Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The voluntary suppression of food intake that accompanies involuntary overfeeding is an effective regulatory response to positive energy balance. Because the pro-opiomelanocortin (POMC)-derived melanocortin system in the hypothalamus promotes anorexia and weight loss and is an important mediator of energy regulation, we hypothesized that it may contribute to the hypophagic response to overfeeding. Two groups of rats were overfed to 105 and 116% of control body weight via a gastric catheter. In the first group, in situ hybridization was used to measure POMC gene expression in the rostral arcuate (ARC). Overfeeding increased POMC mRNA in the ARC by 180% relative to levels in control rats. For rats in the second group, the overfeeding was stopped, and they were infused intracerebroventricularly with SHU9119 (SHU), a melanocortin (MC) antagonist at the MC3 and MC4 receptor, or vehicle. Although SHU (0.1 nmol) had no effect on food intake of control rats, intake of overfed rats increased by 265% relative to CSF-treated controls. This complete reversal of regulatory hypophagia not only maintained but actually increased the already elevated weight of overfed rats, whereas CSF-treated overfed rats lost weight. These results indicate that CNS MCs mediate hypophagic signaling in response to involuntary overfeeding and support the hypothesis that MCs are important in the central control of energy homeostasis.
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PMID:Role of the CNS melanocortin system in the response to overfeeding. 1006 86

In our previous study, xenogeneic mouse neuroblastoma cells bearing the POMC gene, the precursor of ACTH and beta-endorphin, were implanted within polymer capsules into the CSF space of rats. Although ACTH and beta-endorphin were secreted, we were not able to control the amounts or times of hormone release. A promoter that is inducible by administration of tetracycline derivatives (Tet) was linked to the POMC gene to control its gene expression (Neuro2A-Tet-On-POMC; NTP). The results showed that POMC gene expression in the implanted encapsulated NTP cells could be regulated in a dose-dependent manner by Tet administration to the hosts. However, no analysis of gene control with the Tet-On system over a long period has been performed. In this study, encapsulated NTP cells were treated in vitro with doxycycline (Dox) (1.0, 10, 100, 1000 ng/ml) continuously for a month. On day 4, the amount of ACTH secretion was dependent on the Dox dose. But in the course of the experiment, the difference of ACTH secretion among those treated with Dox 10, 100, and 1000 ng/ml was eliminated. On the other hand, NTP cells, which were treated with Dox (1000 ng/ml) just on days 7, 14, 21, and 28, secreted almost the same amount of ACTH in 24 h. From these results, for clinical use, an NTP cell line that secretes enough opiate to reduce pain sensitivity without Dox should be established, and Dox could then be administered if necessary.
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PMID:Long-term functional assessment of encapsulated cells transfected with Tet-On system. 1047 25

A decreased ratio of branched-chain amino acids (BCAA) to aromatic amino acids (AAA) is considered an important pathogenetic factor in hepatic encephalopathy (HE). A relationship between the deranged BCAA/AAA ratio and dopaminergic dysfunction through the formation of "false" neurotransmitters has been postulated. The intermediate lobe of the pituitary is more pronounced in dogs than in humans and because it is primarily under dopaminergic inhibitory influence, it may serve as an indicator of alterations in dopaminergic neurotransmission. We investigated the effects of a diet with a high BCAA/AAA ratio (HR) and an isonitrogenous diet with a low BCAA/AAA ratio (LR) on several physical and biochemical parameters including pituitary function in dogs with portocaval shunts and 40% hepatectomy and in sham-operated pair-fed controls, in a double-blind, randomized cross-over study. Portocaval-shunted dogs had hyperammonemia (33+/-3 microM (mean +/- SEM) before and 214+/-21 after surgery)) and signs of HE. Their BCAA/AAA ratio in plasma and CSF decreased from 4.3+/-0.3 and 2.3+/-0.3 before surgery to 1.3+/-0.1 and 0.5+/-0.1 after surgery, respectively. These parameters remained unaltered in the control dogs. The consumption of the LR diet was significantly higher than consumption of the HR diet. In the portocaval-shunted dogs, plasma ammonia concentration was higher on the HR diet than on the LR diet (344+/-52 v 246+/-45) and the HE grade was worse. The BCAA/AAA ratio remained abnormal in HE dogs during the feeding of both diets. The basal and haloperidol-stimulated release of alpha-melanotropin and cortisol in plasma were not significantly different between or within groups during any period. In contrast, urinary cortisol excretion was increased in the HE dogs after surgery (urinary cortisol:creatinine ratio (x10(-6)) 8.5+/-1.4 before and 30.4+/-8.9 after surgery). The basal plasma concentration of adrenocorticotropin in HE dogs was decreased after surgery (68.3+/-10.2 ng/L before and 40.8+/-4.4 after surgery). This indicates a non-pituitary-dependent hyperresponsiveness of the adrenals. We conclude from these results that chronic HE in dogs is not associated with an abnormal dopaminergic neurotransmission at least at the level of the pituitary, and that it is not the content of the dietary neutral amino acids but rather the total protein intake that may have a beneficial effect on HE.
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PMID:Effects of a branched-chain amino acid-enriched diet on chronic hepatic encephalopathy in dogs. 1048 12

