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Tamas Bartfai - One of the best experts on this subject based on the ideXlab platform.
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novel systemically active Galanin Receptor 2 ligands in depression like behavior
Journal of Neurochemistry, 2013Co-Authors: Johan Runesson, Indrek Saar, Jaak Järv, Kristin Webling, Jaanus Lahe, Kent Langel, Jussi Rytkonen, Ale Narvanen, Tamas BartfaiAbstract:Neuropeptide Galanin and its three G-protein coupled Receptors, Galanin Receptor type 1–Galanin Receptor type 3 (GalR1–GalR3), are involved in the regulation of numerous physiological and disease processes, and thus represent tremendous potential in neuroscience research and novel drug lead development. One of the areas where Galanin is involved is depression. Previous studies have suggested that activation of GalR2 leads to attenuation of depression-like behavior. Unfortunately, lack of in vivo usable subtype specific ligands hinders testing the role of Galanin in depression mechanisms. In this article, we utilize an approach of increasing in vivo usability of peptide-based ligands, acting upon CNS. Thus, we have synthesized a series of novel systemically active Galanin analogs, with modest preferential binding toward GalR2. We have shown that specific chemical modifications to the Galanin backbone increase brain levels upon i.v. injection of the peptides. Several of the new peptides, similar to a common clinically used antidepressant medication imipramine, exerted antidepressant-like effect in forced swim test, a mouse model of depression, at a surprisingly low dose range (< 0.5 mg/kg). We chose one of the peptides, J18, for more thorough study, and showed its efficacy also in another mouse depression model (tail suspension test), and demonstrated that its antidepressant-like effect upon i.v. administration can be blocked by i.c.v. Galanin Receptor antagonist M35. The effect of the J18 was also abolished in GalR2KO animals. All this suggests that systemically administered peptide analog J18 exerts its biological effect through activation of GalR2 in the brain. The novel Galanin analogs represent potential drug leads and a novel pharmaceutical intervention for depression. We utilize several chemical modifications to increase in vivo usability of peptide-based ligands, acting upon CNS. Accordingly, we introduce a series of novel systemically active Galanin analogues, with modest preferential binding towards GalR2, and demonstrate their ability to attenuate depression-like behavior via brain GalR2 in different mouse models of depression.
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L-Ala-substituted rat Galanin analogs distinguish between hypothalamic and jejunal Galanin Receptor subtypes.
The journal of peptide research : official journal of the American Peptide Society, 2009Co-Authors: Anders Juréus, Ülo Langel, Tamas BartfaiAbstract:In order to explore which amino acids or which blocks of amino acids in the 29 amino acid neuropeptide Galanin are important for recognition of the endogenous ligand by Galanin Receptor subtypes present in the jejunum and in the hypothalamus, respectively, we have carried out L-Ala substitutions of individual amino acids or of blocks of amino acids in the rat Galanin sequence and examined the binding of the obtained analogs to the rat hypothalamic and jejunal Galanin Receptor subtypes. This study reveals that the Galanin sequence YLLGPH9–14 is essential for recognition of Galanin by both the rat hypothalamic and jejunal Galanin Receptor subtypes. Substitution of the N-terminal amino acids, GWTL1–4, leads to total loss of affinity of Galanin for both hypothalamic and jejunal Galanin Receptors. The α-helical C-terminal amino acid (25–29) part of Galanin has no greater influence on the affinity of Galanin to the hypothalamic Galanin Receptor subtype. L-Ala substitution of the C-terminal amino acids of Galanin KHGLT25–29 shows, however, that this C-terminal motif is essential for the recognition by the jejunal Galanin Receptor subtype, whereas amino acids in the middle portion of Galanin NSAG5–8 are of importance for binding to the hypothalamic but not to the jejunal Receptor. [Ala5–8] Galanin thus has a more than 100-fold higher affinity to jejunal Receptor than to the hypothalamic Receptor, while [Ala25–29] Galanin has a more than 100-fold higher affinity for the hypothalamic than for jejunal Galanin Receptor subtypes. pH dependence of the Galanin binding to these Receptor subtypes is also different. © Munksgaard 1997.
