Peptides (v.21, #1)
Intravenous injection of major and cryptic peptide epitopes of ribotoxin, Asp f 1 inhibits T cell response induced by crude Aspergillus fumigatus antigens in mice☆ by Elena Svirshchevskaya; Ella Frolova; Ludmila Alekseeva; Olga Kotzareva; Viswanath P Kurup (1-8).
Aspergillus fumigatus, a ubiquitous fungus, is implicated in the pathogenesis of a number of clinically different allergic diseases in man. Peptide-based immunotherapy may offer an alternative in patient care and management. The purpose of this study was to evaluate the role of T cell epitopes of A. fumigatus ribotoxin, Asp f 1 in inducing tolerance in mice exposed to A. fumigatus antigen. The epitope analysis in BALB/c mice using synthetic peptides of Asp f 1 demonstrated both cryptic and dominant epitopes detected from 42 through 54 and 155 through 167 aa, accordingly. Intravenous injection of these peptides markedly inhibited the response induced by the exposure to crude A. fumigatus extract in mice as evidenced by the in vitro interleukin-2 (IL-2) production and proliferation of T-lymphocytes. Cytokine transcription studies indicate that, when stimulated with the peptides in immunogenic conditions, the major peptide (aa 155–167) specific T cell clone produced only IFN-γ, but not IL-4. The ability of both dominant and cryptic peptide epitopes of a single molecule to induce tolerance against the immune response to a multi-molecular allergen complex has significant implication for peptide-based immunotherapy.
Keywords: Allergy; Aspergillus fumigatus; Peptide-induced tolerance; Immunotherapy;
Synthesis and construction of a novel multiple peptide conjugate system: strategy for a subunit vaccine design by Robert A. Boykins; Manju Joshi; Chaing Syin; Subhash Dhawan; Hira Nakhasi (9-17).
We describe the design and synthesis of a novel well characterized multi-peptide conjugate (MPC) system containing antigens from human malaria parasite and the Tat protein of HIV type-1 (HIV-1-Tat). Construction of the MPC utilizes Fmoc solid-phase peptide synthesis coupled with solution chemistry. In the first phase, a core template that serves as primary anchor for the synthesis and attachment of multiple antigens is synthesized. Serine(trityl) and multiple lysine branches with epsilon groups blocked during chain assembly are incorporated forming a tetrameric core. Cysteine whose side chain thiol serves to couple haloacetyl or S-protected haloacetyl peptides is added to complete assembly of the core template. Modification to the coupling solvent, addition of key amino acid derivatives (N-[1-hydroxy-4-methoxybenzyl]) in the peptide sequence allows the synthesis of base peptides on the core template with molecular mass greater than 7500 kDa. Base peptides are then reacted with high performance liquid chromatography purified haloacetyl peptides to generate multiple peptide conjugates with molecular masses of 10 to 13 kDa. MPC constructs thus formed are further characterized by matrix assisted laser desorption-time of flight mass spectroscopy (MALDI-MS), amino acid analysis, size exclusion chromatography, and SDS-polyacrylamide gel electrophoresis (PAGE). To our knowledge, this is the first report describing a chemically well defined multiple conjugate system with potential for development of synthetic subunit vaccines.
Keywords: Linear peptide: Peptide sequence with N-terminal haloacetyl; Base peptide: Peptide sequence synthesized on core template;
Primary structures of a second hyperglycemic peptide and of two truncated forms in the spiny lobster, Jasus lalandii by Heather G. Marco; Wolf Brandt; Stanka Stoeva; Wolfgang Voelter; Gerd Gäde (19-27).
We have isolated a 72-amino acid peptide from extracts of sinus glands of the South African rock lobster, Jasus lalandii, and identified it, functionally and immunologically, as a hyperglycemic hormone. This is the second peptide with hyperglycemic activity found in this palinurid species and, because it occurs in smaller quantities (approximately 3 pmol/sinus gland) than the previously identified hyperglycemic hormone , this minor isoform is designated Jala cHH-II. The complete elucidation of the primary structure of cHH-II, as determined by automated Edman degradation of the N-terminus enzymatic digests of the non-reduced peptide, chemical cleavage and mass spectrometry, is presented here. Jala cHH-II (molecular mass of 8357 Da) is more hydrophobic than Jala cHH-I (8380 Da). The two cHHs have a free N-terminus a blocked C-terminus; and share 90% sequence homology. We also present structural data of a further two peptides isolated from sinus gland extracts that were immunopositive to cHH antisera. These peptides, with masses of 7665 and 7612 Da, structurally represent C-terminally truncated forms of the major and the minor Jala cHH peptides, respectively, but do not have any hyperglycemic activity in vivo. We demonstrate that the prevalence of these truncated forms can be reduced by the addition of proteases to the homogenization buffer during preparation of the tissues.
