A role for galanin in human and experimental inflammatory demyelination

Abstract

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...

Weakened Cholinergic Blockade of Inflammation Associates with Diabetes-Related Depression

“…Our findings further support the identification by Raison and Miller of single nucleotide polymorphisms in cholinergic-related genes associated with major depression (24)(25)(26)(27)(28) and with the beneficial use of vaccination to reduce inflammation in successful independent aging (29). Recently we found that anxiety (which shares many symptoms with depression) ignites exacerbation of pre-existing neuro-immune risks (5), compatible with our previous reports of co-increasing severity of symptoms, shrinkage of the hippocampus and inflammation biomarkers in patients with post-traumatic stress disorder, who tend to be depressed (30).…”

Identification of the Synthetic Cannabinoid R(+)WIN55,212-2 as a Novel Regulator of IFN Regulatory Factor 3 Activation and IFN-β Expression

“…The preparation and immunization of the synthetic cannabinoid R(ϩ)WIN55,212-2 (Sigma) was modified from previous studies (30 Histology-Spinal cords were dissected and fixed in 10% formaldehyde saline. Spinal cords were sectioned and stained with hematoxylin and eosin for inflammatory scoring (31). Inflammatory scores were as follows: 0, no inflammatory cells; 1, a few scattered inflammatory cells; 2, perivascular cuffing; 3, perivascular cuffing with extensions into adjacent parenchyma, or parenchymal infiltration without obvious cuffing.…”

Physiology, Signaling, and Pharmacology of Galanin Peptides and Receptors: Three Decades of Emerging Diversity

“…The BV2 mouse microglia cell line and cultured rat microglial cells solely express GAL 2 (Su et al, 2003;Ifuku et al, 2011), which mediates galanin-induced cell migration and upregulation of class II major histocompatibility complex expression in these innate immune brain cells (Ifuku et al, 2011). Microglial cells also participate in the events leading to multiple sclerosis (Weissert, 2013), and a recent study detected a marked upregulation of galanin expression in microglia associated with multiple sclerosis lesions in postmortem brain tissue from chronic multiple sclerosis patients (Wraith et al, 2009). …”

“…There is also good evidence for a role for galanin signaling in processes of myelination and responses to myelin injury (Wraith et al, 2009;Zhang et al, 2012) along with proliferation, differentiation, and/or migration of oligodendrocyte precursor cells Ubink et al, 2003;Butzkueven and Gundlach, 2010) and neural stem and progenitor cells (the latter topic is covered in section VIII). It is highly likely that ongoing research in these areas will produce further evidence of the pleiotropic actions of galanin and the associated receptor mechanisms.…”

“…GAL mRNA is also detected in the proliferative zones of both the developing and adult brains-the subventricular zone, the rostral migratory stream, and the subgranular zone of the hippocampus -where it may regulate the proliferation, differentiation, and/or migration of neural stem cells (Xia et al, 2005a;Agasse et al, 2013;Mansouri et al, 2013;Zaben and Gray, 2013) (see sections V.D and VIII)-and in oligodendrocyte precursor cells in the corpus callosum Ubink et al, 2003), suggesting a role for galanin in normal myelination and responses to myelin injury (see Wraith et al, 2009, andZhang et al, 2012).…”