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a novel systemically active selective Galanin Receptor type 3 ligand exhibits antidepressant like activity in preclinical tests
Neuroscience Letters, 2006Co-Authors: Alasdair M Barr, Julius Rebek, Jefferson W Kinney, Matthew N Hill, Shannon M Biros, Tamas BartfaiAbstract:The neuropeptide Galanin is widely expressed in limbic nuclei in the brain, and plays an important role in the regulation of homeostatic and affective behaviors, in part through its modulation of central monoamine pathways. Recent evidence suggests that Galanin and its Receptors may be involved in the efficacy of various modalities of antidepressant treatments. We have previously demonstrated that systemically active, non-peptide Galanin Receptor type-1/2 agonists exhibit antidepressant-like effects in the rat forced swim test. Here we evaluate a novel Galanin Receptor type-3 (GalR3) antagonist in preclinical tests of anxiety and depression. At multiple doses, the compound displayed no effects in the elevated plus maze in mice. By contrast, the compound decreased time spent immobile in the tail suspension test by mice. Additionally, the GalR3 drug decreased time spent immobile in the forced swim test in rats, similarly to the effects of desipramine, yet did not increase locomotor activity in an open field test. These combined data from two species indicate that GalR3 Receptor antagonists may exhibit antidepressant-like effects.
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A Galanin Receptor Subtype 1 Specific Agonist
International Journal of Peptide Research and Therapeutics, 2005Co-Authors: Linda Lundström, Tomas Hökfelt, Zsuzsanna Wiesenfeld-hallin, John K. Robinson, Ulla Sollenberg, Ariel Brewer, Poli Francois Kouya, Kang Zheng, Xia Sheng, Tamas BartfaiAbstract:The chimeric peptide M617, Galanin(1–13)-Gln^14-bradykinin(2–9)amide, is a novel Galanin Receptor ligand with increased subtype specificity for GalR1 and agonistic activity in cultured cells as well as in vivo . Displacement studies on cell membranes expressing hGalR1 or hGalR2 show the presence of a high affinity binding site for M617 on GalR1 ( K _i=0.23±.12 nM) while lower affinity was seen towards GalR2 ( K _i=5.71±1.28 nM) resulting in 25-fold specificity for GalR1. Activation of GalR1 upon stimulation with M617 is further confirmed by internalization of a GalR1-EGFP conjugate. Intracellular signaling studies show the ability of M617 to inhibit forskolin stimulated cAMP formation with 57% and to produce a 5-fold increase in inositol phosphate (IP) accumulation. Agonistic effects on signal transduction are shown on both Receptors studied after treatment with M617 in the presence of Galanin. In noradrenergic locus coeruleus neurons, M617 induces an outward current even in the presence of TTX plus Ca^2+, high Mg^2+, suggesting a postsynaptic effect. Intracerebroventricular (i.c.v.) administration of M617 dose-dependently stimulates food uptake in rats while, in contrast, M35 completely fails to affect the feeding behavior. Spinal cord flexor reflex is facilitated by intrathecal (i.t.) administration of M617 as well as Galanin with no significant change upon pre-treatment with M617. M617 dose dependently antagonizes the spinal cord hyperexcitablility induced by C-fiber conditioning stimulus and does neither enhance nor antagonize the effect of Galanin. These data demonstrate a novel Galanin Receptor ligand with subtype specificity for GalR1 and agonistic activity, both in vitro and in vivo .
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Galanin Receptor ligands.
Neuropeptides, 2005Co-Authors: Linda Lundström, Ülo Langel, Tamas BartfaiAbstract:The three Galanin Receptor subtypes (GalR1-3) belong to the G protein-coupled Receptor superfamily. The widespread distribution of Galanin and its Receptors in the CNS and PNS and the numerous physiological and pharmacological effects of Galanin (for review, cf. Vrontakis, 2002) render the three Galanin Receptors attractive drug targets. The industrial efforts, however, have not yet resulted in a wealth of Receptor subtype specific agonists or antagonists with high affinity and selectivity. The present paper summarizes the properties of the Galanin ligands used at the end of 2004 in the ca. 2000 publications and complements their pharmacological characterization with new data.
Ülo Langel - One of the best experts on this subject based on the ideXlab platform.
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Galanin Receptor ligands.
SpringerPlus, 2015Co-Authors: Ülo LangelAbstract:The effect of Galanin is mediated through three GPCR subtypes, GalR1-3. The limited number of specific ligands to the Galanin Receptor subtypes has hindered the understanding of the individual effects of each Receptor subtype. This review summarizes the current data of the importance of the Galanin Receptor subtypes and Receptor subtype specific agonists and antagonists and their involvement in different biological and pathological functions.
