α-MSH Concentrations Research Articles

A role for β-melanocyte-stimulating hormone in human body-weight regulation

Pro-opiomelanocortin (POMC) expressing neurons mediate the regulation of orexigenic drive by peripheral hormones such as leptin, cholecystokinin, ghrelin, and insulin. Most research effort has focused on alpha-melanocyte-stimulating hormone (alpha-MSH) as the predominant POMC-derived neuropeptide in the central regulation of human energy balance and body weight. Here we report a missense mutation within the coding region of the POMC-derived peptide beta-MSH (Y5C-beta-MSH) and its association with early-onset human obesity. In vitro and in vivo data as well as postmortem human brain studies indicate that the POMC-derived neuropeptide beta-MSH plays a critical role in the hypothalamic control of body weight in humans.

Adenohypophyseal function in bitches treated with medroxyprogesterone acetate

The aim of this study was to investigate the effects of treatment with medroxyprogesterone acetate (MPA) on canine adenohypophyseal function. Five Beagle bitches were treated with MPA (10 mg/kg, every 4 weeks) and their adenohypophyseal function was assessed in a combined adenohypophyseal function test. Four hypophysiotropic hormones (CRH, GHRH, GnRH, and TRH) were administered before and 2, 5, 8, and 11 months after the start of MPA treatment, and blood samples for determination of the plasma concentrations of ACTH, cortisol, GH, IGF-1, LH, FSH, prolactin, α-MSH, and TSH were collected at −15, 0, 5, 10, 20, 30, and 45 min after suprapituitary stimulation. MPA successfully prevented the occurrence of estrus, ovulation, and a subsequent luteal phase. MPA treatment did not affect basal and GnRH-induced plasma LH concentrations. The basal plasma FSH concentration was significantly higher at 2 months after the start of MPA treatment than before or at 5, 8, and 11 months after the start of treatment. The maximal FSH increment and the AUC for FSH after suprapituitary stimulation were significantly higher before treatment than at 5, 8, and 11 months of MPA treatment. Differences in mean basal plasma GH concentrations before and during treatment were not significant, but MPA treatment resulted in significantly elevated basal plasma IGF-1 concentrations at 8 and 11 months. MPA treatment did not affect basal and stimulated plasma ACTH concentrations, with the exception of a decreased AUC for ACTH at 11 months. In contrast, the maximal cortisol increment and the AUC for cortisol after suprapituitary stimulation were significantly lower during MPA treatment than prior to treatment. MPA treatment did not affect basal plasma concentrations of prolactin, TSH, and α-MSH, with the exception of slightly increased basal plasma TSH concentrations at 8 months of treatment. MPA treatment did not affect TRH-induced plasma concentrations of prolactin and TSH. In conclusion, the effects of chronic MPA treatment on adenohypophyseal function included increased FSH secretion, unaffected LH secretion, activation of the mammary GH-induced IGF-I secretion, slightly activated TSH secretion, suppression of the hypothalamic–pituitary–adrenocortical axis, and unaffected secretion of prolactin and α-MSH.

Melanotroph Pituitary Adenoma in a Cat with Diabetes Mellitus

A 13-year-old male, castrated, crossbred cat was referred for insulin-resistant diabetes mellitus. The cat had a ravenous appetite and a dull coat. Basal urinary corticoid/creatinine ratios were normal. In the low-dose dexamethasone suppression test there was no suppression of the (nonelevated) plasma cortisol concentration, whereas the (nonelevated) plasma adrenocorticotropic hormone (ACTH) concentration declined to low values. Basal plasma alpha-melanocyte-stimulating hormone (alpha-MSH) concentrations were highly elevated (> 1,500 ng/liter). Computed tomography revealed a pituitary tumor originating from the pars intermedia (PI). After microsurgical transsphenoidal hypophysectomy, the clinical signs resolved and the cat no longer required insulin administration. Microscopic examination of the surgical specimen revealed a pituitary adenoma originating from the PI with infiltration into the neural lobe. The adenoma immunostained intensely positive for alpha-MSH and only weakly for ACTH. It is concluded that the ACTH-independent cortisol production was probably due to the (weak) glucocorticorticotropic effects of the extremely high plasma concentration of alpha-MSH and related peptides.