Despite strong evidence of a physiologic relationship between cholecystokinin (CCK) and corticotropin-releasing hormone (CRH) in the rat central nervous system (CNS), evidence of such a relationship between the two hormones in the human CNS is lacking. A post hoc analysis of serial concentrations of immunoreactive CCK and CRH, obtained every ten minutes from CSF continuously collected over six hours, was performed. A total of 30 subjects were studied: 15 normal volunteers, 10 patients with major depression, and 5 recently-abstinent, alcohol-dependent patients. Overall, we observed an average intra-subject correlation of +.273 (P < 0.001) between CSF CRH and CCK. Inter-subject correlations between mean CSF levels of CRH and CCK were +.948 (P = 0.0001) and +.959 (P = 0.005) in the depressed and abstinent alcoholic patients, respectively. These inter-individual correlations were significantly greater than that seen within the group of normal volunteers (r = +.318, n.s.). The present data suggest that interactions between CCK and CRH are significant in the human CNS, particularly perhaps in depressed and alcoholic patients, and that CSF samples may be used to assess elements of the relationship between these hormones.
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PMID:Intra- and inter-individual correlations between cholecystokinin and corticotropin-releasing hormone concentrations in human cerebrospinal fluid. 1056 31

In mice whose Gi/o-protein function had been impaired by antisense 'knock-down' or pertussis toxin treatment, i.c.v. injection of myr+-Gi/o alpha subunits restored the effectiveness of beta-endorphin, morphine, DPDPE, clonidine and neurotensin to produce antinociception. Myr+-G alpha subunits of the class of G-proteins actually impaired were more effective than unlike but related myr+-G alpha subunits. Selectivity was noted in that only exogenous myr+-G alpha subunits affected (enhanced) the activity of agonists in G alpha-deficient signalling systems. This treatment had little effect on agonist potency when the impairment resided at the receptor level. The potential of the opioids, clonidine and R-PIA to increase G alpha-related in vitro hydrolysis of GTP was also re-established after injecting myr+-Gi2 alpha subunits into Gi2-knocked-down mice. Myr+-Gi2 alpha subunits pre-incubated with GTPgammaS or GDPbetaS before i.c.v. injection did not improve the activity of agonists in vivo (antinociception) or in vitro (regulation of low Km GTPase). After impairing the function of PKCbeta1 by antisense treatment or with the inhibitor H7, the effect of myr+-G alpha subunits on agonist potency was prevented. Electron microscope analysis showed the entry of gold-conjugated myr+-G alpha subunits into neural cells. These particles were found in the cytoplasm, associated with the plasma membranes of different neuronal processes and also in synaptic junctions. In cultured neurons and astrocytes myr+-Gi2 alpha-associated fluorescence was internalised in a dose-dependent manner and distributed in the plasma membrane and cytosol, as well as in nuclei of dividing astrocytes. Thus, G alpha subunits in CSF enter into neurons and functionally couple to the receptor-triggered signalling cascade. As G-proteins have been implicated in the pathophysiology of several neural disorders, this finding may be valuable in the therapy of such dysfunctions.
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PMID:Myr+-Gi2 alpha and Go alpha subunits restore the efficacy of opioids, clonidine and neurotensin giving rise to antinociception in G-protein knock-down mice. 1060 81