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Novel Galanin Receptor subtype specific ligand in depression like behavior.
Neurochemical research, 2012Co-Authors: Indrek Saar, Johan Runesson, Jaak Järv, Kaido Kurrikoff, Ülo LangelAbstract:Neuropeptide Galanin and its three Receptors, Galanin Receptor type 1–Galanin Receptor type 3, are known to be involved in the regulation of numerous psychological processes, including depression. Studies have suggested that stimulation of Galanin Receptor type 2 (GalR2) leads to attenuation of the depression-like behavior in animals. However, due to the lack of highly selective Galanin subtype specific ligands the involvement of different Receptors in depression-like behavior is yet not fully known. In the present study we introduce a novel GalR2 selective agonist and demonstrate its ability to produce actions consistent with theorized GalR2 functions and analogous to that of the anti-depressant, imipramine.
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Pharmacological stimulation of Galanin Receptor 1 but not Galanin Receptor 2 attenuates kainic acid-induced neuronal cell death in the rat hippocampus
2012Co-Authors: Johan Runesson, Indrek Saar, Jessica L. Groves-chapman, Kristin Karlsson, Rannar Sillard, Philip V. Holmes, Ülo LangelAbstract:We now celebrate that it is 30 years since Galanin was first isolated. During these three decades Galanin has been identified in numerous tissues and physiological processes, and in an abundant number of species. In the nervous system Galanin primarily displays a modulatory role. The Galaninergic system consists of a number of bioactive peptides with a highlyplastic expression pattern and three different Receptors, GalR1-GalR3. The lack of Receptor subtype selective ligands and antibodies have severely hampered the characterization of this system. Therefore, most of the knowledgehas been drawn from experiments with transgenic animals, which has givensome major conclusions, despite the risk of inducing compensatory effects inthese animal studies. Therefore, the production of subtype selective ligandsis of great importance to delineate the Galanin system and slowly experimental data from Receptor subtype selective ligand trials is emerging. This thesis aims at studying Galanin Receptor-ligand interactions and to increase and improve the utilized tools in the Galanin research field, especially the development of novel Galanin Receptor subtype selective ligands. Paper I demonstrates the potential to N-terminally extend Galanin analogues and the successful development of a GalR2 selective ligand. In addition, a cell line stably expressing GalR3 was developed to improve and simplify future evaluations of Receptor subtype selective Galanin ligands. Paper II extends the number of GalR2 selective ligands and shows that i.c.v. administration of Galanin Receptor ligands stimulates food intake through GalR1. Paper III demonstrates the successful development of a mixed GalR1/GalR2 agonist without any detectable interaction with GalR3. Subsequently, this peptide was used to delineate which Receptor subtype mediatesthe neuroprotective effects of Galanin in the CA3 region of hippocampus. Furthermore, a robust protocol for detection of Receptor activation was developed to ease the detection of the relative potency of novel ligands at the three Galanin Receptor subtypes. Paper IV describes the finding of several essential amino acids for ligand interaction in GalR3 through the performance of an L-alanine mutagenesis study. A constructed in silico homology model of GalR3 confirmed and extended these findings. In conclusion, this thesis provides a novel design strategy for Galanin Receptor ligands and increases the understanding of ligand interactions with the GalR3. Furthermore, published ligands together with new Galanin analogues have proven to be highly Receptor specific, thus implicating that a future delineation of the Galaninergic system as a therapeutic target is possible.
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Novel Galanin Receptor subtype specific ligands in feeding regulation
Neurochemistry international, 2011Co-Authors: Indrek Saar, Johan Runesson, Jaak Järv, Ilan Mcnamara, John K. Robinson, Ülo LangelAbstract:Galanin a 29/30-residue neuropeptide has been implicated in several functions in the central nervous system, including the regulation of food consumption. Galanin and its analogues administered intraventricularly or into the hypothalamic region of brain have been shown to reliably and robustly stimulate the consumption of food in sated rodents. Three Galanin Receptor subtypes have been isolated, all present in the hypothalamus, but little is known about their specific role in mediating this acute feeding response. Presently, we introduce several novel GalR2 selective agonists and then compare the most selective of these novel GalR2 subtype selective agonists to known GalR1 selective agonist M617 for their ability to stimulate acute consumption of several foods shown to be stimulated by central administration of Galanin. GalR1 selective agonist M617 markedly stimulated acute consumption of high-fat milk, but neither GalR2 selective agonist affected either high-fat milk or cookie mash intake. The present results are consistent with the involvement of GalR1 in mediating the acute feeding consumption by Galanin and suggest an approach applicable to exploring Galanin Receptor specificity in normal and abnormal behavior and physiology.