Effects of season and sample handling on measurement of plasma α-melanocyte-stimulating hormone concentrations in horses and ponies

To investigate effects of sample handling, storage, and collection time and season on plasma alpha-melanocyte-stimulating hormone (alpha-MSH) concentration in healthy equids. 11 healthy Standardbreds and 13 healthy semiferal ponies. Plasma alpha-MSH concentration was measured by use of radioimmunoassay. Effects of delayed processing were accessed by comparing alpha-MSH concentrations in plasma immediately separated with that of plasma obtained from blood samples that were stored at 4 degrees C for 8 or 48 hours before plasma was separated. Effects of suboptimal handling were accessed by comparing alpha-MSH concentrations in plasma immediately stored at -80 degrees C with plasma that was stored at 25 degrees C for 24 hours, 4 degrees C for 48 hours or 7 days, and -20 degrees C for 30 days prior to freezing at -80 degrees C. Plasma alpha-MSH concentrations were compared among blood samples collected at 8:00 AM, 12 noon, and 4:00 PM. Plasma alpha-MSH concentrations were compared among blood samples collected in January, March, April, June, September, and November from horses and in September and May from ponies. Storage of blood samples at 4 degrees C for 48 hours before plasma was separated and storage of plasma samples at 4 degrees C for 7 days prior to freezing at -80 degrees C resulted in significant decreases in plasma alpha-MSH concentrations. A significantly greater plasma alpha-MSH concentration was found in September in ponies (11-fold) and horses (2-fold), compared with plasma alpha-MSH concentrations in spring. Handling and storage conditions minimally affected plasma alpha-MSH concentrations. Seasonal variation in plasma alpha-MSH concentrations must be considered when evaluating pituitary pars intermedia dysfunction in equids.

Correlation between plasma α-melanocyte-stimulating hormone concentration and body mass index in healthy horses

To evaluate the correlation between plasma alpha-melanocyte-stimulating hormone (alpha-MSH) concentration and body mass index (BMI) in healthy horses. 82 healthy horses. Plasma alpha-MSH concentration was determined by radioimmunoassay. At the time blood samples were collected, body condition scores (BCS) were determined and measurements of girth circumference, body length, and height were obtained. Weight was estimated by use of the following formula: estimated weight (kg) = [girth (cm)2 x length (cm)]/11,877. Body mass index was calculated as estimated weight (kg)/height (m)2. A correlation was found between BMI and BCS (rs = 0.60 [95% confidence interval (CI), 0.44 to 0.731). A weak correlation was found between plasma alpha-MSH concentration and BMI (rs = 0.25 [95% CI, 0.03 to 0.45]) and BCS (rs = 0.26 [95% CI, 0.04 to 0.46]). A correlation was found between plasma alpha-MSH concentration and BMI in horses > or = 10 years old (rs = 0.49 [95% CI, 0.20 to 0.69]) but not in horses < 10 years old (rs = -0.04). Horses in the upper quartile of BMI had significantly greater plasma alpha-MSH concentration (median, 9.1 pmol/L; range, 2.0 to 95.3 pmol/L) than horses in the lowest quartile of BMI (median, 70 pmol/L; range, 3.6 to 15.7 pmol/L). A correlation exists between plasma alpha-MSH concentration and BMI in horses. Further study is required to determine whether melanocortin receptor defects underlie this correlation or, alternately, whether plasma alpha-MSH concentration is simply a correlate of adiposity.