Adrenal medullary tissue including chromaffin cells was grafted intrathecally in cancer patients to relieve intractable pain. The central nervous system (CNS) is considered an immune privileged site. Therefore, non-HLA-matched and unencapsulated tissue was grafted in 15 patients and 1 sham control in a series of at least 20 grafts. We observed an increase in CSF lymphocyte counts in 15/20 allografts (75%). In contrast to peripheral blood, CD4 T cells predominated in the CSF, but failed to exhibit an activated phenotype (CD25+ CD45RO+ HLA-DR+). The positive effect of graft on pain, the high met-enkephalin levels, the absence of any increase in CSF cytokine levels particularly for IFN-gamma or IL-2 (but not IL-10 and IL-6), indirectly indicated that the graft was tolerated despite the presence of CSF lymphocytes. The single treatment failure and three of four cases of partial efficacy occurred in grafts where CSF lymphocytes were present. Moreover, when assayed (n = 7), the CD4+ CSF lymphocytes still retained the capacity to exhibit ex vivo a normal or enhanced frequency of T CD4 cells producing IFN-gamma and IL-2. Taken together, our observations indicate that impairment of the local immunosuppressive balance can lead to activation of those CSF CD4 T cells and drive a rejection process. This study suggests further work on the purification and/or the immunoisolation of tissues grafted in the CNS will be necessary, particularly when the possibility of long-term and repeated grafting is considered.
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PMID:Intrathecal grafting of unencapsulated adrenal medullary tissue can bring CD4 T lymphocytes into CSF: a potentially deleterious event for the graft. 1078 70

A number of pre-clinical studies have demonstrated the value of adrenal medullary allografts in the management of chronic pain. The present longitudinal survey studied 15 patients transplanted for intractable cancer pain after failure of systemic opioids due to the persistence of undesirable side-effects. Before inclusion, all the patients had their pain controlled by daily intrathecal (I-Th) morphine administration. The main evaluation criteria of analgesic activity of the chromaffin cell allograft was the complementary requirement of analgesics and in particular the consumption of I-Th morphine required to maintain effective pain control. Out of the 12 patients who profited from enhanced analgesia with long-term follow-up (average 4.5 months), five no longer required the I-Th morphine (with prolonged interruption of systemic opioids as well), two durably decreased I-Th morphine intake and five were stabilized until the end of their follow-up. Durable decline and stabilization were interpreted as indicative of analgesic activity by comparison with the usual dose escalation observed during disease progression. In most cases, we noted a relationship between analgesic responses and CSF met-enkephalin levels. The results of this phase II open study demonstrate the feasibility and the safety of this approach using chromaffin cell grafts for long-term relief of intractable cancer pain. However, while analgesic efficacy was indicated by the reduction or stabilization in complementary opioid intake, these observations will need to be confirmed in a controlled trial in a larger series of patients.
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PMID:Human chromaffin cell graft into the CSF for cancer pain management: a prospective phase II clinical study. 1086 42

The durable effectiveness of intrathecal morphine administration is well established for the management of intractable cancer pain, after failure of systemic opioids, secondary to the persistence of non-reversible undesirable side effects. Many patients are referred to late in the disease course. This conservative method to control pain of malignant origin must not be reserved for last resort treatment for terminal patients. Intra-cerebro-ventricular morphine administration is a very effective and generally safe method for controlling intractable cancer pain. Because of the chronic implantation of an intra-ventricular catheter this method is somewhat invasive. Its indications remain a simple and effective alternative when the topography of nociceptive pain is diffuse or cephalic. In clinical practice, intrathecal and/or intra-cerebro-ventricular administration of opioids is limited by cost, the need for specialized maintenance and mechanical malfunctions if implantable drug delivery systems, or by the risk of bacterial contamination and ambulatory constraints when repeated daily injections via an intrathecal access port are used. To answer these limitations, cell therapy using intrathecal chromaffin cell allograft is a promising approach for the management of cancer pain refractory to traditional drug therapy and pain lesion surgery. The basic rationale and preclinical studies on experimental pain models have enabled starting prospective clinical trials. Prior to transplantation, handling and preparation of the chromaffin tissue is critical for allograft viability. The initial results of clinical trials with human chromaffin cell grafts from intractable cancer pain have reported long-lasting pain relief, in correlation with met-enkephalin release into the CSF. Convincing evidence will require controlled studies. The limitations of this innovative cell therapy and especially the lack of human adrenal gland availability point to the need for new sources of cells. Perspectives include xenogenic or engineered cell lines.
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PMID:[Management of intractable cancer pain: from intrathecal morphine to cell allograft]. 1108 78

