| 1. |
- Mansouri, Shiva, et al.
(author)
-
GalR3 activation promotes adult neural stem cell survival in response to a diabetic milieu
- 2013
-
In: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 127:2, s. 209-220
-
Journal article (peer-reviewed)abstract
- Type 2 diabetes impairs adult neurogenesis which could play a role in the CNS complications of this serious disease. The goal of this study was to determine the potential role of galanin in protecting adult neural stem cells (NSCs) from glucolipotoxicity and to analyze whether apoptosis and the unfolded protein response were involved in the galanin-mediated effect. We also studied the regulation of galanin and its receptor subtypes under diabetes in NSCs in vitro and in the subventricular zone (SVZ) in vivo. The viability of mouse SVZ-derived NSCs and the involvement of apoptosis (Bcl-2, cleaved caspase-3) and unfolded protein response [C/EBP homologous protein (CHOP) Glucose-regulated protein 78/immunoglobulin heavy-chain binding protein (GRP78/BiP), spliced X-box binding protein 1 (XBP1), c-Jun N-terminal kinases (JNK) phosphorylation] were assessed in the presence of glucolipotoxic conditions after 24h. The effect of diabetes on the regulation of galanin and its receptor subtypes was assessed on NSCs in vitro and in SVZ tissues isolated from normal and type 2 diabetes ob/ob mice. We show increased NSC viability following galanin receptor (GalR)3 activation. This protective effect correlated with decreased apoptosis and CHOP levels. We also report how galanin and its receptors are regulated by diabetes in vitro and in vivo. This study shows GalR3-mediated neuroprotection, supporting a potential future therapeutic development, based on GalR3 activation, for the treatment of brain disorders.
|
|
| 2. |
- Runesson, Johan, 1980-, et al.
(author)
-
M1154 – A novel galanin ligand to delineate the galaninergic system
- 2010
-
In: Peptides 2010. - : European Peptide Society and PSP.
-
Conference paper (other academic/artistic)abstract
- The galanin family currently consists of four members, namely galanin, galanin-message-associated peptide (GMAP), galanin-like peptide (GALP) and alarin. The galanin peptide family and its three receptors (GalR1-3) have with compelling evidence been implicated in a variety of human disorders. The co-localization with other neuromodulators and the distinct up-regulation during and after pathological disturbances has drawn attention to this neuropeptide family. Here we present data on receptor binding and preliminary data in functional response for the novel M1154 peptide, including a comparison with several GalR2 selective peptides. M1154 retains high affinity binding to GalR1 and GalR2 although it has no detectable binding to GalR3. We believe that utilizing this selective galanin ligand together with previous published M1145 raise the possibility to delineate the galanin system.
|
|
| 3. |
- Guterstam, Peter, et al.
(author)
-
Characterization of cellular internalization pathways for CPP-mediated oligonucleotide delivery
- 2011
-
In: Cell-penetrating peptides. - New York : Humana Press. - 9781607619185 ; , s. 219-230
-
Book chapter (other academic/artistic)abstract
- The methods for evaluating internalization pathways of cellular CPP-mediated ON delivery utilizing a pre-mRNA splice correction assay and fluorescence-based quantification are described. Examples for characterization of CPP uptake routes, employing various endocytosis inhibitors, and special treatment conditions are demonstrated. The methods are developed to characterize cellular delivery of pre-mRNA splice switching peptide nucleic acids conjugated to CPPs by disulfide bond.
|
|
| 4. |
- Fuxe, K., et al.