The role of cyclooxygenase inhibition in the effect of α-melanocyte-stimulating hormone on reactive oxygen species production by rat peritoneal neutrophils

The effect of α-MSH on reactive oxygen species (ROS) production by rat peritoneal neutrophils and the effect of cyclooxygenase (COX) inhibition were investigated using the chemiluminescence (CL) technique. Cells were obtained by peritoneal lavage 4 h after administration of oyster glycogen to rats and were stimulated with lipopolysaccharide (LPS) from Salmonella enderitidis and phorbol 12-myristate 13-acetate (PMA). The increasing concentrations of α-MSH (10 –12–10 –6 M) were added to stimulated cells alone or along with the COX inhibitors indomethacin, ketorolac or nimesulide (10 −8–10 −5 M). Luminol and lucigenin CL levels were significantly increased in cells stimulated with LPS and PMA compared to unstimulated ones. α-MSH significantly reduced lucigenin CL values and this effect was completely reversed in the presence of indomethacin (10 −8 and 10 −7 M). In conclusion, α-MSH inhibits the production of superoxide radicals by activated rat peritoneal neutrophils and COX contributes to this effect.

Refractory hypothalamic α-MSH satiety and AGRP feeding systems in rats bearing MCA sarcomas

In pre-anorectic tumor-bearing (TB: methylcholanthrene-induced sarcoma) rats, injection of α-melanocyte stimulating hormone (α-MSH) into the perifornical hypothalamus (PFH) had no significant effect on food intake at a dose (5 μg) that reduced feeding in non-TB control rats. Following the development of anorexia, injection of α-MSH MC3/MC4 receptor antagonists, SHU9119 (1 μg) or 4 μg agouti-related protein (AGRP), stimulated feeding in non-TB rats, while having no significant effect in TB rats. Concentrations of α-MSH were not altered significantly in ventromedial, dorsomedial or lateral hypothalamic areas of TB rats, and proopiomelanocortin (POMC) messenger RNA was not changed in TB rats in these hypothalamic areas. Determination of cytokines by ELISA in non-operated TB and non-TB rats revealed elevated IL-2 in plasma and hypothalamus as well as increased TNF-α in the hypothalamus of anorectic TB rats. IL-1B was not detectable in plasma and was not altered significantly in hypothalamus of TB rats. These results suggest that the POMC α-MSH satiety system is refractory in TB rats, even prior to the onset of anorexia. This change in MC3/MC4 receptor response does not appear to be secondary to alterations of endogenous α-MSH in TB rats. Cytokine involvement in the altered response to MC3/MC4 receptor stimulation and blockade is a possibility, since TNF-α and IL-2 were increased in hypothalamus of anorectic TB rats. Therefore, these results suggest major alterations in POMC neuropeptide systems in TB rats as anorexia progresses. Although these changes do not appear to have occurred due to grossly-altered concentrations of α-MSH, elevated cytokine activity in the hypothalamus may be an important factor. Due to the complex multi-factorial nature of feeding control, additional factors are likely to be involved in cancer anorexia.

β-MSH: a functional ligand that regulated energy homeostasis via hypothalamic MC4-R?

