Altered levels of α-melanocyte stimulating hormone in cerebrospinal fluid and plasma of patients with traumatic brain injury.

Traumatic brain injury (TBI) is closely associated with marked inflammation. Although alpha-Melanocyte-Stimulating Hormone (α-MSH) exerts powerful anti-inflammatory effects, changes in endogenous α-MSH levels following TBI remain poorly understood. We investigated the changes of α-MSH levels in the cerebrospinal fluid (CSF) and plasma of post-TBI patients and the association of these changes with the severity of TBI and inflammation. TBI severity was assessed by the GCS coma scale from which, patients were separated into three groups. Clinical data were collected on days 1, 3, 5, and 7 including levels of α-MSH, tumor necrosis factor (TNF-α), and intracranial pressure (ICP). α-MSH levels in CSF steadily increased for one week (peak at day 5) but plasma α-MSH decreased and remained low. These changes were more substantial in the Severe Group of TBI with lower GCS. TNF-α levels were similarly increased in both CSF and plasma (peak at day 3). In the early phase of TBI elevated TNF-α and ICP dominated, and CSF α-MSH displayed a slow and insufficient increase. In later phases of TBI, TNF-α and ICP levels were alleviated concordantly with sustained increases in central α-MSH, wherein an anti-inflammatory environment might predominate. The relationship between plasma α-MSH and TNF-α showed significant negative correlation, and the relationship between CSF α-MSH and TNF-α showed significant positive correlation with a two-day lag. In conclusion, plasma α-MSH levels decreased, but CSF levels increased slowly following TBI. These changes were more substantial in severe patients with a lower GCS. Increases in central α-MSH paralleled alleviation of inflammation.

Galanin and α-MSH autoantibodies in cerebrospinal fluid of patients with Alzheimer's disease.

BACKGROUND: Neuropeptides galanin and α-melanocyte-stimulating hormone (α-MSH) are involved in the regulation of memory and appetite. Increased galanin and decreased α-MSH levels were reported in postmortem brains of patients with Alzheimer's disease (AD) but the underlying mechanisms are uncertain. Here we studied if autoantibodies (autoAbs) reacting with galanin and α-MSH are altered in AD. METHODS: Levels of free and total IgG autoAbs reacting with galanin and α-MSH were measured in sera and cerebrospinal fluid (CSF) of 18 subjects with AD and in 15 age-matched non-demented controls. Values were correlated with Mini-Mental State Examination (MMSE) score, body mass index (BMI) and CSF levels of AD biomarkers. RESULTS: CSF levels of total but not free IgG autoAbs against galanin were increased in AD, resulting in increased percentage of galanin autoAbs present as immune complexes. CSF levels of galanin total autoAbs and α-MSH free autoAbs correlated negatively with the severity of cognitive impairment as measured by MMSE. Both total and free autoAbs against galanin and α-MSH in CSF correlated negatively with age in AD patients but not in controls. CSF levels of galanin autoAbs and free α-MSH AutoAbs negatively correlated with CSF levels of t-Tau, p-Tau and ratios of t-Tau/Aß42 or p-Tau/Aß42 in AD patients but not in controls. CONCLUSIONS: AutoAbs reacting with galanin and α-MSH are present in CSF and are associated with clinical characteristics of AD patients. The functional significance and therapeutic potential of these autoAbs should be further clarified.

Arcuate nucleus of hypothalamus is involved in mediating the satiety effect of electroacupuncture in obese rats.

Obesity is a major health problem in the world. Since effective remedies are rare, researchers are trying to discover new therapies for obesity, and acupuncture is among the most popular alternative approaches. This study investigated the anti-obesity mechanisms of EA, using a rat model of diet-induced obesity. After feeding with a high-fat diet for 9 weeks, a number of rats who gained weight that surpassed the maximal body weight of rats in the chow-fed group were considered obese and employed in the study. A 2 Hz EA treatment at the acupoints ST36/SP6 with the intensity increasing stepwise from 0.5-1-1.5 mA was given once a day for 30 min. Rats treated with EA showed significantly decreased food intake and reduced body weight compared with the rats in DIO and restraint group. EA treatment increased peptide levels of α-MSH and mRNA levels of its precursor POMC in the arcuate nuclear of hypothalamus (ARH) neurons. In addition, the cerebral spinal fluid (CSF) content of α-MSH was elevated by EA application. ARH lesions by monosodium glutamate abolished the inhibition effect of EA on food intake and body weight. A non-acupoint stimulation did not show the benefit effect on food intake inhibition and body weight reduction compared with restraint and ST36/SP6 EA treatment. We concluded that EA treatment at ST36/SP6 acted through ARH to significantly inhibit food intake and body weight gain when fed a high-fat diet and that the stimulation of α-MSH expression and release might be involved in the mechanism.