Keywords: Crustacean hyperglycemic hormone; Neuropeptide; Isoform; Jasus lalandii; Sinus gland; Truncated peptides; Spiny lobster;
Neuropeptide Y receptor(s) mediating feeding in the rat: characterization with antagonists by Carlo Polidori; Roberto Ciccocioppo; Domenico Regoli; Maurizio Massi (29-35).
The present study evaluated the effect of the neuropeptide Y (NPY) Y1 receptor antagonists BIBO 3304 and SR 120562A and of the Y5 receptor antagonists JCF 104, JCF 109, and CGP 71683A on feeding induced either by NPY or food deprivation. In a preliminary experiment, NPY was injected into the third cerebroventricle (3V) at doses of 0.07, 0.15, 0.3, or 0.6 nmol/rat. The dose of 0.3 nmol/rat, which produced a cumulative 2-h food intake of 11.2 ± 1.9 g/kg body weight, was chosen for the following experiments. The antagonists were injected in the 3V 1 min before NPY. The Y1 receptor antagonist BIBO 3304 significantly inhibited NPY-induced feeding at doses of 1 or 10 nmol/rat. The Y1 receptor antagonist SR 120562A, at the dose of 10 but not of 1 nmol/rat, significantly reduced the hyperphagic effect of NPY, 0.3 nmol/rat. The Y5 receptor antagonists JCF 104 and JCF 109 (1 or 10 nmol/rat) and CGP 71683A (10 or 100 nmol/rat) did not significantly modify the effect of NPY, 0.3 nmol/rat. However, JCF 104 (10 nmol/rat) and CGP 71683A (100 nmol/rat), but not JCF 109 (10 nmol/rat), significantly reduced food intake during the interval from 2 to 4 h after injection of a higher dose, 0.6 nmol/rat, of NPY. Feeding induced by 16 h of food deprivation was significantly reduced by the Y1 receptor antagonist BIBO 3304 (10 nmol/rat), but it was not significantly modified by the same dose of SR 120562A or JCF 104. These findings support the idea that the hyperphagic effect of NPY is mainly mediated by Y1 receptors. The results obtained with JCF 104 and CGP 71683A suggest that Y5 receptors may have a modulatory role in the maintenance of feeding induced by rather high doses of NPY after the main initial feeding response.
Keywords: Neuropeptide Y; Neuropeptide Y antagonists; Food intake; BIBO 3304; JCF 104; JCF 109; SR 120562A; CGP 71683A; Nociceptin;
Neuropeptide Y blocks anxiogenic-like behavioral action of corticotropin-releasing factor in an operant conflict test and elevated plus maze by Karen T Britton; Yvette Akwa; Mariarosa G Spina; George F Koob (37-44).
Central administration of neuropeptide Y (NPY) produces anxiolytic-like behavioral effects in rat models of anxiety. Because previous evidence has suggested a relationship between NPY and corticotropin-releasing factor (CRF) in the brain, we have focused on the interaction of these neuropeptide systems in emotional responsiveness to stressful stimuli. Intracerebroventricular administration of CRF produced a marked response suppression in an operant incremental shock conflict paradigm. NPY [(1 μg, intracerebroventricularly (i.c.v.)] significantly antagonized the response-suppressing effects of CRF (0.75 μg, i.c.v.) on punished responding in the conflict test at doses that produced little or no behavioral effect when administered alone. Central administration of the CRF antagonist [D-Phe12, Nle21,38,Cα MeLeu37]CRF (D-Phe CRF12–41) alone did not alter punished or unpunished responding in the conflict test. However, pretreatment with the CRF antagonist before a subthreshold dose of NPY (1 μg, i.c.v.) produced a significant potentiation of the release of punished responding relative to NPY alone and untreated controls. NPY also antagonized the “anxiogenic-like” behavioral effects of CRF in the elevated plus maze. These findings support the hypothesis that NPY and CRF may reciprocally modulate an animal’s behavioral response to stressful stimuli.
