| 1. |
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| 2. |
- Erdling, André, et al.
(författare)
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VIP/PACAP receptors in cerebral arteries of rat: Characterization, localization and relation to intracellular calcium.
- 2013
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Ingår i: Neuropeptides. - : Elsevier BV. - 1532-2785 .- 0143-4179. ; 47:2, s. 85-92
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating peptide (PACAP)-containing nerves surround cerebral blood vessels. The peptides have potent vasodilator properties via smooth muscle cell receptors and activation of adenylate cyclase. The purpose of this study was to describe the effects of two putative VIP/PACAP receptor antagonists and the distribution of the receptor protein in rat brain vessels. METHODS: The vascular effects of VIP, PACAP-27 and PACAP-38 were investigated in segments of rat middle cerebral artery (MCA) by pressurized arteriography, and in a wire myograph. The antagonistic responses to PACAP6-38 and PG99-465 were evaluated. In addition, the receptor subtypes for VIP and PACAP (VPAC(1), VPAC(2) and PAC(1)) were visualized in the rat middle cerebral artery by immunohistochemistry and Western blotting. RESULTS: In the perfusion model, abluminal but not luminal VIP, PACAP-27 and PACAP-38 caused concentration-dependent relaxations of the MCA (27.1±0.2%, 25.2±0.4% and 0.3±0.1%, respectively). In the wire myograph, there was no significant difference in potency of the peptides in the MCA. In both systems, PACAP6-38 and PG99-465 inhibited the VIP induced relaxation. Western blot showed the presence of the receptor proteins in cerebral vasculature and immunohistochemistry showed that all three receptors are present and located in the cytoplasm of smooth muscle cells. CONCLUSION: In both systems, the two blockers antagonized the relaxant VIP effect; the potency order of agonists and the immunohistochemistry suggest the presence of the dilatory VPAC(1) and VPAC(2) receptors on the smooth muscle cells.
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| 3. |
- Fällmar, Helena, 1980-, et al.
(författare)
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Identification of positions in the human neuropeptide Y/peptide YY receptor Y2 that contribute to pharmacological differences between receptor subtypes
- 2011
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Ingår i: Neuropeptides. - : Elsevier BV. - 0143-4179 .- 1532-2785. ; 45:4, s. 293-300
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Tidskriftsartikel (refereegranskat)abstract
- The members of the neuropeptide Y (NPY) family are key players in food-intake regulation. In humans this family consists of NPY, peptide YY (PYY) and pancreatic polypeptide (PP) which interact with distinct preference for the four receptors showing very low sequence identity, i.e. Y1, Y2, Y4 and Y5. The binding of similar peptides to these divergent receptors makes them highly interesting for mutagenesis studies. We present here a site-directed mutagenesis study of four amino acid positions in the human Y2 receptor. T(3.40) was selected based on sequence alignments both between subtypes and between species and G(2.68), L(4.60) and Q(6.55) also on previous binding studies of the corresponding positions in the Y1 receptor. The mutated receptors were characterized pharmacologically with the peptide agonists NPY, PYY, PYY(3-36), NPY(13-36) and the non-peptide antagonist BIIE0246. Interestingly, the affinity of NPY and PYY(3-36) increased for the mutants T(3.40)I and Q(6.55)A. Increased affinity was also observed for PYY to Q(6.55)A. PYY(3-36) displayed decreased affinity for G(2.68)N and L(4.60)A whereas binding of NPY(13-36) was unaffected by all mutations. The antagonist BIIE0246 showed decreased affinity for T(3.40)I, L(4.60)A and Q(6.55)A. Although all positions investigated were found important for interaction with at least one of the tested ligands the corresponding positions in hY1 seem to be of greater importance for ligand binding. Furthermore these data indicate that binding of the agonists and the antagonist differs in their points of interaction. The increase in the binding affinity observed may reflect an indirect effect caused by a conformational change of the receptor. These findings will help to improve the structural models of the human NPY receptors.
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| 4. |
- Holm, Lovisa, et al.