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Galanin Receptor agonists protect against kainic acid-induced excitotoxicity in the rat hippocampus
2011Co-Authors: Jessica L. Groves-chapman, Ülo Langel, Johan Runesson, Philip V. HolmesAbstract:Galanin is a peptide neurotransmitter with neuroprotective actions. Administration of Galanin or selective Galanin Receptor agonists to rats reduces convulsant-induced seizure behavior. However, it ...
José Ángel Narváez - One of the best experts on this subject based on the ideXlab platform.
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Galanin Receptor neuropeptide y Receptor interactions in the central nervous system
Current Protein & Peptide Science, 2014Co-Authors: Zaida Diazcabiale, Concepción Parrado, Manuel Narváez, Carmelo Millón, Araceli Puigcerver, Rafael Coveñas, Kjell Fuxe, Antonio Floresburgess, José Ángel NarváezAbstract:The presence of Galanin and Neuropeptide Y and/or their Receptors in several areas of the brain involved in memory, mood, cardiovascular control and food intake indicates that Galanin, and Neuropeptide Y could equilibrate the physiological actions of each other. There is evidence for the existence of interactions between Galanin Receptor and Neuropeptide Y Receptor in the nucleus of the solitarii tract (NTS), hypothalamus and dorsal raphe nucleus probably taking place with the formation of heteromers between Galanin Receptor and Neuropeptide Y Y1 Receptor. The Galanin fragment (Gal 1-15) preferring Receptors may instead be formed by the GalR1-GalR2 heteromer which in the NTS may interact with Neuropeptide Y Y2 Receptors. These Receptor heteromers may be one key molecular mechanism for Galanin and its N-terminal fragment (Galanin 1-15) to modulate the function of different types of glia-neuronal networks in the CNS, especially the emotional, metabolic and cardiovascular networks.
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Galanin Receptor/Neuropeptide Y Receptor Interactions in the Central Nervous System
Current protein & peptide science, 2014Co-Authors: Zaida Díaz-cabiale, Antonio Flores-burgess, Concepción Parrado, Manuel Narváez, Carmelo Millón, Araceli Puigcerver, Rafael Coveñas, Kjell Fuxe, José Ángel NarváezAbstract:The presence of Galanin and Neuropeptide Y and/or their Receptors in several areas of the brain involved in memory, mood, cardiovascular control and food intake indicates that Galanin, and Neuropeptide Y could equilibrate the physiological actions of each other. There is evidence for the existence of interactions between Galanin Receptor and Neuropeptide Y Receptor in the nucleus of the solitarii tract (NTS), hypothalamus and dorsal raphe nucleus probably taking place with the formation of heteromers between Galanin Receptor and Neuropeptide Y Y1 Receptor. The Galanin fragment (Gal 1-15) preferring Receptors may instead be formed by the GalR1-GalR2 heteromer which in the NTS may interact with Neuropeptide Y Y2 Receptors. These Receptor heteromers may be one key molecular mechanism for Galanin and its N-terminal fragment (Galanin 1-15) to modulate the function of different types of glia-neuronal networks in the CNS, especially the emotional, metabolic and cardiovascular networks.