α-Melanocyte stimulating hormone (MSH) has generally been assumed to be the endogenous ligand acting at the melanocortin-4 receptor (MC4-R), activation of which in the hypothalamus leads to reduced feeding. However, β-MSH is also capable of activating MC4-R and inhibiting feeding. Here, we investigated the possibility that β-MSH acts as an endogenous MC4-R agonist and that this melanocortin peptide plays a role in the regulation of feeding and energy balance. We found that β-MSH had significantly higher affinities than α-MSH at both human MC4-R transfected into CHO cells ( K i: β-MSH, 11.4±0.4 nmol/l versus α-MSH, 324±16 nmol/l, P<0.001) and MC4-R in rat hypothalamic homogenates ( K i: β-MSH, 5.0±0.4 nmol/l versus α-MSH, 22.5±2.3 nmol/l, P<0.001). Incubation of brain slices with 5 μM β-MSH significantly increased [ 35 S ]GTPγS binding by 140–160% ( P<0.001), indicating activation of G-protein-coupled receptors (GPCRs), in the hypothalamic ventromedial (VMH), dorsomedial (DMH), arcuate (ARC) and paraventricular (PVN) nuclei. These sites match the distribution of β-MSH immunoreactive fibres and also the distribution of MC4-R binding sites which we and others previously reported. Food-restriction significantly increased β-MSH levels in the VMH, DMH and ARC (all P<0.05) above freely-fed controls, whilst α-MSH concentrations were unchanged. We propose that increased β-MSH concentrations reflect blockade of the peptide’s release in these sites, consistent with the increased hunger and the known up-regulation of MC4-R in the same nuclei. Thus, we conclude that (1) β-MSH has higher affinity at MC4-R than α-MSH; (2) β-MSH activates GPCR in these sites, which are rich in MC4-R; and (3) β-MSH is present in hypothalamic nuclei that regulate feeding and its concentrations alter with nutritional state. We suggest that β-MSH rather than α-MSH is the key ligand at the MC4-R populations that regulate feeding, and that inhibition of tonic release of β-MSH is one mechanism contributing to hunger in under-feeding.

Temperature-Induced Changes in Thyrotropin-Releasing Hormone Sensitivity in Carp Melanotropes

This study investigates whether thyrotropin-releasing hormone (TRH), α-melanocyte-stimulating hormone (α-MSH) and N-acetyl β-endorphin (NAc β-END), or the thyroid hormones thyroxine (T4) and 3,5,3′-triiodothyronine (T3) are involved in the physiological response to temperature changes in the poikilotherm common carp (Cyprinus carpio). Carps were either subjected to a rapid cold exposure or acclimated over time to three different temperatures. Acute cold exposure did not influence blood plasma α-MSH concentrations. Acclimation to 15, 22 or 29°C led to a temperature-dependent increase of both α-MSH and NAc β-END plasma concentrations. Moreover, the in vitro sensitivity to TRH of melanotrope cells (that synthesise these peptides) also correlated positively with ambient temperature. Increased TRH activation stimulated processing of the precursor of α-MSH and NAc β-END, resulting in increased release of both peptides and storage of a surplus of NAc β-END within melanotropes. Plasma T4 levels were highest in carps acclimated to the intermediate temperature tested, and correlated strongly with hypothalamic TRH content. Plasma T3 levels were unaffected by ambient water temperature. We conclude that ambient water temperature influences the sensitivity of melanotrope cells to TRH in carps. This effect, however, is not due to acute temperature change, but evolves during the acclimation process of carps to a new temperature.

I plasma concentrations of adrenocorticotrophic hormone and alpha-melanocyte-stimulating hormone in ferrets (Mustela putorius furo) with hyperadrenocorticism.

To determine plasma concentrations of adrenocorticotrophic hormone (ACTH) and alpha-melanocyte stimulating-hormone (alpha-MSH) in healthy ferrets and ferrets with hyperadrenocorticism. 16 healthy, neutered, privately owned ferrets, 28 healthy laboratory ferrets (21 sexually intact and 7 neutered), and 28 ferrets with hyperadrenocorticism. Healthy ferrets were used for determination of reference plasma concentrations of ACTH and a-MSH. Diagnosis of hyperadrenocorticism was made on the basis of history, clinical signs, urinary corticoid-to-creatinine ratios, ultrasonography of the adrenal glands, and macroscopic or microscopic evaluation of the adrenal glands. Blood samples were collected during isoflurane anesthesia. Plasma concentrations of ACTH and alpha-MSH were measured by radioimmunoassay. Plasma concentrations of ACTH in 23 healthy neutered ferrets during the breeding season ranged from 4 to 145 ng/L (median, 50 ng/L). Plasma concentrations of alpha-MSH in 44 healthy neutered or sexually intact ferrets during the breeding season ranged from < 5 to 617 ng/L (median, 37 ng/L). Reference values (the central 95% of the values) for ACTH and alpha-MSH were 13 to 100 ng/L and 8 to 180 ng/L, respectively. Plasma concentrations of ACTH and alpha-MSH in ferrets with hyperadrenocorticism ranged from 1 to 265 ng/L (median, 45 ng/L) and 10 to 148 ng/L (median, 46 ng/L), respectively. These values were not significantly different from those of healthy ferrets. Plasma ACTH concentrations of sexually intact female ferrets in estrus were significantly higher than those of neutered females. Ferrets with hyperadrenocorticism did not have detectable abnormalities in plasma concentrations of ACTH or alpha-MSH. The findings suggest that hyperadrenocorticism in ferrets is an ACTH and alpha-MSH-independent condition.