(author)
-
Intramembrane receptor-receptor interactions: a novel principle in molecular medicine
- 2007
-
In: Journal of neural transmission. - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 114:1, s. 49-75
-
Journal article (peer-reviewed)abstract
- In 1980/81 Agnati and Fuxe introduced the concept of intramembrane receptor-receptor interactions and presented the first experimental observations for their existence in crude membrane preparations. The second step was their introduction of the receptor mosaic hypothesis of the engram in 1982. The third step was their proposal that the existence of intramembrane receptor-receptor interactions made possible the integration of synaptic (WT) and extrasynaptic (VT) signals. With the discovery of the intramembrane receptor-receptor interactions with the likely formation of receptor aggregates of multiple receptors, so called receptor mosaics, the entire decoding process becomes a branched process already at the receptor level in the surface membrane. Recent developments indicate the relevance of cooperativity in intramembrane receptor-receptor interactions namely the presence of regulated cooperativity via receptor-receptor interactions in receptor mosaics (RM) built up of the same type of receptor (homo-oligomers) or of subtypes of the same receptor (RM type1). The receptor-receptor interactions will to a large extent determine the various conformational states of the receptors and their operation will be dependent on the receptor composition (stoichiometry), the spatial organization (topography) and order of receptor activation in the RM. The biochemical and functional integrative implications of the receptor-receptor interactions are outlined and long-lived heteromeric receptor complexes with frozen RM in various nerve cell systems may play an essential role in learning, memory and retrieval processes. Intramembrane receptor-receptor interactions in the brain have given rise to novel strategies for treatment of Parkinson's disease (A2A and mGluR5 receptor antagonists), schizophrenia (A2A and mGluR5 agonists) and depression (galanin receptor antagonists). The A2A/D2, A2A/D3 and A2A/mGluR5 heteromers and heteromeric complexes with their possible participation in different types of RM are described in detail, especially in the cortico-striatal glutamate synapse and its extrasynaptic components, together with a postulated existence of A2A/D4 heteromers. Finally, the impact of intramembrane receptor-receptor interactions in molecular medicine is discussed outside the brain with focus on the endocrine, the cardiovascular and the immune systems.
|
|
| 5. |
- Runesson, Johan, 1980-, et al.
(author)
-
Receptor subtype selective galanin analogous for better understanding of the role of galanin in cancer progression
- 2010
-
Conference paper (other academic/artistic)abstract
- Galanin and galanin receptors have been found in several tumors. Galanin signaling has been studied in more detail in small cell lung carcinoma, where signaling via the GalR2 decreases the tumor growth. Galanin has also been included in a clinical therapy for pancreatic tumor together with a somatostatin agonist and serotonin. However, galanin signals via three receptors subtype with a broad expression pattern. We have therefore, developed several subtype selective galanin analogous that should reduce the side effects caused by galanin treatment. Therefore, we hope that the successful design of galanin receptor subtype selective ligands increase the interest for galanin and cancer progression.
|
|
| 6. |
- Bell, Thomas J., et al.
(author)
-
PAIR technology : exon-specific RNA binding protein isolation in live cells
- 2011
-
In: Cell-penetrating peptides. - New York : Humana Press. - 9781607619185 - 9781607619192 ; , s. 473-486
-
Book chapter (peer-reviewed)abstract
- RNA-binding proteins (RBPs) are fundamental regulatory proteins for all forms of transcriptional and posttranscriptional control of gene expression. However, isolating RBPs is technically challenging for investigators. Currently, the most widely used techniques to isolate RBPs are in vitro biochemical approaches. Although these approaches have been useful, they have several limitations. One key limitation to using in vitro biochemical approaches is that RBP–RNA interactions are isolated under nonbiological conditions. Here we review a novel experimental approach to identify RBPs called peptide nucleic acid (PNA)-assisted identification of RBPs (PAIR) technology (Zielinski et al., Proc Natl Acad Sci USA 103:1557–1562, 2006). This technology has two significant advantages over traditional approaches. (1) It overcomes the in vitro limitation of biochemical approaches by allowing investigators to isolate RBP–RNA interactions under in vivo conditions. (2) This technology is highly mRNA specific; it isolates RBPs in an exon-specific manner. By selectively targeting alternatively spliced exons with PAIR technology, investigators can isolate splice variant-specific and mRNA region-specific (5-UTR and 3-UTR) RBP complexes for any mRNA of interest.
|
|
| 7. |
- Hawes, Jessica, et al.
(author)
-
Galanin Protects Against Behavioral and Neurochemical Correlates of Opiate Reward
- 2008
-
In: Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 0893-133X .- 1740-634X. ; 33:8, s. 1864-1873
-
Journal article (peer-reviewed)abstract
- The mechanisms underlying responses to drugs of abuse have been widely investigated; however, less is known about pathways normally protective against the development of drug reinforcement. These pathways are also important since they may regulate individual differences in vulnerability to addiction. The neuropeptide galanin and its binding sites are expressed in brain areas important for drug reward. Previous studies have shown that centrally infused galanin attenuates morphine place preference and peripheral injection of galnon, a galanin agonist, decreases opiate withdrawal signs. The current studies in galanin knockout (GKO) mice examined the hypothesis that galanin is an endogenous negative regulator of opiate reward and identified downstream signaling pathways regulated by galanin. We show that GKO mice demonstrate increased locomotor activation following morphine administration, which is inhibited by acute administration of galnon. GKO mice also show enhanced morphine place preference, supporting the idea that galanin normally antagonizes opiate reward. In addition, morphine-induced ERK1/2 phosphorylation was increased in the VTA of both wild-type and GKO mice, but only the GKO mice showed increases in ERK1/2 and CREB phosphorylation in the amygdala or nucleus accumbens. Furthermore, a single systemic injection of galnon in GKO mice was sufficient to reverse some of the biochemical changes brought about by morphine administration. These data suggest that galanin normally attenuates behavioral and neurochemical effects of opiates; thus, galanin agonists may represent a new class of therapeutic targets for opiate addiction.