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Galanin Receptor 1 modulates 5 hydroxtryptamine 1a signaling via heterodimerization
Biochemical and Biophysical Research Communications, 2010Co-Authors: Dasiel O Borrotoescuela, Concepción Parrado, Manuel Narváez, José Ángel Narváez, Zaida Diazcabiale, Daniel Marcellino, Alexander O Tarakanov, Luigi F Agnati, Kjell FuxeAbstract:Previous biochemical, cardiovascular and behavioral work has given evidence for the existence of antagonistic Galanin Receptor-5-HT1A Receptor interactions in the brain. In this study we investigated the existence of GalR1-5-HT1A Receptor heteromers and their functional characteristics. In mammalian cells transfected with GFP2-tagged 5-HT1A Receptor and YFP-tagged GalR1 Receptor, a proximity-based fluorescence resonance energy transfer technique was used and it has been demonstrated that GalR1-5-HT1A Receptors heteromerize. Furthermore, signaling by either the mitogen-activated protein kinase (MAPK) or adenylyl cyclase (AC) pathways by these heteromers indicates a trans-inhibition phenomenon through their interacting interface via allosteric mechanisms that block the development of an excessive activation of G(i/o) and an exaggerated inhibition of AC or stimulation of MAPK activity. The presence of these heteromers in the discrete brain regions is postulated based on the existence of GalR-5-HT1A Receptor-Receptor interactions previously described in the brain and gives rise to explore possible novel therapeutic strategies for treatment of depression by targeting the GalR1-5-HT1A heteromers.
Kjell Fuxe - One of the best experts on this subject based on the ideXlab platform.
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Galanin Receptor neuropeptide y Receptor interactions in the central nervous system
Current Protein & Peptide Science, 2014Co-Authors: Zaida Diazcabiale, Concepción Parrado, Manuel Narváez, Carmelo Millón, Araceli Puigcerver, Rafael Coveñas, Kjell Fuxe, Antonio Floresburgess, José Ángel NarváezAbstract:The presence of Galanin and Neuropeptide Y and/or their Receptors in several areas of the brain involved in memory, mood, cardiovascular control and food intake indicates that Galanin, and Neuropeptide Y could equilibrate the physiological actions of each other. There is evidence for the existence of interactions between Galanin Receptor and Neuropeptide Y Receptor in the nucleus of the solitarii tract (NTS), hypothalamus and dorsal raphe nucleus probably taking place with the formation of heteromers between Galanin Receptor and Neuropeptide Y Y1 Receptor. The Galanin fragment (Gal 1-15) preferring Receptors may instead be formed by the GalR1-GalR2 heteromer which in the NTS may interact with Neuropeptide Y Y2 Receptors. These Receptor heteromers may be one key molecular mechanism for Galanin and its N-terminal fragment (Galanin 1-15) to modulate the function of different types of glia-neuronal networks in the CNS, especially the emotional, metabolic and cardiovascular networks.
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Galanin Receptor/Neuropeptide Y Receptor Interactions in the Central Nervous System
Current protein & peptide science, 2014Co-Authors: Zaida Díaz-cabiale, Antonio Flores-burgess, Concepción Parrado, Manuel Narváez, Carmelo Millón, Araceli Puigcerver, Rafael Coveñas, Kjell Fuxe, José Ángel NarváezAbstract:The presence of Galanin and Neuropeptide Y and/or their Receptors in several areas of the brain involved in memory, mood, cardiovascular control and food intake indicates that Galanin, and Neuropeptide Y could equilibrate the physiological actions of each other. There is evidence for the existence of interactions between Galanin Receptor and Neuropeptide Y Receptor in the nucleus of the solitarii tract (NTS), hypothalamus and dorsal raphe nucleus probably taking place with the formation of heteromers between Galanin Receptor and Neuropeptide Y Y1 Receptor. The Galanin fragment (Gal 1-15) preferring Receptors may instead be formed by the GalR1-GalR2 heteromer which in the NTS may interact with Neuropeptide Y Y2 Receptors. These Receptor heteromers may be one key molecular mechanism for Galanin and its N-terminal fragment (Galanin 1-15) to modulate the function of different types of glia-neuronal networks in the CNS, especially the emotional, metabolic and cardiovascular networks.