Diplodus sargus interrenal–pituitary response: chemical communication in stressed fish

In the present study the response of white sea-bream ( Diplodus sargus), used as experimental model, to different stocking densities was tested to assess whether the induced stress conditions were able to activate a chemical communication. Once a good recovery was evident, six days after capture and transportation, experiments started to evaluate eventual changes in cortisol plasma levels as well as in both plasma and pituitary α-melanocyte stimulating hormone (α-MSH) levels. These studies demonstrated that a low stocking density (2.5 kg/1000 L) is not deleterious for this species while a higher one (10 kg/1000 L) induces the activation of the hypothalamus–pituitary–interrenal axis (HPI). Thus, in these fish were evident both a significant increase of cortisol plasma levels and a significant decrease of α-MSH pituitary levels, while no significant changes were detected in α-MSH plasma concentrations. The most relevant result reported in this study, for the first time in marine species, is the presence of a chemical communication among stressed fish. It also should be noted that the data obtained from cortisol and α-MSH detections strongly indicate a gender specificity of this chemical signal.

Plasma concentrations of ACTH precursors correlate with pituitary size and resistance to dexamethasone in dogs with pituitary-dependent hyperadrenocorticism

This study was performed to determine whether in dogs with pituitary-dependent hyperadrenocorticism (PDH) excessive release of adrenocorticotrophic hormone (ACTH) is accompanied by secretion of ACTH precursor molecules. In addition, we investigated whether the plasma ACTH precursor concentrations were correlated with the size of the pituitary gland and with the degree of resistance to negative glucocorticoid feedback. In 72 dogs with PDH, the plasma ACTH precursor concentration was determined by calculating the difference between the results of a radioimmunoassay (RIA) in which besides ACTH, ACTH precursors were also measured and a highly specific immunoradiometric assay (IRMA) using a polyclonal antibody against ACTH. The degree of resistance to glucocorticoid feedback was established by determining the effect of dexamethasone administration (0.1 mg/kg) on the urinary corticoid/creatinine ratio. The pituitary height/brain area (P/B) ratio, determined by computed tomography, was used as a measure for the size of the pituitary gland. The plasma ACTH precursors concentration ranged from 18 to 2233 ng/L (median 93 ng/L). In 38 dogs, the pituitary was enlarged and plasma ACTH precursors concentrations in these dogs (median 130 ng/L, range 24–2233 ng/L) were significantly ( P<0.05) higher than those in the dogs without pituitary enlargement (median 72 ng/L, range 18–481 ng/L). In concordance, P/B ratios correlated significantly with plasma ACTH precursor concentrations ( r=0.35, P<0.01). In addition, the P/B ratios were significantly correlated with the degree of dexamethasone resistance ( r=0.42, P<0.001). Plasma ACTH precursor concentrations in the dexamethasone-resistant dogs (median 210 ng/L, range 24–628 ng/L) were significantly higher ( P<0.01) than those in the dexamethasone-sensitive dogs (median 72 ng/L, range 18–2233 ng/L). Similarly, the degree of dexamethasone resistance was also significantly correlated with the plasma ACTH precursor concentrations ( r=0.33, P<0.01). Dogs with an elevated plasma α-MSH concentration ( n=14) had significantly ( P<0.001) higher plasma ACTH precursor concentrations (median 271 ng/L, range 86–2233 ng/L) than dogs with non-elevated α-MSH (median 73 ng/L, range 18–481 ng/L). In addition, the plasma concentrations of α-MSH correlated significantly with both plasma ACTH precursor concentrations ( r=0.53, P<0.001) and P/B ratios ( r=0.26, P<0.05). In conclusion, in all dogs with PDH the ACTH concentrations determined by the RIA were higher than the concentrations measured by IRMA indicating the presence of circulating ACTH precursors. High plasma ACTH precursor concentrations were especially found in dexamethasone-resistant dogs with large corticotroph adenomas, some of them probably of PI origin. In the association of large corticotroph adenoma, dexamethasone resistance and high plasma concentrations of ACTH precursors, the decreased sensitivity of the corticotroph cells to glucocorticoid feedback may play a pivotal role.