|
|
| 8. |
- Kuteeva, Eugenia, et al.
(author)
-
Differential Role of Galanin Receptors in the Regulation of Depression-Like Behavior and Monoamine/Stress-Related Genes at the Cell Body Level
- 2008
-
In: Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 0893-133X .- 1740-634X. ; 33:11, s. 2573-2585
-
Journal article (peer-reviewed)abstract
- The present study on rat examined the role of galanin receptor subtypes in regulation of depression-like behavior as well as potential molecular mechanisms involved in the locus coeruleus (LC) and dorsal raphe (DR). The effect of intracerebroventricular (i.c.v.) infusion of galanin or galanin receptor GalR1- and GalR2-selective ligands was studied in the forced swim test, followed by quantitative in situ hybridization studies. Naive control, non-treated (swim control), saline-and fluoxetine-treated rats were used as controls in the behavioral and in situ hybridization studies. Subchronic treatment with fluoxetine reduced immobility and climbing time. Intracerebroventricular infusion of galanin, the GalR1 agonist M617 or the GalR2 antagonist M871 increased, while the GalR2(R3) agonist AR-M1896 decreased, immobility time compared to the aCSF-treated animals. Galanin also decreased the time of climbing. Galanin mRNA levels were upregulated by the combination of injection + swim stress in the saline-and the fluoxetine-treated groups in the LC, but not in the DR. Also tyrosine hydroxylase levels in the LC were increased following injection + swim stress in the saline-and fluoxetine-treated rats. Tryptophan hydroxylase 2 and serotonin transporter mRNAs were not significantly affected by any treatment. 5-HT(1A) mRNA levels were downregulated following i.c.v. galanin, M617 or AR-M1896 infusion. These results indicate a differential role of galanin receptor subtypes in depression-like behavior in rodents: GalR1 subtype may mediate 'prodepressive' and GalR2 'antidepressant' effects of galanin. Galanin has a role in behavioral adaptation to stressful events involving changes of molecules important for noradrenaline and/or serotonin transmission.
|
|
| 9. |
- Adlerz, Linda, et al.
(author)
-
Down-regulation of amyloid precursor protein by peptide nucleic acid oligomer in cultured rat primary neurons and astrocytes
- 2003
-
In: Neuroscience Letters. - 0304-3940 .- 1872-7972. ; 336:1, s. 55-59
-
Journal article (peer-reviewed)abstract
- The amyloid precursor protein (APP) and its proteolytic cleavage products, the amyloid P peptides, have been implicated as a cause of Alzheimer's disease. Peptide nucleic acids (PNA), the DNA mimics, have been shown to block the expression of specific proteins at both transcriptional and translational levels. Generally, the cellular uptake of PNA is low. However, recent studies have indicated that the effect of unmodified antisense PNA uptake is more pronounced in nervous tissue. In this study we have shown that biotinylated PNA directed to the initiator codon region of the APP mRNA (-4 - +11) was taken up into the cytoplasm of primary rat cerebellar granule cells and cortical astrocytes, using fluorescence and confocal microscopy studies. Uptake of PNA was faster in neurons than in astrocytes. Western blotting analysis showed that APP was strongly down-regulated in both neurons and astrocytes. Thus, unmodified PNA can be used for studies on the function of APP in neurons and astrocytes.
|
|
| 10. |
- Keimpema, Erik, et al.
(author)
-
GABAergic Terminals Are a Source of Galanin to Modulate Cholinergic Neuron Development in the Neonatal Forebrain
- 2014
-
In: Cerebral Cortex. - : Oxford University Press (OUP). - 1047-3211 .- 1460-2199. ; 24:12, s. 3277-3288
-
Journal article (peer-reviewed)abstract
- 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.-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.
|
|