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Galanin Receptor 1 modulates 5 hydroxtryptamine 1a signaling via heterodimerization
Biochemical and Biophysical Research Communications, 2010Co-Authors: Dasiel O Borrotoescuela, Concepción Parrado, Manuel Narváez, José Ángel Narváez, Zaida Diazcabiale, Daniel Marcellino, Alexander O Tarakanov, Luigi F Agnati, Kjell FuxeAbstract:Previous biochemical, cardiovascular and behavioral work has given evidence for the existence of antagonistic Galanin Receptor-5-HT1A Receptor interactions in the brain. In this study we investigated the existence of GalR1-5-HT1A Receptor heteromers and their functional characteristics. In mammalian cells transfected with GFP2-tagged 5-HT1A Receptor and YFP-tagged GalR1 Receptor, a proximity-based fluorescence resonance energy transfer technique was used and it has been demonstrated that GalR1-5-HT1A Receptors heteromerize. Furthermore, signaling by either the mitogen-activated protein kinase (MAPK) or adenylyl cyclase (AC) pathways by these heteromers indicates a trans-inhibition phenomenon through their interacting interface via allosteric mechanisms that block the development of an excessive activation of G(i/o) and an exaggerated inhibition of AC or stimulation of MAPK activity. The presence of these heteromers in the discrete brain regions is postulated based on the existence of GalR-5-HT1A Receptor-Receptor interactions previously described in the brain and gives rise to explore possible novel therapeutic strategies for treatment of depression by targeting the GalR1-5-HT1A heteromers.
Zsuzsanna Wiesenfeld-hallin - One of the best experts on this subject based on the ideXlab platform.
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A Galanin Receptor Subtype 1 Specific Agonist
International Journal of Peptide Research and Therapeutics, 2005Co-Authors: Linda Lundström, Tomas Hökfelt, Zsuzsanna Wiesenfeld-hallin, John K. Robinson, Ulla Sollenberg, Ariel Brewer, Poli Francois Kouya, Kang Zheng, Xia Sheng, Tamas BartfaiAbstract:The chimeric peptide M617, Galanin(1–13)-Gln^14-bradykinin(2–9)amide, is a novel Galanin Receptor ligand with increased subtype specificity for GalR1 and agonistic activity in cultured cells as well as in vivo . Displacement studies on cell membranes expressing hGalR1 or hGalR2 show the presence of a high affinity binding site for M617 on GalR1 ( K _i=0.23±.12 nM) while lower affinity was seen towards GalR2 ( K _i=5.71±1.28 nM) resulting in 25-fold specificity for GalR1. Activation of GalR1 upon stimulation with M617 is further confirmed by internalization of a GalR1-EGFP conjugate. Intracellular signaling studies show the ability of M617 to inhibit forskolin stimulated cAMP formation with 57% and to produce a 5-fold increase in inositol phosphate (IP) accumulation. Agonistic effects on signal transduction are shown on both Receptors studied after treatment with M617 in the presence of Galanin. In noradrenergic locus coeruleus neurons, M617 induces an outward current even in the presence of TTX plus Ca^2+, high Mg^2+, suggesting a postsynaptic effect. Intracerebroventricular (i.c.v.) administration of M617 dose-dependently stimulates food uptake in rats while, in contrast, M35 completely fails to affect the feeding behavior. Spinal cord flexor reflex is facilitated by intrathecal (i.t.) administration of M617 as well as Galanin with no significant change upon pre-treatment with M617. M617 dose dependently antagonizes the spinal cord hyperexcitablility induced by C-fiber conditioning stimulus and does neither enhance nor antagonize the effect of Galanin. These data demonstrate a novel Galanin Receptor ligand with subtype specificity for GalR1 and agonistic activity, both in vitro and in vivo .
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Systemic galnon, a low-molecular weight Galanin Receptor agonist, reduces heat hyperalgesia in rats with nerve injury.
European journal of pharmacology, 2003Co-Authors: Jingxia Hao, Ülo Langel, Zsuzsanna Wiesenfeld-hallin, Linda Lundström, Tamas BartfaiAbstract:We have examined the effect of systemically administered galnon, a novel low-molecular weight agonist of Galanin Receptors, on neuropathic pain-like behaviors in rats after photochemically induced partial nerve injury. Galnon is a Galanin Receptor ligand with moderate affinity to spinal cord membranes (K(D) of 6+/-0.6 microM). While intraperitoneally applied galnon produced no significant effect on mechanical or cold hypersensitivity, it dose-dependently prolonged heat withdrawal latency in nerve-injured rats. The effect of galnon was more potent on the injured side which has significantly shorter latency than the contralateral side. The anti-hyperalgesic effect of galanon was prevented by intrathecal M35, a Galanin Receptor antagonist. No side effects, such as sedation or motor impairment, were seen following systemic galnon treatment at the doses used. It is concluded that systemic galnon alleviated heat-hyperalgesic response in rats with partial sciatic nerve injury. This effect was likely to be mediated by activation of spinal Galanin Receptors.
