Galanin Transgenic Mice with Elevated Circulating Galanin Levels Alleviate Demyelination in a Cuprizone-Induced MS Mouse Model

Abstract

Multiple Sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system (CNS) with a presumed autoimmune etiology. Approved treatments for MS are immunoregulatory and are able to reduce the inflammatory components of the disease. However, these treatments do not suppress progressive clinical disability. Approaches that directly protect myelin-producing oligodendrocytes and enhance remyelination are likely to improve long-term outcomes and reduce the rate of axonal damage. Galanin (GAL) is a bioactive neuropeptide that is widely distributed throughout the nervous system and has diverse neuromodulatory effects. In this study, using the cuprizone (CPZ) demyelination model of MS, we demonstrate that GAL has pronounced neuroprotective effects with respect to demyelination and remyelination. Using our GAL transgenic mouse (GAL-Tg), we identified a novel attenuation of OLs against CPZ induced demyelination, which was exerted independently of progenitor cells. Alleviation of myelin breakdown in the GAL-Tg mice was observed to be significant. Furthermore, we observed changes in the expression of the GAL receptor GalR1 during the demyelination and remyelination processes. Our data strongly indicate that GAL has the capacity to influence the outcome of primary insults that directly target OLs, as opposed to cases where immune activation is the primary pathogenic event. Taken together, these results suggest that GAL is a promising next-generation target for the treatment of MS.

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

“…No difference in intact mechanical thresholds but higher after nerve injury, returned to intact values by day 7 (Bacon et al, 2007;Hulse et al, 2011) Reduction in acetone-induced pain-like behavior after PSNI (Hulse et al, 2012) Lower levels of cell death in vivo and in vitro (Elliott-Hunt et al, 2004) Decrease in opiate withdrawal behavior Galanin (inducible) (Pope et al, 2010)/tTA under control of 20 kb murine genomic galanin, 4.6 kb murine genomic galanin under control of tetO/CBA/BL6 F1 hybrid Increased mechanical thresholds after nerve injury reduced by galanin suppression (Pope et al, 2010) Growth hormone (Perumal and Vrontakis, 2003)/320 bp rat GH promoter driving full-length rat preprogalanin cDNA including poly A tail (4.5 kb transgene)/C57BL6/SJL F2 Â Swiss CD Increased serum levels of galanin, prolactin and GH (GH in males only) Pituitary hyperplasia and adenomas in older mice (Perumal and Vrontakis, 2003) Reduced CPZ-induced myelin breakdown (Zhang et al, 2012) Platelet-derived growth factor driving galanin (Holmberg et al, 2005a)/1.3 kb PDGF-b with galanin/GMAP gene construct, including intron 2 of the mouse galanin gene (genomic DNA and cDNA)/CBA/BL6 F1 hybrid Increase in learned helplessness in old mice (Pirondi et al, 2005b). Increase in learned helplessness (Kuteeva et al, 2005) Reduced neuronal loss postaxotomy, 35% reduction in plasma extravasation, increased response in phase 2 of formalin test (Holmberg et al, 2005a) Elevated thermal thresholds but no difference in mechanical thresholds or cold thermal in intact adults (Blakeman et al, 2001) Decreased response to evoked seizures (Kokaia et al, 2001) Delayed reduction in NA after intracerebroventricular injection of galanin to ventral hippocampus.…”

“…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).…”

“…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.…”

“…For example, the development of antibodies and small-molecule drugs that are CNS penetrant (Robertson et al, 2010;Zhang et al, 2012) and specific for the different galanin receptors will help provide more detailed information on the distribution and function of each receptor. Finally, with many preclinical studies indicating that the galanin system is of particular importance in a range of pathologies, the hope is that both current and new information will be translated through to clinical studies, resulting in novel pharmacological therapeutic strategies for a number of diseases.…”

An elevated level of circulating galanin promotes developmental expression of myelin basic protein in the mouse brain

“…Furthermore, GAL has neurotrophic effects in the developing and adult brain (Shen et al, 2005). It has also been suggested that GAL plays a role in neurogenesis, specifically in the proliferation and differentiation of neural stem cells (Agasse et al, 2013) and that GAL acts as a growth and survival factor O'Meara et al, 2000;Elliott-Hunt et al, 2004;Butzkueven and Gundlach, 2010) for various neurons (Shen et al, 2003) and oligodendrocytes (Habert-Ortoli et al, 1994;Ubink et al, 2003;Zhang et al, 2012). GAL acts through the three receptor subtypes GalR1, GalR2 and GalR3 (Habert-Ortoli et al, 1994;Fathi et al, 1997;Howard et al, 1997;Wang et al, 1997;Lang et al, 2007).…”