Galanin, a neuropeptide co-released from noradrenergic and serotonergic projection neurons to the dentate gyrus, has recently emerged as an important mediator for signaling neuronal activity to the subgranular neurogenic stem cell niche supporting adult hippocampal neurogenesis. Galanin and its receptors appear to play key roles in depression-like behavior, and effects on hippocampal neurogenesis are relevant to pharmacological strategies for treating depression, which in part appear to rely on restoring altered neurogenesis. We previously demonstrated that the Ga1R2/3 receptor agonist Gal 2-11 is proliferative and proneurogenic for postnatal hippocampal progenitor cells; however, the specific receptor mediation remained to be identified.With the recent availability of M1145 (a specific Ga1R2 agonist), and SNAP 37889 (Ga1R3 specific antagonist), we extend our previous studies and show that while M1145 has no proliferative effect, the co-treatment of postnatal rat hippocampal progenitors with Gal 2-11 and SNAP 37889 completely abolished the Gal 2-11 proliferative effects. Taken together, these results clearly demonstrate that GalR3 and not GalR2 is the specific receptor subtype that mediates the proliferative effects of galanin on hippocampal progenitor cells. These results implicate GALR3 in the mediation of galanin neurogenic effects and, potentially, its neurogenic anti-depressant effects.

It is over 30years since the regulatory peptide galanin was discovered by Professor Mutt and co-workers. Galanin exerts its effects by binding to three galanin G-protein coupled receptors, namely GAL1R, GAL2R and GAL3R. Each galanin receptor has a different distribution in the central nervous system and the peripheral nervous system as well as distinctive signaling pathways, which implicates that the receptors are involved in different biological- and pathological effects. The delineation of the galaninergic system is however difficult due to a lack of stable, specific galanin receptor ligands. Herein, a new short GAL2R specific ligand, Ala5-galanin (2-11), is presented. The galanin (2-11) modified analogue Ala5-galanin (2-11) was tested in 125I-galanin competitive binding studies for the three galanin receptors and the G-protein coupled receptor signaling properties was tested by the ability to influence second-messenger molecules like inositol phosphate and cyclic adenosine monophosphate. In addition, two different label-free real-time assays, namely EnSpire® based on an optical biosensor and xCELLigence® based on an electric biosensor, were used for evaluating the signaling properties using cell lines with different levels of receptor expression. Ala5-galanin (2-11) was subsequently found to be a full agonist for GAL2R with more than 375-fold preference for GAL2R compared to both GAL1R and GAL3R. The single amino acid substitution of serine to alanine at position 5 in the short ligand galanin (2-11) resulted in a ligand subsequently unable to bind neither GAL3R nor GAL1R, even at concentrations as high as 0.1mM.

The neuropeptide galanin is widely distributed in the central and peripheral nervous systems and part of a bigger family of bioactive peptides. Galanin exerts its biological activity through three G-protein coupled receptor subtypes, GAL1-3R. Throughout the last 20years, data has accumulated that galanin can have a neuroprotective effect presumably mediated through the activation of GAL1R and GAL2R. In order to test the pharmaceutical potential of galanin receptor subtype selective ligands to inhibit excitotoxic cell death, the GAL1R selective ligand M617 and the GAL2R selective ligand M1145 were compared to the novel GAL1/2R ligand M1154, in their ability to reduce the excitotoxic effects of intracerebroventricular injected kainate acid in rats. The peptide ligands were evaluated in vitro for their binding preference in a competitive (125)I-galanin receptor subtype binding assay, and G-protein signaling was evaluated using both classical signaling and a label-free real-time technique. Even though there was no significant difference in the time course or severity of the kainic acid induced epileptic behavior in vivo, administration of either M617 or M1154 before kainic acid administration significantly attenuated the neuronal cell death in the hippocampus. Our results indicate the potential therapeutic value of agonists selective for GAL1R in the prevention of neuronal cell death.

