ACTH 1-13 (Adrenocorticotropic Hormone (1-13))

Analyzing the effects of co-expression of chick (Gallus gallus) melanocortin receptors with either chick MRAP1 or MRAP2 in CHO cells on sensitivity to ACTH(1-24) or ACTH(1-13)NH2: Implications for the avian HPA axis and avian melanocortin circuits in the hypothalamus

In order to better understand the roles that melanocortin receptors (cMCRs) and melanocortin-2 receptor accessory proteins (cMRAP1 and cMRAP2) play in the HPA axis and hypothalamus, adrenal gland and hypothalamus mRNA from 1day-old white leghorn chicks (Gallus gallus), were analyzed by real-time PCR. mRNA was also made for kidney, ovary, and liver. Mrap1 mRNA could be detected in adrenal tissue, but not in any of the other tissues, and mrap2 mRNA was also detected in the adrenal gland. Finally, all five melanocortin receptors mRNAs could be detected in the adrenal gland; mc2r and mc5r mRNAs were the most abundant. To evaluate any potential interactions between MRAP1 and the MCRs that may occur in adrenal cells, individual chick mcr cDNA constructs were transiently expressed in CHO cells either in the presence or absence of a chick mrap1 cDNA, and the transfected cells were stimulated with hACTH(1-24) at concentrations ranging from 10-13M to 10-6M. As expected, MC2R required co-expression with MRAP1 for functional expression; whereas, co-expression of cMC3R with cMRAP1 had no statistically significant effect on sensitivity to hACTH(1-24). However, co-expression of MC4R and MC5R with MRAP1, increased sensitivity for ACTH(1-24) by approximately 35 fold and 365 fold, respectively. However, co-expressing of cMRAP2 with these melanocortin receptors had no effect on sensitivity to hACTH(1-24). Since the real-time PCR analysis detected mrap2 mRNA and mc4r mRNA in the hypothalamus, the interaction between cMC4R and cMRAP2 with respect to sensitivity to ACTH(1-13)NH2 stimulation was also evaluated. However, no effect, either positive or negative, was observed. Finally, the highest levels of mc5r mRNA were detected in liver cells. This observation raises the possibility that in one-day old chicks, activation of the HPA axis may also involve a physiological response from liver cells.

Melanotropins as growth factors

Peptides that regulate the growth of tissues, whether in a positive or negative manner, are termed growth factors. The melanocortins, neurotrophic sequences that correspond to peptide fragments contained within ACTH-(1-13), beneficially affect neural growth during development and regeneration. Analogues of ACTH-(4-9) (Org 2766) and ACTH-(4-10) (BIM 22015) are capable of sustaining neurite outgrowth from cultured dorsal root ganglion and spinal cord cells in the absence of nerve growth factor. The development of sexually dimorphic behavior in both male and female rats is influenced by perinatal administration of ACTH. This change appears to be correlated with changes in the growth and metabolism of developing serotonergic and dopaminergic systems in the hypothalamic nuclei associated with male and female sexual behavior. Similar melanotropic influences are found in the developing neuromuscular system. Neuromuscular development is accelerated by perinatal administration of melanocortins, provoking both nerve and muscle to attain early maturation. However, the responding tissue varies pivotally with age: early in gestation, embryonic muscle is acutely sensitive to peptide exposure; but once innervation has occurred, only the developing nerve reacts to melanocortin treatment. Melanocortins have little if any effect on the normal, adult neuromuscular system. Following peripheral nerve injury or pathology, melanotropins once again become effective growth factors, accelerating and enhancing nerve regeneration and muscle reinnervation. Electrophysiological, morphological, biochemical, and functional tests all indicate that ACTH-(4-10), Org 2766, BIM 22015, and alpha-MSH improve various facets of nerve regeneration, the degree to which the specific parameter is improved being dependent on the peptide fragment, its dosage, and pattern of administration. BIM 22015, while less effective as a neurotrophic factor, has potent myotrophic effects that the other peptides lack. Org 2766 may provide some protective action to the injured CNS as demonstrated by tests of cognitive function following brain lesions, although evaluation of recovery is sometimes enigmatic. Recovery from destruction of the nigrostriatal system is more easily measured through tests of motor function and open field behavior, both of which support a protective role for Org 2766. Compensatory mechanisms, including the presence of increased tyrosine hydroxylase and greater density of dopaminergic fibers, may be involved. Melanocortins are effective growth factors in sciatic nerve regeneration in neonatal rats. Both alpha-MSH and ACTH-(4-10) favor the formation of morphologically normal end plates despite the trauma following nerve crush at postnatal day 2.(ABSTRACT TRUNCATED AT 400 WORDS)