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Intrathecal administration of PNA targeting Galanin Receptor reduces Galanin-mediated inhibitory effect in the rat spinal cord.
Neuroreport, 2001Co-Authors: Khadijeh Rezaei, Tomas Hökfelt, Tiit Land, Ursel Soomets, Zsuzsanna Wiesenfeld-hallin, Tiejun Shi, Tamas BartfaiAbstract:Peptide nucleic acids (PNA) are nucleic acid analogues containing neutral amide backbone, forming stable and tight complexes with complementary DNA/RNA. However, it is unclear whether unmodified PNA can efficiently penetrate neuronal tissue in order to act as antisense reagent. Here we show that intrathecal (i.t.) injection of an unmodified antisense PNA complementary to the rat Galanin Receptor type I (GaIRI) mRNA is able to block the inhibitory effect of i.t. administered Galanin on spinal nociceptive transmission. Autoradiographic ligand binding studies using [ 125 I]Galanin show that the unmodified PNA is able to reduce the density of Galanin binding sites in the dorsal horn. Thus, unmodified PNA applied i.t. appears to function as an effective antisense reagent in rat spinal cord in vivo.
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Cell penetrating PNA constructs regulate Galanin Receptor levels and modify pain transmission in vivo.
Nature biotechnology, 1998Co-Authors: Margus Pooga, Külliki Saar, Ursel Soomets, Khadijeh Rezaei, Ulrika Kahl, Jingxia Hao, Mattias Hällbrink, Andres Valkna, Zsuzsanna Wiesenfeld-hallinAbstract:Peptide nucleic acids (PNAs) form stable and tight complexes with complementary DNA and/or RNA and would be promising antisense reagents if their cellular delivery could be improved. We show that a 21-mer PNA, complementary to the human Galanin Receptor type 1 mRNA, coupled to the cellular transporter peptides, transportan or pAntennapedia(43–58), is efficiently taken up into Bowes cells where they block the expression of Galanin Receptors. In rat, the intrathecal administration of the peptide-PNA construct results in a decrease in Galanin binding in the dorsal horn. The decrease in binding results in the inability of Galanin to inhibit the C fibers stimulation-induced facilitation of the rat flexor reflex, demonstrating that peptide-PNA constructs act in vivo to suppress expression of functional Galanin Receptors.
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New high affinity peptide antagonists to the spinal Galanin Receptor
British journal of pharmacology, 1995Co-Authors: Zsuzsanna Wiesenfeld-hallin, Ülo Langel, Katarina Bedecs, Tamas BartfaiAbstract:1. The role of endogenous Galanin in somatosensory processing has been studied with Galanin Receptor antagonists. The new Galanin Receptor ligands C7, M32, M38 and M40 bind with high affinity (Kd in nanomolar range) to spinal cord Galanin Receptors and possess oxidative stability as compared to earlier generations of peptide ligands. These peptides have been examined in the spinal flexor reflex model where exogenous Galanin exhibited biphasic excitatory and inhibitory effects. 2. Intrathecal administration of C7 [Galanin(1-13)-spantide] and M32 [Galanin (1-13)-neuropeptide Y(25-36) amide] blocked facilitation of the nociceptive flexor reflex induced by 30 pmol intrathecal Galanin in decerebrate, spinalized rats in a dose-dependent manner, thus behaving as antagonists of the Galanin Receptor. In contrast, M38[Galanin(1-13)-(Ala-Leu)3-Ala amide] and M40 [Galanin(1-13)-Pro-Pro-(Ala-Leu)2-Ala amide], exhibited only weak antagonism at high doses in this model. Moreover, lower doses of M40 potentiated Galanin-induced reflex facilitation. C7 was neurotoxic at high doses in the rat spinal cord. 3. M32 and C7 were potent antagonists of Galanin Receptors in rat spinal cord, in correlation with their in vitro binding characteristics. In contrast, M38 and M40, despite their high in vitro affinity, exhibited only very weak antagonism. Moreover, M40 may also behave as a partial agonist. 4. Previous studies have shown that the Galanin Receptor may be heterogeneous. The discrepancy between in vitro binding and in vivo antagonistic potency of M38 and M40 may also suggest the presence of different Galanin Receptor subtypes within the rat spinal cord. However, other explanations for the discrepancy, such as differences in metabolic stability, diffusion rates and penetration to the site of action are also possible.