Proopiomelanocortin-derived peptides in rat cerebrospinal fluid and hypothalamic extracts: evidence that secretion is regulated with respect to energy balance.

Regulation of proopiomelanocortin (POMC) is an important means of controlling the central melanocortin system. It has never been established whether the spectrum of POMC-derived peptides synthesized and secreted from the hypothalamus is altered in response to changes in energy homeostasis in vivo. To monitor secretion, we analyzed peptide content of rat cerebrospinal fluid. Strikingly, both the POMC precursor and ACTH were readily detected. Moreover, levels of both were lower in samples from obese Zucker rats (fa/fa) vs. lean Zucker rats (+/+, fa/+) and from fasted vs. fed rats, whereas alpha MSH could not be detected. POMC levels were also decreased in hypothalamic extracts from obese and fasted animals. In contrast, despite being the most predominant peptide in extracts, alpha MSH levels were not significantly changed in any of the rat models. The ratio of precursor to derived peptides in cerebrospinal fluid was significantly higher in obese vs. lean and fed vs. fasted rats, indicating that secretion of POMC-derived peptides is differentially down-regulated during negative energy balance. In contrast to peptide analysis, we found that POMC gene expression was not significantly decreased in fasted rat hypothalami. We conclude that regulation of peptide secretion is an important mechanism by which the POMC system is controlled.

Cerebrospinal fluid and plasma concentrations of leptin, NPY, and alpha-MSH in obese women and their relationship to negative energy balance.

Leptin and its principal mediators, NPY and alpha-MSH are postulated to play a pivotal role in energy balance. To determine the possibility of the disturbance in neuropeptides in human obesity and their consequent changes in response to negative energy balance, we evaluated plasma and cerebrospinal fluid (CSF) leptin, NPY, and alpha-MSH levels in obese women before and after weight loss in comparison with normal control women. Subjects included 16 obese women [mean body mass index (BMI), 35.6 kg/m(2)] before and after weight loss induced by a 2-wk very low caloric diet (800 kcal/d) and 14 normal weight women (mean BMI, 20.4 kg/m(2)). The CSF to plasma leptin ratio in normal weight subjects was 2.3-fold higher than that in obese subjects. After weight loss in obese subjects, plasma leptin levels decreased by 40% and CSF levels decreased by 51%. There was a positive linear correlation between CSF and plasma leptin levels at baseline in obese subjects (r = 0.74, P < 0.05) and a positive logarithmic correlation in normal weight subjects (r = 0.89, P < 0.05) and in obese subjects after weight loss (r = 0.64, P < 0.05). The BMI was negatively correlated with the CSF to plasma leptin ratio (r = -0.86, P < 0.05) in all subjects. Neither the baseline plasma levels nor the baseline CSF levels of NPY were different between normal weight subjects and obese subjects. After weight loss, the CSF NPY level decreased significantly compared with baseline values in obese subjects. The alpha-MSH levels in plasma and CSF did not differ significantly from controls in obese subjects at baseline or after weight loss. Baseline CSF leptin level correlated with neither the baseline CSF NPY level nor the baseline CSF alpha-MSH level. In conclusion, this study demonstrated that the efficiency of brain leptin delivery is reduced in human obesity and central nervous system leptin uptake involves a combination of a saturable and an unsaturable mechanism. CSF NPY and alpha-MSH did not differ from controls in human obesity, and the CSF NPY level decreased significantly whereas alpha-MSH did not differ after weight loss in obese subjects compared with baseline. There was no significant correlation between CSF leptin and CSF NPY or alpha-MSH. This could be the result of leptin resistance present in human obesity and/or the more complex mechanisms involved in modulating appetite and regulating energy balance in human obesity.

Asphyxia-induced release of alpha-melanocyte-stimulating hormone in newborn pigs.