The protective effect of co-administration of recombinant mouse granulocyte-macrophage colony-stimulating factor (rmGM-CSF) and synthetic peptide met-enkephalin (M-ENK) against blood-induced Plasmodium berghei infection in Swiss mice was investigated. Mice co-administered with rmGM-CSF (10.0 mug/kg) and M-ENK (2.0 mg/kg) x 3/day, i.p., beginning on day -1 and continuing through day +4 after the initiation of infection, showed significant suppression (p < 0.05) (sometimes even complete elimination) of parasitaemia compared to vehicle-treated controls. However, when administered separately, neither of these agents induced any detectable protective effect. Surprisingly, mice similarly co-administered with rmGM-CSF (10.0 mug/kg) and higher doses of M-ENK (10.0 mg/kg), showed no protection. Polyclonal neutralizing (100%) antibody to rmGM-CSF abrogated the combined protective effect of these agents. Additionally, naloxone (10.0 mg/kg/day x 6, i.p.), a non-selective, opioid receptor antagonist, also blocked the combined protection. Mice that survived the challenge showed a significant increase (p < 0.05) in total circulating leukocytes counts, and the pool-size and the phagocytic activity of both the peritoneal and splenic macrophages, ex vivo. Silica (3.0 mg/mouse, i.v.) abrogated the combined protective effect of rmGM-CSF and M-ENK. These results indicate that co-administration of rmGM-CSF and dose dependent quantities of M-ENK in P. berghei-infected mice can protect against malaria, apparently through macrophage-mediated mechanisms.
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PMID:Protection of mice from malaria after co-administration of recombinant mouse granulocyte-macrophage colony- stimulating factor and methionine-enkephalin. 1156 34

Neuropeptide Y (NPY) has a potent inhibitory effect on TRH gene expression in the paraventricular nucleus (PVN) and contributes to the fall in circulating thyroid hormone levels during fasting mediated by a reduction in serum leptin levels. Because alpha-MSH activates the TRH gene by increasing the phosphorylation of CREB in the nucleus of these neurons, we raised the possibility that at least one of the mechanisms by which NPY reduces TRH mRNA in hypophysiotropic neurons is by antagonizing the ability of alpha-MSH to phosphorylate CREB. As NPY increases CRH mRNA in the hypothalamus, we further determined whether intracerebroventricular (i.c.v.) administration of NPY regulates the phosphorylation of CREB in hypophysiotropic CRH neurons. NPY [10 micro g in artificial CSF (aCSF)] was administered into the lateral ventricle i.c.v. 30 min before the i.c.v. administration of aCSF or alpha-MSH (10 micro g in aCSF), the latter in a dose previously demonstrated to increase proTRH mRNA and phosphorylate CREB in TRH neurons. By double-labeling immunocytochemistry, only few TRH neurons in the PVN contained phosphoCREB (PCREB) in animals treated only with aCSF (4 +/- 0.2%) or with NPY followed by aCSF (9.7 +/- 2.5), whereas alpha-MSH-infused animals dramatically increased the percentage of TRH neurons containing PCREB (75.3 +/- 6.9%). Pretreatment with NPY before alpha-MSH infusion, however, significantly reduced the percentage of TRH neurons containing PCREB (40.8 +/- 3.5%) compared with alpha-MSH infused animals (P = 0.01). Only 12.2 +/- 0.9% of CRH neurons of the medial parvocellular neurons contained PCREB nuclei in vehicle-treated animals, whereas 30 min following NPY infusion, the number of CRH neurons containing PCREB increased dramatically to 88 +/- 2.9%. Whereas alpha-MSH infusion increased the percentage of CRH neurons that contained PCREB to 56 +/- 2.2% compared with control, animals pretreated with NPY further increased the number of CRH neurons colocalizing with PCREB to 87 +/- 2.5%. These data demonstrate a functional interaction between NPY and alpha-MSH in the regulation of proTRH neurons in the PVN, suggesting that NPY can antagonize alpha-MSH induced activation of the TRH gene by interfering with melanocortin signaling at the postreceptor level, preventing the phosphorylation of CREB. In contrast, NPY infusion increases the phosphorylation of CREB in CRH neurons, indicating that NPY has independent effects on discrete populations of neurons in the PVN, presumably mediated through different signaling mechanisms.
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PMID:Central administration of neuropeptide Y reduces alpha-melanocyte-stimulating hormone-induced cyclic adenosine 5'-monophosphate response element binding protein (CREB) phosphorylation in pro-thyrotropin-releasing hormone neurons and increases CREB phosphorylation in corticotropin-releasing hormone neurons in the hypothalamic paraventricular nucleus. 1248 56


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