(författare)
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Changes in galanin and GalR1 gene expression in discrete brain regions after transient occlusion of the middle cerebral artery in female rats
- 2012
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Ingår i: Neuropeptides. - : Elsevier. - 0143-4179 .- 1532-2785. ; 46:1, s. 19-27
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Tidskriftsartikel (refereegranskat)abstract
- Injury to neurons results in upregulation of galanin in some central and peripheral systems, and it has been suggested that this neuropeptide may play a protective and trophic role, primarily mediated by galanin receptor 2 (GalR2). The objective of the present study was to investigate galanin, GalR1, GalR2 and GalR3 gene expression in the female rat brain seven days after a 60-min unilateral occlusion of the middle cerebral artery followed by reperfusion. Quantitative real-time PCR was employed in punch-biopsies from the locus coeruleus, somatosensory cortex and dorsal hippocampal formation including sham-operated rats as controls. Galanin gene expression showed a ~2.5-fold increase and GalR1 a ~1.5-fold increase in the locus coeruleus of the ischemic hemisphere compared to the control side. Furthermore, the GalR1 mRNA levels decreased by 35% in the cortex of the ischemic hemisphere. The present results indicate that a stroke-induced forebrain lesion upregulates synthesis of galanin and GalR1 in the locus coeruleus, a noradrenergic cell group projecting to many forebrain areas, including cortex and the hippocampal formation. These results support the notion that galanin may play a role in the response of the central nervous system to injury and have trophic eff ects.
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| 5. |
- Holm, Lovisa, et al.
(författare)
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Effects of intracerebroventricular galanin or a galanin receptor 2/3 agonist on the lesion induced by transient occlusion of the middle cerebral artery in female rats
- 2011
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Ingår i: Neuropeptides. - : Elsevier Science B.V., Amsterdam. - 0143-4179 .- 1532-2785. ; 45:1, s. 17-23
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Tidskriftsartikel (refereegranskat)abstract
- Several studies have shown that injury to the central and peripheral nervous system can increase expression of galanin, a 29 amino acid neuropeptide. Moreover, there is evidence that galanin, especially through its galanin receptor 2 (GalR2) receptor, plays a neuroprotective role in different injury models. However, direct studies of a possible neuroprotective effect of galanin in experimental stroke models are lacking. Galanin, a GalR2/3 agonist or artificial CSF was continuously infused intracerebroventricularly (i.c.v.) in naive female rats after a 60 min transient and focal occlusion of the middle cerebral artery. The animals were sacrificed, and the ischemic lesion was visualized using 2,3,5-triphenyltetrazolium hydrochloride (TTC) staining. The lesion was 98% larger after i.c.v, administration of the GalR2/3 agonist (2.4 nmol/day) seven days after occlusion compared to artificial CSF (p = 0.023). No statistically significant differences were found after seven days in the groups treated with galanin in three different concentrations (0.24, 2.4 and 24 nmol/day; p = 0.939, 0.715 and 0.977, respectively). There was no difference in the size of the ischemic lesions measured after three days in the galanin-treated group (2.4 nmol/d) compared to artificial CSF (p = 0.925). The present results show, surprisingly, that a GalR2/3 agonist doubled the size of the ischemic lesion. Whether this effect primarily reflects the properties of the current model, species, gender and/or the mode of galanin administration, e.g. causing desensitization, or whether galanin indeed lacks neuroprotective effect of its own, remains to be corroborated.
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| 6. |
- Lindahl, Andreas E, et al.
(författare)
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Plasma chromogranin A after severe burn trauma
- 2013
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Ingår i: Neuropeptides. - : Elsevier. - 0143-4179 .- 1532-2785. ; 47:3, s. 207-212
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Tidskriftsartikel (refereegranskat)abstract
- Background: Chromogranin A (CgA) in plasma (P-CgA), a neuroendocrine marker of sympathetic stress, has been shown to predict mortality in medical intensive care. We hypothesized that the magnitude of CgA release would reflect stress load, and thereby injury severity in burn intensive care patients. Methods: Fifty-one consecutive patients with a burn area exceeding 10% were included. P-CgA was measured twice daily for seven days after injury. The point value at 24 h, the mean and maximum values and the AUC at days 1-7, were tested as possible predictors. Injury severity in the form of organ dysfunction was measured as SOFA score at day 7. Results: P-CgA could be classified into two types with respect to variability over time. Patients with high variability had more deep injuries and were older than those with low variability. All measures of CgA correlated with SOFA score at day 7, but not with total burn size. Univariate regressions showed that age, burn size and three of four measures of P-CgA predicted organ dysfunction. Multiple regressions showed that age, burn size, and either P-CgA at 24 h, the mean value up to day 7, or the maximum value up to day 7, were independent predictors for organ dysfunction. Significant organ dysfunction was best predicted by age, burn area and the CgA point value at 24 h with an AUC value of 0.91 in a ROC-analysis. Conclusions: The extent of neuroendocrine activation assessed as P-CgA after a major burn injury is independently related to organ dysfunction.