Our previous studies testified the beneficial effect of central galanin on insulin sensitivity of type 2 diabetic rats. The aim of the study was further to investigate whether central M617, a galanin receptor 1 agonist, can benefit insulin sensitivity. The effects of intracerebroventricular administration of M617 on insulin sensitivity and insulin signaling were evaluated in adipose tissues of type 2 diabetic rats. The results showed that central injection of M617 significantly increased plasma adiponectin contents, glucose infusion rates in hyperinsulinemic-euglycemic clamp tests, GLUT4 mRNA expression levels, GLUT4 contents in plasma membranes, and total cell membranes of the adipose cells but reduced the plasma C-reactive protein concentration in nondiabetic and diabetic rats. The ratios of GLUT4 contents were higher in plasma membranes to total cell membranes in both nondiabetic and diabetic M617 groups than each control. In addition, the central administration of M617 enhanced the ratios of pAkt/Akt and pAS160/AS160, but not phosphorylative cAMP response element-binding protein (pCREB)/CREB in the adipose cells of nondiabetic and diabetic rats. These results suggest that excitation of central galanin receptor 1 facilitates insulin sensitivity via activation of the Akt/AS160 signaling pathway in the fat cells of type 2 diabetic rats.

It is over 30 years since the regulatory peptide galanin was discovered by Professor Mutt and co-workers. Galanin exerts its effects by binding to three galanin G-protein coupled receptors, namely GAL(1)R, GAL(2)R and GAL(3)R. Each galanin receptor has a different distribution in the central nervous system and the peripheral nervous system as well as distinctive signaling pathways, which implicates that the receptors are involved in different biological and pathological effects. The delineation of the galaninergic system is however difficult due to a lack of stable, specific galanin receptor ligands. Herein, a new short GAL(2)R specific ligand, Alas-galanin (2-11), is presented. The galanin (2-11) modified analogue Alas-galanin (2-11) was tested in I-125-galanin competitive binding studies for the three galanin receptors and the G-protein coupled receptor signaling properties was tested by the ability to influence second-messenger molecules like inositol phosphate and cyclic adenosine monophosphate. In addition, two different label-free real-time assays, namely EnSpire (R) based on an optical biosensor and xCELLigence (R) based on an electric biosensor, were used for evaluating the signaling properties using cell lines with different levels of receptor expression. Alas-galanin (2-11) was subsequently found to be a full agonist for GAL(2)R with more than 375-fold preference for GAL(2)R compared to both GAL(1)R and GAL(3)R. The single amino acid substitution of serine to alanine at position 5 in the short ligand galanin (2-11) resulted in a ligand subsequently unable to bind neither GAL(3)R nor GAL(1)R, even at concentrations as high as 0.1 mM. (C) 2016 The Authors. Published by Elsevier Ltd.

Galanin is a 29/30-amino acid long neuropeptide that has been implicated in many physiological and behavioral functions. Previous research has shown that i.c.v. administration of galanin strongly stimulates food intake in sated rats when food is freely available, but fails to stimulate this consumption when an operant response requirement is present. Using fixed ratio (FR) schedules, we sought to further clarify galanin's role in motivated behavior by administering galanin i.c.v. to rats working on fixed ratio schedules requiring either a low work condition (FR1) or higher work conditions (FR>1) to obtain a 0.2% saccharin reward. Rats in the FR>1 group were assigned to either an FR3, FR5 or FR7 schedule of reinforcement. The rate of reinforcement decreased for only the FR>1 group as compared to saline controls. Furthermore, injections of GalR1 receptor agonist M617 led to a similar, marginally significant decrease in the number of reinforcers received in the FR>1 condition, but a decrease was not seen after injections of GalR2 receptor agonist M1153. Taken together, these results show that galanin may be playing a role in decreasing motivation at times of high appetitive behavior, and that this effect is likely mediated by the GalR1 receptor.

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.