Asphyxia and reperfusion induced changes in the plasma and cerebrospinal fluid (CSF) concentrations of alpha-melanocyte-stimulating hormone (alpha-MSH) were studied in newborn pigs using a specific radioimmunoassay technique. Cardiovascular and metabolic failure induced by neonatal asphyxia resulted in a 3-fold, significant (P < 0.05) increase in plasma alpha-MSH levels, whereas the hormone concentration in CSF was significantly (P < 0.05) reduced by 50% during postasphyxial reperfusion. Our data indicate an asphyxia-induced release of alpha-MSH, and suggest a discordant regulation of plasma and CSF concentrations in newborn pigs.

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

UNLABELLED: 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. CONCLUSION: CSF alpha-MSH is elevated in children with severe bacterial meningitis who had neurological sequelae.

Inhibition of antigen-stimulated effector T cells by human cerebrospinal fluid.

The brain is an immune-privilege site. To understand the mechanism of immune privilege in the brain, human cerebrospinal fluid (CSF) was examined for characteristics associated with fluids derived from other immune-privileged tissues. We first assayed for CSF suppression of effector T cell inflammatory activities. Primed T cells were activated with antigen and antigen-presenting cells in the presence of normal human or rabbit CSF, and T cell proliferation and interferon-gamma production were assayed. Human and rabbit CSF enhanced antigen-stimulated lymph node T cell proliferation and human CSF suppressed IFN-gamma production. T cell proliferation was suppressed by a low molecular weight (< 5 kDA) fraction of CSF and by transiently acidified unfractionated CSF. Normal CSF, similar to fluids from other immune-privileged sites, has the capacity to suppress production of proinflammatory lymphokines by antigen-stimulated effector T cells. Normal CSF also contains factors that have the potential to suppress effector T cell proliferation. Human CSF was assayed for factors known to mediate immunosuppression in other immune-privileged sites. Human CSF contained the immunosuppressive cytokine-transforming growth factor-beta (1.7 +/- 0.6 ng/ml), and the immunosuppressive neuropeptides alpha-melanocyte stimulating hormone (60 +/- 11 pg/ml), and vasoactive intestinal peptide (42 +/- 3 ng/ml). Much as fluids from other immune-privileged sites, CSF contains immunosuppressive cytokines that prevent activation of inflammatory-mediating (delayed-typed hypersensitivity) T cells. This suggests that, similar to other immune-privileged sites, cytokines and neuropeptides mediate immunosuppression in the brain.

Alpha-melanocyte-stimulating hormonelike immunoreactivity is increased in cerebrospinal fluid of patients with Parkinson's disease.

We measured alpha-melanocyte-stimulating hormonelike immunoreactivity in cerebrospinal fluid of 12 healthy control subjects and nine patients with Parkinson's disease, four of whom had never been treated. Mean cerebrospinal fluid alpha-melanocyte-stimulating hormonelike immunoreactivity concentration was two-fold greater in parkinsonian patients (44.1 +/- 9.3 [SD] pg/mL) as compared with control subjects (21.8 +/- 10.0 pg/mL). No significant correlation was found between cerebrospinal fluid alpha-melanocyte-stimulating hormonelike immunoreactivity concentrations and patient age, disease severity, or duration of disease. These results suggest a functional relation between dopaminergic and melanotropinergic systems in the human brain.

CSF alpha-MSH in dementia of the Alzheimer type.

We measured CSF alpha-melanocyte stimulating hormone-like immunoreactivity (alpha-MSH-LI) in 35 patients with dementia of the Alzheimer type (DAT) and in 27 healthy control subjects. Mean alpha-MSH-LI concentration was significantly decreased in DAT patients as compared with age-matched controls. However, when the DAT patients were analyzed according to age at onset of dementia or presence of extrapyramidal signs, alpha-MSH-LI concentrations remained significantly lower than in controls only in DAT patients with late onset of dementia (greater than 65 years of age). No correlation was found between alpha-MSH levels and degree of mental impairment. A significant negative correlation was found between CSF concentrations of alpha-MSH and homovanillic acid in the group of all DAT patients (p less than 0.001). These results suggest that hypothalamic neurons which produce pro-opiomelanocortin-related peptides may be involved in Alzheimer's disease.