Keywords: Neuropeptide Y; Corticotropin releasing factor; Conflict test; Elevated plus maze; Anxiety;
Regulation of neuropeptide Y release from hypothalamic slices by melanocortin-4 agonists and leptin by Peter J King; Peter S Widdowson; Henri Doods; Gareth Williams (45-48).
We have examined the regulation of the orexigenic neurotransmitter, NPY, in hypothalamic slices of rat brain to discover whether the leptin or melanocortin receptor-4 (MCR-4) agonists, which act as satiety signals, can influence the release of this neurotransmitter. Basal and potassium-stimulated NPY release from hypothalamic slices was not significantly altered by the addition of recombinant murine leptin. However, the melanocortin-4 agonists, α-MSH and MT-II, significantly inhibited potassium-stimulated NPY release (p < 0.01) without significantly altering basal NPY release. However, the MCR-4 antagonist, agouti-related protein, did not significantly alter either basal or stimulated NPY release. In conclusion, hypothalamic NPY release can be attenuated by MCR-4 agonists, but not by leptin, suggesting that the activation of MCR-4 receptors leading to satiety can also further inhibit food intake through an inhibition of orexigenic NPYergic activity.
Keywords: Neuropeptide Y; Leptin; Hypothalamus; Melanocortin receptor-4; Neurotransmitter release; Energy balance;
Structure activity studies of the melanocortin antagonist SHU9119 modified at the 6, 7, 8, and 9 positions☆ by Carrie Haskell–Luevano; Sejin Lim; Wei Yuan; Roger D Cone; Victor J Hruby (49-57).
The melanocortin system is involved in the regulation of several diverse physiological pathways, including energy homeostasis. Several synthetic peptide analogs have been designed, synthesized, and pharmacologically characterized at the mouse melanocortin receptor subtypes MC1R, MC3R, MC4R, and MC5R. These peptides incorporate modifications of the melanocortin core amino acids His-Phe-Arg-Trp by using the cyclic lactam templates of the lead structures MTII and SHU9119. Analogs containing DNal(2′) at position 7 resulted in partial agonist and antagonistic activities at the mMC3R while possessing full antagonistic activities at the mMC4R. Recently, the melanocortin-5 receptor (MC5R) has been demonstrated to have a role in the regulation of exocrine gland function. This study has characterized the following analogs of SHU9119 that possess antagonist activity at the MC5R: Ac-Nle-c[Asp-(1-Me)His6-DNal(2′)7-Arg-Trp-Lys]-NH2, pA2 = 7.1; Ac-Nle-c[Asp-(1-Me)His6-DNal(2′)7-Arg-Nal(2′)9-Lys]-NH2, pA2 = 7.2; and Ac-Nle-c[Asp-Trp6-DNal(2′)7-Arg-Nal(2′)9-Lys]-NH2, pA2 = 6.6.
Keywords: α-MSH; MTII; SHU9119; Melanocortin antagonists; Melanotropin;
Neural mechanism of the antisecretory effect of peptide YY in the rat colon in vivo by Jacques Chariot; Annick Tsocas; Abdelaziz Souli; Olivier Presset; Claude Rozé (59-63).
The purpose of this work was to determine the mechanism of the antisecretory effect of peptide YY in the rat colon and whether this effect is physiological. In this prospect, doses of exogenous peptide YY producing physiological and supraphysiological plasma levels were intravenously infused in rats provided with colonic and jejunal ligated loops in vivo, under secretory stimulation by vasoactive intestinal peptide. Peptide YY decreased the secretory effect of VIP in a dose-related fashion. The effect of peptide YY was blocked or strongly decreased by tetrodotoxin, hexamethonium, idazoxan, haloperidol, and the σ antagonist BMY 14, 802 in both the colon and jejunum. We conclude that peptide YY decreases water and electrolyte secretion in the colonic mucosa by a complex neural mechanism involving at least two neurons connected through a nicotinic synapse, α-2 adrenoceptors and σ receptors, and that this effect can occur with physiological doses of peptide YY.