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| 7. |
- Mikrouli, Elli, et al.
(författare)
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Increased numbers of orexin/hypocretin neurons in a genetic rat depression model.
- 2011
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Ingår i: Neuropeptides. - : Elsevier BV. - 1532-2785 .- 0143-4179. ; 45, s. 401-406
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Tidskriftsartikel (refereegranskat)abstract
- The Flinders Sensitive Line (FSL) rat is a genetic animal model of depression that displays characteristics similar to those of depressed patients including lower body weight, decreased appetite and reduced REM sleep latency. Hypothalamic neuropeptides such as orexin/hypocretin, melanin-concentrating hormone (MCH) and cocaine and amphetamine regulated transcript (CART), that are involved in the regulation of both energy metabolism and sleep, have recently been implicated also in depression. We therefore hypothesized that alterations in these neuropeptide systems may play a role in the development of the FSL phenotype with both depressive like behavior, metabolic abnormalities and sleep disturbances. In this study, we first confirmed that the FSL rats displayed increased immobility in the Porsolt forced swim test compared to their control strain, the Flinders Resistant Line (FRL), which is indicative of depressive-like behavior. We then examined the number of orexin-, MCH- and CART-immunopositive neurons in the hypothalamus using stereological analyses. We found that the total number of orexin-positive neurons was higher in the hypothalamus of female FSL rats compared to female FRL rats, whereas no changes in the MCH or CART populations could be detected between the strains. Chronic treatment with the selective serotonin reuptake inhibitor (SSRI) escitalopram reduced immobility only in the FRL rats where it also increased the number of MCH positive neurons compared to untreated rats. These findings support the view that orexin may be involved in depression and strengthen the notion that the "depressed" brain responds differently to pharmacological interventions than the normal brain.
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| 8. |
- Olesen, M. V., et al.
(författare)
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Y5 neuropeptide Y receptor overexpression in mice neither affects anxiety- and depression-like behaviours nor seizures but confers moderate hyperactivity
- 2012
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Ingår i: Neuropeptides. - : Elsevier BV. - 1532-2785 .- 0143-4179. ; 46:2, s. 71-79
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Tidskriftsartikel (refereegranskat)abstract
- Neuropeptide Y (NPY) has been implicated in anxiolytic- and antidepressant-like behaviour as well as seizure-suppressant effects in rodents. Although these effects appear to be predominantly mediated via other NPY receptors (Y1 and/or Y2), several studies have also indicated a role for Y5 receptors. Gene therapy using recombinant viral vectors to induce overexpression of NPY, Y1 or Y2 receptors in the hippocampus or amygdala has previously been shown to modulate emotional behaviour and seizures in rodents. The present study explored the potential effects of gene therapy with the Y5 receptor, by testing effects of recombinant adeno-associated viral vector (rAAV) encoding Y5 (rAAV-Y5) in anxiety- and depression-like behaviour as well as in kainate-induced seizures in adult mice. The rAAV-Y5 vector injected into the hippocampus and amygdala induced a pronounced and sustained increase in Y5 receptor mRNA expression and functional Y5 receptor binding, but no significant effects were found with regard to anxiety- and depression-like behaviours or seizure susceptibility. Instead, rAAV-mediated Y5 receptor transgene overexpression resulted in moderate hyperactivity in the open field test. These results do not support a potential role for single transgene overexpression of Y5 receptors for modulating anxiety-/depression-like behaviours or seizures in adult mice. Whether the induction of hyperactivity by rAAV-Y5 could be relevant for other conditions remains to be studied. (C) 2012 Elsevier Ltd. All rights reserved.
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| 9. |
- Oreland, Sadia, et al.