The distribution and (patho-)physiological role of neuropeptides in the adult and aging brain have been extensively studied. Galanin is an inhibitory neuropeptide that can coexist with γ-aminobutyric acid (GABA) in the adult forebrain. However, galanin's expression sites, mode of signaling, impact on neuronal morphology, and colocalization with amino acid neurotransmitters during brain development are less well understood. Here, we show that galaninergic innervation of cholinergic projection neurons, which preferentially express galanin receptor 2 (GalR2) in the neonatal mouse basal forebrain, develops by birth. Nerve growth factor (NGF), known to modulate cholinergic morphogenesis, increases GalR2 expression. GalR2 antagonism (M871) in neonates reduces the in vivo expression and axonal targeting of the vesicular acetylcholine transporter (VAChT), indispensable for cholinergic neurotransmission. During cholinergic neuritogenesis in vitro, GalR2 can recruit Rho-family GTPases to induce the extension of a VAChT-containing primary neurite, the prospective axon. In doing so, GalR2 signaling dose-dependently modulates directional filopodial growth and antagonizes NGF-induced growth cone differentiation. Galanin accumulates in GABA-containing nerve terminals in the neonatal basal forebrain, suggesting its contribution to activity-driven cholinergic development during the perinatal period. Overall, our data define the cellular specificity and molecular complexity of galanin action in the developing basal forebrain.

Problemstallning: Cementproduktionen i varlden star idag for 5% av varldens totala utslapp av koldioxid. Hojda miljokrav de senaste decennierna har gjort detta till en belastning for cement och betongindustrin. Situationen har hanterats framst genom att ta fram nya cement dar den hallfasthetsskapande Portlandklinkern delvis ersatts med andra material som genererar mindre koldioxidutslapp. Ett annat grepp for att reducera koldioxidutslappen ar att minska mangden anvant material och bygga for ett langre perspektiv. Att bygga slankt och att dimensionera for lang livslangd blir da viktigt. Nar man med stalarmering bygger slankt i betong blir armeringens tackskikt ofta styrande for hur tunt man kan bygga. Tackskiktets uppgift ar att over den bestamda livslangden skydda armeringsjarnen fran korrosionsangrepp. For betongplattor i exempelvis sandwichvaggar innebar detta att ytterplattans tjocklek blir 70 mm, ofta mer an vad som kravs med hansyn till barformagan vid bojbelastning. Ett satt att ga runt detta ar att armera med icke korroderande armeringsmaterial som galvaniserat stal, basalt och polypropylen, de tre ingaende materialen i denna studie. Studien behandlar fiberarmering tillsatt i den farska betongen. Fibrerna sprider sig i blandningen och forbattrar betongens egenskaper vid dragbelastning. Hur stor effekt fibrerna far beror pa hur manga fibrer som skar en uppkommen spricka. Antalet fibrer tvars en uppkommen spricka beror i forsta hand pa fiberdoseringen men aven pa konstruktionsdelens dimensioner. En skiva med ett tunt tvarsnitt tvingar fibrerna att orientera sig i skivans plan. Vid bojbelastning uppstar dragande krafter och sprickor tvars skivans plan. Ligger fibrerna tvars sprickorna innebar detta att fler fibrer skar den uppkomna sprickan, vilket ger en battre effekt av den aktuella fiberdoseringen. Dagens standardiserade testmetoder for att utvardera fiberarmerad betong vid bojbelastning foreskriver storre tvarsnittshojder an de 30‐45 mm som med hansyn till produktionstekniska parametrar anses intressanta for olika typer av skivprodukter. For att utvardera dessa tvarsnittshojder med inverkan av fiberorientering kravs att man testar just de aktuella tvarsnittshojderna. Syfte: Syftet med denna studie var att ta fram underlag for att anvanda fiberarmering i produktionen av prefabricerade betongplattor med tvarsnittshojder kring 30‐45 mm. Metod: En teoristudie genomfordes for att erhalla kunskap om fiberarmerad betong och dess egenskaper i saval farskt som hardnat tillstand. Dimensionering genom provning enligt den gallande byggnormen SS‐EN 1990 anvandes for att bestamma karakteristisk barformaga vid bojbelastning for fiberarmerade balkar med tvarsnittshojderna 30 och 45 mm. Barformagan bestamdes med trepunkts bojtester. Mojligheten att placera ingjutna byglar i betongplattor med de aktuella tvarsnittshojderna studerades aven genom att genomfora utdragstester. Bojbalkar och utdragsprover tillverkades i fyra gjutningar, en oarmerad, en stalfiberarmerad, en basaltfiberarmerad och en polypropylenfiberarmerad. Resultaten fran testerna analyserades for att utreda fiberorienteringens effekt pa barformagan samt framtida mojliga anvandningsomraden. Slutsatser: Studien visade att anvandning av fiberarmerad betong ger mojlighet att tillverka betongplattor med tvarsnittshojder omkring 30‐45 mm med hansyn till bojbelastning. Ett underlag for vidare utveckling av fiberdoseringar och betongsammansattningar for specifika anvandningsomraden har erhallits. Vid utdrag av byglar ingjutna i betongplattor med tvarsnittshojderna 30 och 45 mm erholls bojbrott i betongprovet. Ytterligare arbete kravs for att utvardera anvandandet av ingjutningsgods i tunna betongplattor. Dimensionering genom provning har visat sig anvandbart vid utvardering av de genomforda testerna. Omrakningsfaktorn kraver vidare arbete. En positiv effekt av fiberorienteringen kunde konstateras pa sprickspanningen for tvarsnittshojden 30 mm.

