The galanin‐R2 agonist AR‐M1896 reduces glutamate toxicity in primary neural hippocampal cells

Pirondi, Stefania; Fernández, Mercedes; Schmidt, Ralf; Hökfelt, Tomas; Giardino, Luciana; Calzà, L.

doi:10.1111/j.1471-4159.2005.03437.x

Cited by 46 publications

(38 citation statements)

References 72 publications

(77 reference statements)

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“…We have preliminary results showing protective effects of galanin against apoptotic cell death induced by the broad kinase inhibitor staurosporine in primary hippocampal neurons (R.T., unpublished data). These data are in agreement with previous results where galanin or GalR2 agonist AR-M1896 promotes survival of hippocampal neurons undergoing exicitotoxic injuries (62,63), by activation of GalR2 and hence Akt and ERK pathway (62). Our present data, showing that galanin causes chromatin condensation, loss of membrane potential, release of cyt c into the cytosol, and activation of caspases only in GalR2 cells as a result of inhibition of PI3K/Akt pathway, enlighten the opposing roles of GalR2 in tumor and nontumor cells.…”

Section: Figsupporting

confidence: 83%

Galanin decreases proliferation of PC12 cells and induces apoptosis via its subtype 2 receptor (GalR2)

Tofighi

Joseph

Sheng

et al. 2008

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

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Galanin is a neuropeptide with a wide range of effects in the nervous and endocrine systems, mediated through three G protein-coupled receptor subtypes (GalR1-3). Interestingly, galanin and its receptors are also expressed in certain tumors. Here we studied the effects of galanin in rat pheochromocytoma (PC12) cells stably transfected with GFP-tagged GalR2. Galanin at 100 nM inhibited cell proliferation in both nontransfected and transfected cells. Conversly, both galanin and the GalR2(R3)-agonist AR-M1896 induced caspase-dependent apoptotic cell death only in GalR2-transfected cells. Western-blot analyses of downstream mediators of the G q/11-type G protein showed down-regulation of pAkt and pBad in galanin-exposed transfected cells. Also, the specific PI3 kinase inhibitor LY-294002 increased the level of pBad and decreased activation of caspases. In addition, p21 cip1 levels were up-regulated in galanin-exposed PC12 cells and down-regulated in galanin-exposed GalR2-transfected cells. In agreement, FACS analyses of galanin exposed cells showed occurrence of cell cycle arrest in PC12 cells and cell death in transfected cells. Finally, as shown with real-time PCR, galanin and its receptors were expressed at very high levels in human pheochromocytoma tissues as compared with normal adrenal medulla. These findings point to GalR2 as a possible target for therapeuthic interventions in pheochromocytoma.adrenal medulla ͉ galanin receptor ͉ neuropeptide ͉ pheochromocytoma ͉ tumor

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Section: Figsupporting

confidence: 83%

Galanin decreases proliferation of PC12 cells and induces apoptosis via its subtype 2 receptor (GalR2)

Tofighi

Joseph

Sheng

et al. 2008

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

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“…We have recently extended these findings by demonstrating that organotypic hippocampal cultures from mice with a loss-of-function mutation in GalR2 (GalR2-MUT) treated with glutamate show more cell death than WT controls and this cannot be rescued with the addition of either exogenous galanin or Gal2-11 (16). In support of these findings, studies by Pirondi and colleagues have shown that glutamate induced upregulation of c-fos can be reversed using galanin or Gal2-11 (17). Similarly, in vivo studies using an adeno-associated virus expressing the coding sequence for the galanin peptide reduced kainic acid-induced hippocampal cell death in rats (18), whilst addition of galanin or Gal2-11 in vitro protected basal forebrain cultures from A-beta-induced neurotoxicity (19).…”

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confidence: 66%

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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“…Several lines of evidence indicate that activation of the GALR2 receptor elicits a neuroprotective signal. The AR-M1896 GALR2 agonist protects both mouse [32] and rat [99] primary neuronal hippocampal cultures from glutamate or staurosporine-induced [32] cell death. More recently, GAL failed to prevent glutamate-induced hippocampal cell death in cultures from GALR2 knockout (GALR2KO) mice [100].…”

Section: Galanin Plasticity As a Neuroprotective Factor In Admentioning

confidence: 99%

Galanin – 25 years with a multitalented neuropeptide

Counts

Perez

Mufson

2008

Cell. Mol. Life Sci.

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Galanin (GAL) and GAL receptors (GALRs) are overexpressed in degenerating brain regions associated with cognitive decline in Alzheimer's disease (AD). The functional consequences of GAL plasticity in AD are unclear. GAL inhibits cholinergic transmission in the hippocampus and impairs spatial memory in rodent models, suggesting GAL overexpression exacerbates cognitive impairment in AD. By contrast, gene expression profiling of individual cholinergic basal forebrain (CBF) neurons aspirated from AD tissue revealed that GAL hyperinnervation positively regulates mRNAs that promote CBF neuronal function and survival. GAL also exerts neuroprotective effects in rodent models of neurotoxicity. These data support the growing concept that GAL overexpression preserves CBF neuron function which in turn may slow the onset of AD symptoms. Further elucidation of GAL activity in selectively vulnerable brain regions will help gauge the therapeutic potential of GALR ligands for the treatment of AD.

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The galanin‐R2 agonist AR‐M1896 reduces glutamate toxicity in primary neural hippocampal cells

Cited by 46 publications

References 72 publications

Galanin decreases proliferation of PC12 cells and induces apoptosis via its subtype 2 receptor (GalR2)

Galanin decreases proliferation of PC12 cells and induces apoptosis via its subtype 2 receptor (GalR2)

A role for galanin in human and experimental inflammatory demyelination

Galanin – 25 years with a multitalented neuropeptide

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