Transgenic over-expression of galanin in injured primary sensory neurons

Bacon, Andrea; Holmes, Fiona E.; Small, Caroline J.; Ghatei, Mohammed A.; Mahoney, Sally; Bloom, Stephen R.; Wynick, David

doi:10.1097/00001756-200211150-00028

Cited by 25 publications

(25 citation statements)

References 10 publications

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“…3A). Identical findings were observed in line OE46, which was generated from the same transgene (20). In contrast, Gal-KO mice developed clinical disease earlier than strainmatched WT controls (time to peak EAE clinical score 14 Ϯ 0.6 vs. 20 Ϯ 0.8 days respectively, P Ͻ 0.01, Fig.…”

Section: Resultssupporting

confidence: 70%

“…Gal-OE mice (20), which fully recapitulate the endogenous expression pattern of galanin in the intact animal and inducibly overexpress the peptide following axotomy (21), were compared with lines carrying loss-of-function mutations in the galanin peptide (22) (Gal-KO) and GalR2 (23) (GalR2-MUT). Gal-OE (line OE2) mice (20) were completely resistant to the development of any clinical disease in the EAE model, compared to strain-, age-, and sex-matched WT controls, with cumulative total EAE scores (equivalent to the area under the curve (AUC) of the mean EAE clinical score against time) of 0.1 Ϯ 0.1 vs. 26.1 Ϯ 1.9, P Ͻ 0.001 (Fig. 3A).…”

Section: Resultsmentioning

confidence: 99%

“…Details of the strain and breeding history have been previously described (20,21). In brief, galanin over expressing mice, bred to homozygosity, were generated using a Ϸ25-kb transgene containing the entire murine galanin coding region and 19.9kb of upstream sequence.…”

Section: Methodsmentioning

confidence: 99%

“…The transgene was excised by restriction digest and microinjected into fertilised oocytes. Two transgenic lines, denoted OE2 and OE46, were then bred and characterized, see Bacon et al for further details (20). Both transgenic lines have remained inbred on the CBA ϫ C57BL6 F1 hybrid background.…”

Section: Methodsmentioning

confidence: 99%

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A role for galanin in human and experimental inflammatory demyelination

Wraith¹,

Pope²,

Butzkueven

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The neuropeptide galanin is widely expressed by many differing subsets of neurons in the nervous system. There is a marked upregulation in the levels of the peptide in a variety of nerve injury models and in the basal forebrain of humans with Alzheimer's disease. Here we demonstrate that galanin expression is specifically and markedly upregulated in microglia both in multiple sclerosis (MS) lesions and shadow plaques. Galanin expression is also upregulated in the experimental autoimmune encephalomyelitis (EAE) model of MS, although solely in oligodendrocytes. To study whether the observed increase in expression of galanin in inflammatory demyelination might modulate disease activity, we applied the EAE model to a panel of galanin transgenic lines. Over-expression of galanin in transgenic mice (Gal-OE) abolishes disease in the EAE model, whilst loss-of-function mutations in galanin or galanin receptor-2 (GalR2) increase disease severity. The pronounced effects of altered endogenous galanin or GalR2 expression on EAE disease activity may reflect a direct neuroprotective effect of the neuropeptide via activation of GalR2, similar to that previously described in a number of neuronal injury paradigms. Irrespective of the mechanism(s) by which galanin alters EAE disease activity, our findings imply that galanin/GalR2 agonists may have future therapeutic implications for MS.EAE ͉ GalR2 ͉ Glia ͉ multiple sclerosis T he neuropeptide galanin (1) is widely, but by no means ubiquitously, expressed in the adult brain (2-5), and following injury there is a dramatic increase in the levels of the peptide in many neuronal subpopulations (6-8) and in the basal forebrain of patients with Alzheimer's disease (9, 10). In addition to the neuronal expression of galanin, a small number of reports have shown that the neuropeptide is also expressed by oligodendrocyte or microglial cells following cortical spreading depression (11), transient forebrain ischaemia (12) or colchicine treatment (13,14). Of note, the adult Gal-OE mice used in this study have a marked increase in neuronal galanin expression that is predominantly in the terminal fields of the hippocampus (15). Before the current study there was no evidence that galanin was expressed in non-neuronal cells in these mice.We have previously shown that kainic acid-induced cell death in the CA1 and CA3 regions of the hippocampus is markedly reduced in Gal-OE mice compared to WT controls (15). Similarly, in vitro treatment with staurosporine or glutamate induced significantly less cell death in hippocampal cultures from Gal-OE animals than in WT controls (15). In contrast, Gal-KO mice demonstrated more hippocampal cell death following in vivo and in vitro neuronal damage than WT controls (15). Furthermore the addition of exogenous galanin peptide or the GalR2/3-specific agonist Gal2-11 reduced the amount of cell death when co-administered with either glutamate or staurosporine in WT primary hippocampal cultures (15). We have recently extended these findings by demonstrating that organo...