Melanocyte-Stimulating Hormone Plasma Levels and Environmental Illumination in the Cuttlefish, Sepia officinalis: A Role for the Neurosecretory System of the Vena Cava in Cephalopods

A melanotropin-like peptide (α-melanocyte-stimulating hormone or α-MSH) is suggested to be released into the circulatory system of cephalopods via the neurosecretory system of the vena cava or NSV, where neurosecretory vesicles contained within the axons of the NSV-neuropil on the inner surface of the vena cava lie in close contact with the venous circulation. Radioimmunoassay of blood plasma samples taken from the cephalic vein of anaesthetised cuttlefish, Sepia officinalis showed that immunoreactive α-MSH (ir α-MSH) was detectable within the cuttlefish circulatory system. The validity of the assay for determination of cuttlefish ir α-MSH was determined by parallelism of the α-MSH standard curve against serially diluted cuttlefish plasma samples. Plasma samples taken during a natural day–night–day illumination cycle showed a significant elevation in ir α-MSH concentration to 1.44 ± 0.26 ng ml−1 during the middle of the dark phase compared to concentrations of 0.48 ± 0.13 and 0.35 ± 0.10 ng ml−1 in the middle of the light phases of the illumination cycle. So far, indirect evidence suggests Sepia officinalis may modulate chromatophore activity, body patterning, and behaviour via neuroendocrine release and circulating titres of this proopiomelanocortin-derived peptide.

MOLECULAR AND PHARMACOLOGICAL CHARACTERISATION OF THE MSH-R ALLELES IN SWISS CATTLE BREEDS

ABSTRACTThe coat colour in mammals is determined by the relative amounts of eumelanin (black/brown) and phaeomelanin (red/yellow), produced in melanocytes, which are controlled by melanocyte stimulating hormone receptor (MSH-R). Melanocyte stimulating hormone receptor is activated by α-melanocyte-stimulating hormone (α-MSH). Stimulated MSH-R activates adenylyl cyclase (AC), thereby increasing the amount of cyclic AMP in the cell, which activates the enzyme tyrosinase resulting in eumelanin synthesis. In this study the complete coding sequences of five alleles of the MSH-R gene found in Holstein, Red Holstein, Simmental, and Brown Swiss cattle were cloned into a mammalian expression vector and transfected into human embryonic kidney (HEK) 293 cells. The expressed receptors were analyzed for their ability to increase intracellular cAMP in response to stimulation by α-MSH. The recessive red allele (e) found in Red Holstein and Simmental and the dominant black allele (ED) found in Holstein were unresponsive to a wide range of α-MSH concentrations. Two alleles from Brown Swiss (Ed1, Ed2) and one allele found in the Simmental breed (ef) responded to stimulation by α-MSH in a dose-dependent manner. When compared to Ed1 and Ed2, the cells transfected with the ef MSH-R allele, however, reached the corresponding intracellular cAMP concentrations at a 10-fold higher concentration of α-MSH. In conjunction with the mode of inheritance of coat colour, the results indicate that the e MSH-R allele is a non-functional receptor, ED is constitutively activated receptor, and Ed1 and Ed2 are hormonally activated receptors. The delay in ef MSH-R response may explain the similarity between the e and ef phenotypes.