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 (<0.5mg/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 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 num ...

The family of GPCR’s has for long served as the most common pharmaceutical drug target. Even so, some receptors have failed to show potent interactions when exposed to big screenings libraries in t ...

The neuropeptide galanin was first discovered 30 years ago. Today, the galanin family consists of galanin, galanin-like peptide (GALP), galanin-message associated peptide (GMAP), and alarin and this family has been shown to be involved in a wide variety of biological and pathological functions. The effect 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 aims to summarize 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.

The neuropeptide galanin family currently consists of four members, namely galanin, galanin-message-associated peptide (GMAP), galanin-like peptide (GALP) and alarin. Galanin has been shown to influence several physiological processes including cognition, affective behavior, nerve injury, Alzheimer’s disease, neuroregeneration, seizures, feeding, and hormone release. The co-localization with other neuromodulators and the distinct up-regulation during and after pathological disturbances has drawn attention to this neuropeptide family. The regionally specific expression of the galanin receptors (GalR1-3) suggests different physiological roles, a feature which mostly remains unexplored due to the lack of stable, selective and potent ligands acting on the galanin receptor subtypes.The introduction of galanin(2-11) as a GalR2 selective ligand was an important advance in the galanin field. Unfortunately, later publications described that galanin(2-11) also binds with similar affinity to GalR3, a critical limitation when delineating the interplay between galanin receptor subtypes. Even so, galanin(2-11) has been given extensive attention and been used in numerous study as a non-GalR1 ligand. We now introduce an analogue of galanin(2-11) that combines the GalR2 selective binding, comparable with the published M1145 with the small size of galanin(2-11). Utilizing this true GalR2 selective ligand will help to define the role GalR2 in general and especially for already published studies that has been exploit galanin(2-11).

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.

The family of GPCR’s has for long served as the most common pharmaceutical drug target. Even so, some receptors have failed to show any interactions when exposed to big screenings libraries in the past and consequently they also lack potent small molecules acting as ligands on these different receptors. Three of these receptors are the so called galanin receptors (GalR).Galanin is a neuroendocrine peptide that is widely distributed in both the central and peripheral nervous systems as well as in the endocrine system. The galanin peptide family currently consists of four members, namely galanin, galanin-message-associated peptide (GMAP), galanin-like peptide (GALP) and alarin. Galanin has been shown to influence several physiological processes including cognition, affective behavior, nerve injury, Alzheimer’s disease, neuroregeneration, seizures, feeding, and hormone release. The co-localization with other neuromodulators and the distinct up-regulation during and after pathological disturbances has drawn attention to this peptide family. The regionally specific expression of the galanin receptors (GalR1-3) suggests different physiological roles, a feature which mostly remains unexplored due to the lack of selective ligands acting on the galanin receptor subtypes.The first introduced receptor subtype specific ligand in the field was galanin(2-11) as a GalR2 selective ligand, which was an important advance in the galanin field. Unfortunately, later publications described that galanin(2-11) also binds with similar affinity to GalR3, a critical limitation when delineating the interplay between galanin receptor subtypes. Even so, galanin(2-11) has been given extensive attention and been used in numerous study as a non-GalR1 ligand.We here present several promising ligands that are GalR subtype selective and these might be future candidates to unravel the function of GalR subtypes. We are currently testing their signalling in order to find novel agonists/antagonists for each receptor, and prepare to test them in relevant biological systems.

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 ...