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Section: Resultssupporting

confidence: 70%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

A role for galanin in human and experimental inflammatory demyelination

Wraith¹,

Pope²,

Butzkueven

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Transgenic mice (CBA͞B6 strain) that inducibly overexpress galanin in the DRG after nerve injury were generated by using a transgene corresponding to an Ϸ20-kb upstream enhancer region of the murine galanin locus and the 4.6-kb galanin-coding region, as described recently (40).…”

Section: Methodsmentioning

confidence: 99%

Transgenic overexpression of galanin in the dorsal root ganglia modulates pain-related behavior

Holmes

Bacon

Pope

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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The neuropeptide galanin is expressed in the dorsal root ganglia (DRG) and spinal cord and is thought to be involved in the modulation of pain processing. However, its mechanisms of action are complex and poorly understood, as both facilitatory and inhibitory effects have been described. To understand further the role played by galanin in nociception, we have generated two transgenic lines that overexpress galanin in specific populations of primary afferent DRG neurons in either an inducible or constitutive manner. In the first line, a previously defined enhancer region from the galanin locus was used to target galanin to the DRG (Gal-OE). Transgene expression recapitulates the spatial endogenous galanin distribution pattern in DRG neurons and markedly overexpresses the peptide in the DRG after nerve injury but not in the uninjured state. In the second line, an enhancer region of the c-Ret gene was used to constitutively and ectopically target galanin overexpression to the DRG (Ret-OE). The expression of this second transgene does not alter significantly after nerve injury. Here, we report that intact Ret-OE, but not Gal-OE, animals have significantly elevated mechanical and thermal thresholds. After nerve damage, using a spared nerve-injury model, mechanical allodynia is attenuated markedly in both the Gal-OE and Ret-OE mice compared with WT controls. These results support an inhibitory role for galanin in the modulation of nociception both in intact animals and in neuropathic pain states.T he neuropeptide galanin is widely distributed within the somatosensory system, where it has been implicated in the modulation of nociception (reviewed in refs. 1-3). In the adult dorsal root ganglia (DRG), galanin is expressed at relatively low levels in Ͻ5% of neurons that are predominantly small-diameter C fiber type (4). Expression of the peptide also is detected in the primary afferent terminals of the dorsal spinal cord and in subsets of dorsal horn interneurons (5). Galanin mRNA and peptide levels markedly increase in the DRG after axotomy and in several neuropathic pain models of sciatic nerve injury (4, 6-9). After axotomy, galanin is expressed in Ϸ40-50% of all DRG neurons (4, 10). In the dorsal horn, axotomy-induced galanin immunoreactivity increases in the afferent terminals, with a concurrent enhancement of synaptic release of the peptide (11).The role of galanin in pain signaling is complex (reviewed in refs. 2, 12, and 13). Electrophysiological and behavioral studies in the intact, uninjured peripheral nervous system have demonstrated both facilitatory (14-21) and inhibitory (22, 23) effects of exogenously applied galanin on nociception, sometimes in a modality-specific manner (14,16,20,21), tending toward inhibition at higher doses.A number of groups have used rodent models of neuropathic pain to study the role of galanin in the modulation of chronic pain behavior. The oldest and least understood pain model involves the scoring of autotomy behavior (self-mutilation of the denervated limb) after sciatic nerve a...

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Identification and characterization of phosphorylated proteins in the human pituitary

Giorgianni¹,

Beranová-Giorgianni

Desiderio

2004

Proteomics

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Post-translational modifications of proteins from the human pituitary gland play an important role in the regulation of different body functions. We report on the application of a liquid chromatography-tandem mass spectrometry (MS/MS) based approach to detect and characterize phosphorylated proteins in a whole human pituitary digest. By combining an immobilized metal affinity column-based enrichment method with MS/MS conditions that favor the neutral loss of phosphoric acid from a phosphorylated precursor ion, we identified several previously undescribed phosphorylated peptides. The identified peptides were matched to the sequences of six pituitary proteins: the human growth hormone, chromogranin A, secretogranin I, 60S ribosomal protein P1 and/or P2, DnaJ homolog subfamily C member 5, and galanin. The phosphorylation sites of these important regulatory proteins were determined by MS/MS and MS(3) analysis.

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Transgenic over-expression of galanin in injured primary sensory neurons

Cited by 25 publications

References 10 publications

A role for galanin in human and experimental inflammatory demyelination

A role for galanin in human and experimental inflammatory demyelination

Transgenic overexpression of galanin in the dorsal root ganglia modulates pain-related behavior

Identification and characterization of phosphorylated proteins in the human pituitary

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