Hypothalamic control of photoperiod-induced cycles in food intake, body weight, and metabolic hormones in rams.

This study used a hypothalamo-pituitary disconnected (HPD) sheep model to investigate the central regulation of long-term cycles in voluntary food intake (VFI) and body weight (BW). VFI, BW, and circulating concentrations of metabolic hormones [alpha-melanocyte-stimulating hormone (alpha-MSH), insulin-like growth factor-1 (IGF-1), insulin, and leptin] were measured in HPD and control Soay rams exposed to alternating 16 weekly periods of long and short days for 80 wk. In the controls, the physiology was cyclical with a 32-wk periodicity corresponding to the lighting regimen. VFI and BW increased under long days to a maximum early into short days, and there were associated increases in blood concentrations of alpha-MSH, insulin, and leptin. In the HPD rams, there were no significant photoperiod-induced changes in any of the parameters. VFI increased after surgery for 8 wk and then gradually declined, although BW increased progressively and the HPD rams became obese. Concentrations of alpha-MSH, insulin, and leptin in peripheral blood were permanently increased (>200%), and levels of IGF-1 decreased (<55%). The HPD lesion effectively destroyed the entire median eminence [no nerve terminals immunostained for tyrosine hydroxylase (TH) and gonadotropin-releasing hormone] and the adjacent arcuate nucleus (no perikarya immunostained for proopiomelanocortin or TH, and no cells expressed neuropeptide Y mRNA). The results support the conclusion that arcuate hypothalamic systems generate long-term rhythms in VFI, BW, and energy balance.

Failure of alpha-melanocyte stimulating hormone to attenuate cerebral complications in experimental pneumococcal meningitis

Alpha-melanocyte-stimulating hormone (α-MSH) is an endogenous neuroimmunomodulatory peptide that can inhibit a broad range of inflammatory mediators known to be involved in the pathophysiology of bacterial meningitis. We evaluated the effect of α-MSH in a rat model of pneumococcal meningitis. Rats were intracisternally infected with Streptococcus pneumoniae and treatment was started 6 h after infection. Both systemic and intracisternal α-MSH failed to influence blood–brain barrier disruption, increased intracranial pressure, brain cytokine concentrations (IL-1β, IL-6, TNF-α, MIP-2, and IL-10), CSF bacterial titers, and clinical parameters of disease severity (weight loss, body temperature, and blood pressure), although the treatment strongly increased the CNS concentrations of α-MSH. However, systemic but not intracisternal α-MSH slightly reduced the CNS leukocyte accumulation, indicating that leukocyte extravasation is inhibited by α-MSH from the blood side. Our results show that α-MSH reduces the CNS leukocyte accumulation by its systemic action, but does not attenuate meningitis-associated intracranial complications.

α-Melanocyte-stimulating hormone peptides inhibit HIV-1 expression in chronically infected promonocytic U1 cells and in acutely infected monocytes

The purpose of the present research was to determine if alpha-melanocyte-stimulating hormone (alpha-MSH) and its C-terminal tripeptide [alpha-MSH (11-13), KPV] alter HIV expression in infected cells. The results indicate that chronically HIV-1-infected promonocytic U1 cells produce alpha-MSH and that immunoneutralization of the endogenous peptide enhances HIV expression. Because U1 cells express the alpha-MSH receptor 1 (MC1R), an autocrine-inhibitory circuit based on the peptide and its receptor likely occurs in these cells. To determine effects of pharmacological concentrations of alpha-MSH peptides on HIV expression, we measured p24 antigen release by TNF-alpha-stimulated U1 cells exposed to a wide range of concentrations of synthetic alpha-MSH and KPV. Viral expression was reduced by both peptides. KPV also effectively reduced HIV replication in acutely infected monocyte-derived macrophages (MDM). The basis of the peptide influence on viral replication is at the transcriptional level; KPV inhibited activation of NF-kappaB that is known to enhance viral expression. Endogenous alpha-MSH likely contributes to natural defense against HIV. However, greater concentrations of synthetic peptide are much more effective in reducing HIV expression in infected cells.

