Validation of a novel biomarker for acute axonal injury in experimental autoimmune encephalomyelitis

Gresle, Melissa; Shaw, Gerry; Jarrott, Bevyn; Alexandrou, Estella; Friedhuber, Anna; Kilpatrick, Trevor J.; Butzkueven, Helmut

doi:10.1002/jnr.21803

Cited by 47 publications

(50 citation statements)

References 29 publications

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“…Our data also indicate that galanin expression is markedly upregulated in both the brains of patients with MS and mice with EAE. Importantly, it is now the consensus view that the clinical severity of inflammatory demyelination, in both mouse and man, is likely to be a consequence of the degree of axonal degeneration (24)(25)(26). It is therefore of considerable interest that our prior work indicates that galanin exerts neuroprotective effects after injury (15) and that these activities have been shown to be principally mediated via neuronally expressed GalR2 (16).…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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 same volume of CFA and pertussis toxin was injected into each mouse in the control group. Animals were weighed, monitored, and clinically assessed according to the following grading scale: 0 = no signs; 1 = distal tail weakness; 1.5 = tail weakness and some hind limb weakness; 2 = complete tail paralysis; 2.5 = complete tail paralysis and partial hind limb weakness; 3 = complete hind limb weakness; 3.5 = inability to right when placed on back or significant forelimb weakness; 4 = euthanized or spontaneous death (17,18 Twelve lupus-like mice per group were injected i.p. with 5 mg/kg TACI-IgG and/or 1 mg/kg anti-IL-15 neutralizing Ab at 1, 2, 3, and 4 wk (twice per week) after the mice had reached 6 mo of age.…”

Section: Eae Inductionmentioning

confidence: 99%

BAFF Suppresses IL-15 Expression in B Cells

Chen²,

Xiao³

et al. 2014

The Journal of Immunology

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Clinical trials have shown that BAFF inhibitors do not reduce memory B cell levels but can reduce the number of mature B cells. It remains uncertain whether BAFF affects memory-maintaining cytokines such as IL-15. We found that BAFF suppressed IL-15 expression in B cells from lupus-like or experimental allergic encephalomyelitis mice. When BAFF was blocked with atacicept-IgG, IL-15 expression was upregulated in lupus-like or experimental allergic encephalomyelitis mice. Finally, we showed that BAFF suppressed IL-15 expression in transitional 2 B cells by reducing Foxo1 expression and inducing Foxo1 phosphorylation. This study suggests that BAFF suppresses IL-15 expression in autoimmune diseases, and this opens up the possible opportunity for the clinical application of BAFF- and IL-15–specific therapeutic agents.

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“…Blood samples were collected at the time of culling and were used in an ELISA for pNfH as previously described (6). Antibodies used included chicken anti-pNfH capture and rabbit antipNfH detection.…”

Section: Tcgcagcaaagatccacacagmentioning

confidence: 99%

“…One limitation of human CNS gene expression profiling in MS is that it is by necessity usually performed on autopsy tissue with highly heterogeneous disease course and little ongoing inflammation and with variable RNA degradation post-mortem. Therefore, we investigated neuronal gene expression changes during acute inflammatory CNS axon injury using murine myelin oligodendrocyte glycoprotein 35-55-induced (MOG -induced) experimental autoimmune encephalomyelitis (EAE) (6)(7)(8). The analysis of gene expression in the EAE mouse noninflamed motor cortex, a region containing pyramidal neurons with direct axonal projection to the spinal cord, revealed a significantly altered expression of several mRNAs encoding proteins associated with the extracellular matrix (ECM).…”

Section: Introductionmentioning

confidence: 99%