Keywords: Peptide YY; Jejunum; Colon; Rat; Water transport; Neural mechanisms;
Inhibitory effect of sorbin on pepsin secretion in conscious cats and rabbits by G Charpin–Elhamri; M Elbaba; M Descroix–Vagne; D Pansu; J.P Perret (65-72).
Sorbin, a 153 amino acid polypeptide isolated from porcine upper small intestine and its shortest synthetic derivative, the C-terminal heptapeptide (C7-sorbin), substituted by D alaninamide in the last position (D7-sorbin), have proabsorptive and antisecretory effect in the different parts of the intestine. We showed that labeled C7-sorbin accumulated not only in the enterocytes and the enteric nervous system but also in the gastric chief cells in the rat. The chief cell secretion of pepsin was then studied in two other species, the cat and the rabbit, simultaneously with the acid secretion of parietal cells. Lipase secretion was studied in the rabbit because lipase is exclusively secreted by the upper cells of the fundic glands, which do not secrete pepsin. The animals were equipped with a gastric fistula, fully innervated, and a Heidenhain pouch, vagally denervated, during a continuous perfusion of pentagastrin (PG) 2 μg/kg · h and vasoactive intestinal peptide (VIP) 4 μg/kg · h. D7-sorbin (100 pmol/kg · h) inhibited cat and rabbit pepsin secretion from the innervated gastric fistula secretion and from the cat denervated Heidenhain pouc secretion, but was without effect on acid secretion and lipase secretion. These data indicate that the inhibitory effect of sorbin is specific on chief cells because the acid parietal cell secretion in both species and lipase upper cell secretion of the fundic glands, in the rabbit, are not implicated.
Keywords: Cat; Rabbit; Gastric secretion; Acid secretion; Pepsin; Lipase; Chief cells;
Structure, measurement, and secretion of human glucagon-like peptide-2 by Bolette Hartmann; Anders H Johnsen; Cathrine Ørskov; Kim Adelhorst; Lars Thim; Jens J Holst (73-80).
By using radioimmunoassays toward the cDNA-predicted amino acid sequence of human glucagon-like peptide-2, a peptide was isolated from extracts of human ileum. By mass spectrometry and Edman sequencing, this peptide was identified as human proglucagon 126-158. High-performance liquid chromatography analyses indicated that a similar immunoreactive peptide (iGLP-2) was present in human plasma. Human plasma concentrations of iGLP-2 were elevated 3- to 4-fold at 1 to 2 h after ingestion of 800 to 1200 kcal meals.
Keywords: Proglucagon; Radioimmunoassay; GLP-2; GLP-1; DPP-IV;
Vasoactive intestinal peptide inhibits degranulation and changes granular content of mast cells: a potential therapeutic strategy in controlling septic shock by Neşe Tunçel; Fatma Töre; Varol Şahintürk; Dilek Ak; Muzaffer Tunçel (81-89).
Vasoactive intestinal peptide (VIP) has potent protective activity against sepsis and increases the survival rate of septic rats and mice. The present study was planned to evaluate the effect of VIP on mast cell activity, histamine and methylhistamine levels and oxidative stress in the liver and kidneys of septic rats. The effect of VIP was compared to that of nitric oxide synthesis inhibition, previously tested extensively in septic shock models, with doubtful benefit. The present study showed that endotoxic shock did not lead to oxidative stress in either liver or kidney of the rats. On the other hand, mast cells, based on their location, displayed functional heterogeneity to the septic insults. VIP possibly modulated the specific reactions of the tissues to mediators released from mast cells during septic shock. The most prominent effect of VIP as compared to nitric oxide synthesis inhibition was related to mast cells. In conclusion, the prevention of mast cell reactivity by VIP could be a potential therapeutic strategy in controlling septic shock.
Keywords: Endotoxic shock; Sepsis; VIP; Mast cells; Histamine; 1-Methylhistamine; Oxidative stress; Antioxidant enzymes; Lipid peroxidation; Rat; Kidney; Liver;
Characterization of the contractile and relaxant action of the endothelin-1 precursor, big endothelin-1, in the isolated rat basilar artery by L. Schilling; H. Vatter; K. Mursch; H. Ehrenreich; P. Schmiedek (91-99).