α-Melanocyte Stimulating Hormone Acts as a Selective Inducer of Secretory Functions in Human Mast Cells

In the present study, we have investigated the pro-opiomelanocortin (POMC)-derived neuropeptide α-MSH for its ability to modulate activation of human mast cells. The in vitro ability of purified human skin mast cells to secrete various types of mast cell mediators was monitored in response to α-MSH at the mRNA and at the protein level. Picomolar concentrations of α-MSH induced a dose-dependent release of histamine from isolated human skin mast cells and from skin punch biopsies. However, no effect of α-MSH was seen regarding the expression of IL-1, IL-6, IL-8, TGF-β, and TNF-α. Melanocortin receptor MC-1 was identified at the transcriptional level by RT-PCR analysis but not at the protein level, whereas, in leukemic human mast cells (HMC-1), the mRNAs and the proteins for the MC-1 and MC-5 receptor were identified. These results suggest that α-MSH may selectively induce acute inflammary effects via secretion of histamine.

Cerebrospinal fluid concentrations of α-melanocyte-stimulating hormone in bacterial and aseptic meningitis

alpha-Melanocyte-stimulating hormone (alpha-MSH) has potent anti-inflammatory effects in several experimental models of inflammation. It inhibits both the actions and production of proinflammatory cytokines and neutrophil migration. We investigated whether alpha-MSH in cerebrospinal fluid (CSF) increases during the acute stage in patients with bacterial and aseptic meningitis by measuring alpha-MSH in CSF via radioimmunoassay. The alpha-MSH concentrations in CSF from the children with bacterial meningitis who survived (n = 8), those with aseptic meningitis (n = 16), and the control subjects (n = 23) were all below the detection limit. However, CSF alpha-MSH was elevated in four of the five children with bacterial meningitis who had neurological sequelae. We speculate that elevated alpha-MSH levels in CSF during acute bacterial meningitis reflect negative feedback in response to severe inflammation associated with neurological sequelae induced by proinflammatory cytokines. CSF alpha-MSH is elevated in children with severe bacterial meningitis who had neurological sequelae.

α-Melanocyte-stimulating Hormone Reduces Impact of Proinflammatory Cytokine and Peroxide-generated Oxidative Stress on Keratinocyte and Melanoma Cell Lines

We have previously shown that alpha-melanocyte-stimulating hormone (alpha-MSH) can oppose tumor necrosis factor alpha activation of NF-kappaB (1-2 h) and intercellular adhesion molecule 1 up-regulation (mRNA by 3 h and protein by 24 h) in melanocytes and melanoma cells. The present study reports on the ability of four MSH peptides to control intracellular peroxide levels and glutathione peroxidase (GPx) activity in pigmentary and nonpigmentary cells. In human HBL melanoma and HaCaT keratinocytes tumor necrosis factor alpha and H(2)O(2) both activated GPx in a time- and concentration-dependent manner (by 30-45 min). alpha-MSH peptides were found to inhibit the stimulated GPx activity and had biphasic dose-response curves. MSH 1-13 and MSH [Nle(4)-d-Phe(7)] achieved maximum inhibition at 10(-10) and 10(-12) m, respectively. Higher concentrations (10-100 fold) of MSH 4-10 and MSH 11-13 were required to produce equivalent levels of inhibition. alpha-MSH was also capable of reducing peroxide accumulation within 15 min, and again this inhibition was biphasic. The data support a role of alpha-MSH in acute protection of cells to oxidative/cytokine action that precedes NF-kappaB and GPx activation. The rapidity and potency of the response to alpha-MSH in pigmentary and nonpigmentary cells suggest this to be a central role of this peptide in cutaneous cells.