge: 7-16)
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Melanocyte Associated Antigen gp100
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Melanocyte Associated Antigen gp 100 (17 - 25)
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Melanotropin - Potentiating Factor, MPF
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MSH - Release Inhibiting Factor
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[Nle4, D - Phe7] - α - MSH, amide
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RAB38/NY - MEL - 1 (50 - 58)
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