The presence of functional endothelin converting enzyme (ECE) activity in basilar artery ring segments was investigated by measuring the contractile and relaxant effects of big endothelin (ET)-1. Under resting tension conditions cumulative application of big ET1-1 elicited a concentration-related contraction with the concentration-effect curve (CEC) shifted to the right against ET-1 by a factor of 31 and 29 in segments with the endothelium intact or mechanically removed, respectively. Preincubation with the ET(A) receptor antagonist, BQ123, induced an apparently parallel rightwards shift without affecting the maximum contraction. This shift was more pronounced for ET-1 than for big ET-1. With the putative ECE inhibitor phosphoramidon (10−3 M) in the bath a small rightwards shift of the CEC for big ET-1 was observed in control segments and a more marked one in de-endothelialized segments. In segments precontracted with prostaglandin (PG) F2α big ET-1 induced a significant although transient relaxation whereas ET-1 did not. However, in the presence of BQ123 both ET-1 and big ET-1 elicited concentration-related relaxation with a significantly higher maximum effect obtained with big ET-1. The potency was 13 fold higher for ET-1, which is markedly less than that found for contraction. The results, therefore, suggest 1) the presence of functional ECE-activity in the rat basilar artery wall, and 2) differences in the functional ECE activity located in the endothelium and media.
Keywords: Big endothelin-1; Endothelin-1; Endothelin converting enzyme; Endothelial function; Rat basilar artery; In vitro;
Proadrenomedullin NH2-terminal 20 peptide (PAMP) and adrenomedullin bind to teratocarcinoma cells☆ by T.W Moody; D Coy; F Cuttitta; L.M Montuenga (101-107).
Proadrenomedullin NH2-terminal 20 peptide (PAMP) and adrenomedullin (ADM) bind to teratocarcinoma cells. The effects of PAMP and ADM on teratocarcinoma cells were investigated. 125I-PAMP bound to PA1 cells with moderate affinity (K d = 110 nM) to a single class of sites (B max = 110 000/cell). Specific 125I-PAMP binding was inhibited by PAMP (IC50 of 100 nM) but not ADM, calcitonin gene-related peptide (CGRP), or amylin. Specific 125I-ADM binding was inhibited with high affinity by ADM, CGRP, and CGRP(8–37) (IC50 values of 10, 10, and 15 nM respectively) but not PAMP or amylin. ADM elevated cAMP (ED50 value of 100 nM), whereas PAMP had no effect on basal cAMP but inhibited the increase in cAMP caused by 10 nM ADM. Also, the increase in cAMP caused by ADM was inhibited CGRP(8–37), suggesting that ADM is binding to CGRP receptors. ADM (100 nM) stimulated transiently c-fos mRNA, whereas PAMP (1000 nM) had little effect; however, PAMP inhibited the increase in c-fos mRNA caused by ADM. ADM stimulated [3H]thymidine uptake into PA1 cells, whereas PAMP inhibited the increase in thymidine uptake caused by ADM. These results indicate that ADM and PAMP are both biologically active in teratocarcinoma cells.
Keywords: PAMP; Adrenomedullin; Receptors; cAMP; C-fos mRNA; Growth;
Electron microscopic observation of pituitary adenylate cyclase-activating polypeptide (PACAP)-containing neurons in the rat retina☆ by Tamotsu Seki; Seiji Shioda; Sachiko Izumi; Akira Arimura; Ryohei Koide (109-113).
The distribution and localization of pituitary adenylate cyclase-activating polypeptide (PACAP) in the rat retina were studied by immunocytochemistry with both light and electron microscopy. PACAP-like immunoreactivity (PACAP-LI) was detected in the amacrine and horizontal cells as well as in the inner plexiform layer, the ganglion cell layer and the nerve fiber layer. PACAP-LI seemed to be concentrated predominantly in the neuronal perikarya and their processes, but not in other cells in the retina. At the ultrastructural level, PACAP-LI was visible in the plasma membranes, rough endoplasmic reticulum, and cytoplasmic matrix in the PACAP-positive neurons in the inner nuclear layer. In the inner plexiform layer, PACAP-positive amacrine cell processes made synaptic contact with immunonegative amacrine cell processes, bipolar cell processes, and ganglion cell terminals. These findings suggest that PACAP may function as a neurotransmitter and/or neuromodulator.