(författare)
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Short- and long-term consequences of different early environmental conditions on central immunoreactive oxytocin and arginine vasopressin levels in male rats
- 2010
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Ingår i: Neuropeptides. - : Elsevier BV. - 0143-4179 .- 1532-2785. ; 44:5, s. 391-398
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Tidskriftsartikel (refereegranskat)abstract
- Numerous studies have provided evidence for an important role for the neuropeptides oxytocin (OT) and arginine vasopressin (AVP) in establishment of social behaviour early in life, such as mother-pup interactions. However, there are few reports examining the consequences of early-life experiences on OT and AVP in male offspring. We have used the maternal separation (MS) model to study the effect of different early environmental conditions in rats. The purpose was to study OT and AVP in rats subjected to prolonged daily MS (360 min, MS360), short daily MS (15 min, MS15) and conventional animal facility rearing (AFR) during postnatal days 1-21. In addition, the influence of the presence or absence of littermates during MS, i.e. litter-wise (l) or individual (i) MS, was assessed. The immunoreactive (ir) peptide levels were measured in the hypothalamus, amygdala and pituitary gland of 3 and 10 weeks old male rats. Assessment in 3-week-old rats revealed that MS15 was associated with low ir OT levels in the hypothalamus and amygdala and high levels in the pituitary gland compared with the MS360 and AFR condition. In the amygdala, differences between groups were also detected in adulthood. MS studies commonly use either MS15 or AFR as a control for prolonged MS. The present results show differences in MS360 rats as compared to MS15 but not AFR rats. Consequently, comparisons between prolonged MS with either short periods of MS or AFR will generate divergent results, hence, making the outcome of MS difficult to compare between studies. Moreover, the different early environments had no effect on ir AVP levels. In conclusion, OT in the amygdala was most sensitive to MS. Besides both short- and long-term consequences, distinct effects were seen after litter and individual separation, respectively. We propose that environmentally induced alterations in OT transmission due to disrupted mother-pup interactions early in life may cause altered susceptibility to challenges later in life.
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| 10. |
- Samuelsson, Martin, et al.
(författare)
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Glutathione in the blood and cerebrospinal fluid: A study in healthy male volunteers
- 2011
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Ingår i: Neuropeptides. - : Elsevier. - 0143-4179 .- 1532-2785. ; 45:4, s. 287-292
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Tidskriftsartikel (refereegranskat)abstract
- Glutathione (GSH) is an important regulator of intracellular redox homeostasis. In the brain, glutathione is considered a major antioxidant, which is also found at high concentrations in the extracellular environment. Altered GSH balance in plasma, blood and cerebrospinal fluid (CSF) has been observed in several disorders suggesting that an impaired antioxidant function is part of the pathophysiology. The aim of the present study was to investigate a possible relationship between glutathione in plasma and CSF. Blood samples were collected from 26 healthy male volunteers at 8 a.m., noon, 4 p.m. and 8 p.m. At 8 a.m. the following morning, blood was drawn and three 6-ml fractions of CSF were collected by lumbar puncture. In CSF, a disrupted gradient was found showing the highest glutathione concentration in the second compared to the first and third fraction (P andlt; 0.002). Moreover, correlation and regression analyses between glutathione in plasma and CSF revealed an association between the third fraction CSF and plasma glutathione 8 p.m. the day before lumbar puncture. Thus, if carefully standardised due to the disrupted gradient in CSF, it might be possible to estimate glutathione levels in CSF by analysing plasma in healthy males.
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| 11. |
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| 13. |
- Vukojevic, Vladana, et al.
(författare)
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Fluorescence Imaging with Single-Molecule Sensitivity and Fluorescence Correlation Spectroscopy of Cell-Penetrating Neuropeptides
- 2011
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Ingår i: Neuropeptides. - Totowa, NJ : Humana Press. - 9781617793097 ; 789, s. 147-70
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Bokkapitel (refereegranskat)abstract
- Neuropeptide plasma membrane interactions in the absence of a corresponding specific receptor may result in neuropeptide translocation into the cell. Trans location across the plasma membrane may represent a previously unknown mechanism by which neuropeptides can signal information to the cell interior. We introduce here two complementary optical methods with single-molecule sensitivity, fluorescence imaging with avalanche photodiode detectors (APD imaging) and fluorescence correlation spectroscopy (FCS), and demonstrate how they may be applied for the analysis of neuropeptide ability to penetrate into live cells in real time. APD imaging enables us to visualize fluorescently labeled neuropeptide molecules at very low, physiologically relevant concentrations, whereas FCS enables us to characterize quantitatively their concentration and diffusion properties in different cellular compartments. Application of these methodologies for the analysis of the endogenous opioid peptide dynorphin A (Dyn A), a ligand for the kappa-opioid receptor (KOP), demonstrated that this neuropeptide may translocate across the plasma membrane of living cells and enter the cellular interior without binding to its cognate receptor.
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| 14. |
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