[Pharmacodynamic properties of a combination of met-enkephalin and alpha 1-13 adrenocorticotropic hormone]

ENKORTEN is newly registered drug in Bosnia and Herzegovina. It consists of two peptide components: met-enkephalin and alpha 1-13-corticotropine (alpha-ACTH 1-13), previously called alpha-melanocyte-stimulating hormone-like (alpha-MSH-like) Met-enkephalin and alpha-MSH exhibited cytoprotective effects individually and statistically significant additive effect was registered when both peptides were applied in combination on the model of ethanol induced gastric lesions in rats. Combination has immunomodulatory effects. Method of selective immunomodulation with antigens and peptides in immunological mediated diseases and malignant tumors is directed towards long-term remission without so many adverse effects characteristic for immunosuppressive drugs. Adverse reactions registered for so long with ENKORTEN were mild, reversible and usually developed during and immediately after drug application.

ACTH modulation of nerve development and regeneration

(1) The availability of short amino acid sequences of the naturally occurring ACTH 1-39 molecule has made it possible to separate the corticotropic characteristics of the parent molecule from its neurotrophic effects. Potent neurotrophic fragments are ACTH 4-10, an analog of ACTH 4-9 (Org 2766), and alpha-MSH (ACTH 1-13), peptide fragments that do not evoke corticosteroid secretion, yet clearly affect both the development and regeneration of peripheral nerve. (2) Early postnatal administration of either ACTH 4-10 or Org 2766 accelerates the neuromuscular development of the immature rat, increasing the contractile strength of the EDL muscle and inducing more rapid muscle contractions. Grasping strength and motor activity are increased; these are all changes indicative of more rapid neuromuscular maturation. Prenatal peptide treatment elicits a more complex pattern of response since administration early in gestation (GD 3-12) accelerates neuromuscular development whereas later administration (GD 13-21) decelerates maturation. (3) ACTH peptides have a similar accelerating effect on the morphology of the developing neuromuscular junction. At two weeks of age, nerve arborization is conspicuously increased by postnatal administration of either ACTH 4-10 or Org 2766, as is nerve terminal branching within the endplate itself. However, this is preceded by an initial depression of nerve branching in the 7-day-old rat pup. We conclude that while the developing neuromuscular system is sensitive to ACTH peptides, this susceptibility is age-related. The crucial role of these peptides may be limited to very brief, defined periods during which the peptides may interact with trophic or growth-associated substances, each of which may have its own decisive, circumscribed time frame of influence. (4) Perinatal administration of ACTH peptides affects CNS development. One measurable indication of this is an acceleration of eye opening. Early exposure to ACTH peptides has long-lasting effects on behavior, apparent when these animals are tested as adults. Increased spontaneous motor activity, heightened states of arousal and agitation, and changes in social behavior have been reported. Certain avoidance responses and tests of visual discrimination in male rats are improved by neonatal treatment with alpha-MSH. Overall motor activity is increased and the normal period of hyperactivity is initiated earlier. Male sexual behavior is decreased and sexually dimorphic behaviors in males are eliminated. alpha-MSH may alter the development of its own dopaminergic feedback circuitry while ACTH affects serotonin levels in the preoptic nucleus.(ABSTRACT TRUNCATED AT 400 WORDS)

Non-corticotropic ACTH peptides modulate nerve development and regeneration

Short peptide sequences of ACTH 1-39 (the ACTH 4-9 analog Org 2766, ACTH 4-10 and its analog BIM 22015, and ACTH 1-13 [alpha-MSH]), which do not stimulate the adrenal cortex, have profound effects on the developing and regenerating neuromuscular system, in neonatal and in adult rats. Both development and regeneration are accelerated, as indicated by improved morphological, electrophysiological, behavioral and biochemical parameters. Regeneration in the central nervous system is problematic but the ACTH peptides may provide protection for CNS neurons, enhance denervation sensitivity or permit compensatory processes which facilitate functional recovery. Neuronal cells in culture respond to ACTH peptides by greater neurite outgrowth, and in some cell types, by increased B-50 expression. In all cases, susceptibility to ACTH peptide treatment varies with cell type, age, the specific peptide administered, its dosage and pattern of administration. External stress and the gender of the animal are additional factors that interact with the neurotrophic actions of the melanocortins.