Keywords: Pituitary adenylate cyclase-activating polypeptide; Retina; Rat; Amacrine cell; Horizontal cell; Immunocytochemistry; Electron microscopy;
Suppression of osteoclastic activities by calcitonin in the scales of goldfish (freshwater teleost) and nibbler fish (seawater teleost) by Nobuo Suzuki; Tohru Suzuki; Tadahide Kurokawa (115-124).
Using a tartrate-resistant acid phosphatase (TRACP) activity, the effects of calcitonin (CT) and estradiol-17β(E2) on osteoclastic activities in cultured scales of goldfish (freshwater fish) and nibbler fish (seawater fish) were examined. In mature male and female goldfish, scales were collected and incubated in Earle’s minimun essential medium (MEM) supplemented with either CT (100 ng/ml) or E2 (100 ng/ml). In both sexes, CT suppressed TRACP activities in the scales, whereas E2 increased them. When CT (100 ng/ml) and E2 (100 ng/ml) were added simultaneously to MEM, TRACP activities in the scales did not change as compared with the control. Similar results were obtained with the scales of female nibbler fish. In goldfish, furthermore, the activation of scale TRACP by E2 was suppressed, depending on CT concentrations (100 pg/ml to 1 μg/ml). In fish reproduction, this function of CT may be useful to protect scales from excess degradation of calcium at vitellogenesis.
Keywords: Calcitonin; Estradiol-17β; Osteoclast; Scale; Teleost; Tartrate-resistant acid phosphatase;
Enkephalin-degrading enzymes and their inhibitors in human saliva by Mario Marini; L.Giorgio Roda (125-135).
The possible presence of enzymes able to hydrolyze leucine enkephalin has been investigated in human saliva. The data obtained indicate that, in the presence of saliva, Leu-enkephalin is partially hydrolyzed. The disappearance of the substrate is paired with the formation of hydrolysis byproducts whose composition indicates the presence of all three classes of enzymes known to hydrolyze enkephalins: aminopeptidases, dipeptidylaminopeptidases, and dipeptidylcarboxypeptidases. The presence of low molecular weight substances with inhibitory activity on proteolytic enzymes has also been detected. These substances are active on all three classes of enkephalin-degrading enzymes, although the inhibition is more evident on dipeptidylpeptidases than on aminopeptidases. Substrate degradation was found to be higher in male than in female saliva: this seems to be caused by the activities both of enzymes and low molecular weight inhibitors that are different in the two sexes.
Keywords: Saliva; Opioid peptides; Enzyme degradation;
Isolation of the opioid peptide Leu-Val-Val-hemorphin-7 from bronchoalveolar lavage fluid of a patient with non-small cell lung cancer by David Duethman; Naresh Dewan; J.Michael Conlon (137-142).
The decapeptide Leu-Val-Val-Tyr-Pro-Trp-Thr-Gln-Arg-Phe was isolated in high yield (1.5 nmol/ml) from bronchoalveolar lavage (BAL) fluid from a patient with an adenocarcinoma of the lung. This peptide, termed LVV-hemorphin-7 represents residues 32–41 of the β-chain of hemoglobin and has been shown to be an endogenous ligand for opioid receptors. The N-terminal flanking peptide of LVV-hemorphin-7 [residues (1–31) of hemoglobin β-chain] was also isolated in high yield. Neither peptide was detected in BAL fluid from the tumor-free lung of the same patient or from patients with non-neoplastic inflammatory lung disease. LVV-hemorphin-7 was not identified in BAL fluid from seven additional patients with non-small cell lung cancer, indicating that the formation of the peptide is unlikely to be of any diagnostic significance. However, the ability of LVV-hemorphin-7 to inhibit angiotensin-converting enzyme suggests that its formation may be of pathophysiological significance in the regulation of tumor blood flow in certain patients.
Keywords: Hemorphin; Hemoglobin; Non-small cell lung cancer;
Effect of cytokines on hypothalamic neuropeptide Y release in vitro by Peter J King; Peter S Widdowson; Henri Doods; Gareth Williams (143-146).
Studies involving altered energy balance states in rodents have demonstrated that hypothalamic neuropeptide Y (NPY) activity is strongly activated in states of negative energy balance, such as periods of dietary restriction or starvation. However, in cancer cachexia, when there is a significant reduction in body weight as a result of appetite loss, leading to loss in fat and lean tissue mass, there is no augmentation in the activity of the hypothalamic NPY system. Therefore, we have examined whether cytokines, interleukin (IL)-1, IL-1β, IL-6, and tumor-necrosis factor-α (TNF-α; cachectin), which are elevated in cancer patients, can attenuate NPY release from hypothalamic slices in vitro. None of the cytokines altered either the basal or stimulated NPY release from the hypothalamic slices. However, we were able to measure a significant reduction in potassium-stimulated NPY release (−60%) by using the nonselective voltage-dependent calcium channel blocker NiCl (30 μM) without any effect on basal release, as a positive control. Therefore, we suggest that the failure to activate the hypothalamic NPY system in states of cancer cachexia cannot be attributed to a cytokine-induced reduction in neurotransmitter release.
Keywords: Neuropeptide Y; IL-1β; IL-6; TNFα; Cachexia energy balance;
Effects of galanin on the secretion and proliferative activity of the immature and regenerating adrenal glands of rats☆ by Anna Hochól; Giuliano Neri; Natasza Jêdrzejczak; Marcin Trejter; Anna Markowska; Gastone G Nussdorfer; Ludwik K Malendowicz (147-150).
The effects of galanin and the galanin-receptor antagonist (galanin-A) [d-Thr6,d-Trp8,9,15-ol]-galanin(1–15) on the immature and regenerating rat adrenal glands have been investigated in vivo. Adult female rats with adrenal regeneration and their offpring (20-day-old) were given three subcutaneous injections (28,16, and 4 h before being killed) of 2 nmol/100 g galanin and/or galanin-A, and 0.1 mg/100 g vincristin 3 h before being killed. Plasma corticosterone concentration was measured by radioimmunoassay, and the mitotic index (‰ of metaphase-arrested cells) was evaluated. In immature rats, galanin increased plasma corticosterone concentration, without affecting mitotic index; the secretagogue effect was reversed by galanin-A, which alone was ineffective. In rats with regenerating adrenal, galanin-A increased both blood level of corticosterone and mitotic index; galanin was ineffective, but blocked the effects of galanin-A. These findings allowed us to draw the following conclusions: 1) galanin exerts a moderate glucocorticoid secretagogue action on immature rat adrenals, but endogenous galanin does not play a major physiological role in the functional control of the gland; and 2) endogenous galanin exerts a maximal tonic inhibitory control on both glucocorticoid secretion and proliferative activity of regenerating rat adrenals, whose physiological relevance remains to be investigated.
Keywords: Galanin; Galanin-receptor antagonist; Glucocorticoid secretion; Cell proliferation; Immature adrenal; Regenerating adrenal; Rat;
Opiate modulating properties of nociceptin/orphanin FQ☆ by Laura M Harrison; David K Grandy (151-172).
The recently discovered peptide nociceptin/orphanin FQ (N/OFQ) and its receptor NOR share many structural similarities with the opioid peptides and their receptors. The anatomical distributions of N/OFQ and NOR are similar to those of opioid peptides and receptors. In addition, NOR and opiate receptors couple via the same G-proteins to similar effectors, such as Ca2+ channels, K+ channels, adenylyl cyclase, and several protein kinases. Thus, the behavioral effects of N/OFQ have been investigated in the context of known opiate effects, and a possible connection has been sought between the effects of these two homologous signaling systems. Originally characterized as a nociception-producing peptide, N/OFQ has now been shown to have diverse effects on nociception, as well as effects on many other behaviors. With regard to nociception, the peptide has been reported to produce hyperalgesia, reversal of opioid-mediated analgesia, analgesia, and allodynia. N/OFQ also has effects on other behaviors, such as locomotion, feeding, anxiety, spatial attention, reproductive behaviors, and opiate tolerance. The relationship between opiates and N/OFQ is strengthened by the fact that opiates also affect these behaviors. However, the exact nature of the relationship of N/OFQ with opiates—opiate-like versus antiopiate—remains controversial. This review will detail the diverse effects of N/OFQ and suggest that this peptide, like other putative antiopiate peptides, can be described as ‘opiate modulating.’
Keywords: Antiopiate; Orphanin FQ; Nociceptin; Neuropeptide FF; Tyr-MIF-1;