br Acknowledgements br Introduction Galanin shows widespread

Acknowledgements
Introduction Galanin shows widespread distribution in the central nervous system (CNS) and peripheral nervous system (PNS) as well as in the immune, endocrine and endothelial vascular systems (Lang et al., 2007). Galanin controls diverse physiological processes such as arousal/sleep, energy and osmotic homeostasis, reproduction, nociception and cognition. Furthermore, galanin has been correlated with pathological processes of the nervous system, including nerve injury (Hokfelt et al., 1987), Alzheimer's disease (Chan-Palay, 1988) and epileptic seizures (Mazarati et al., 1998). In the periphery, galanin plays a role in inflammatory disorders (Lang and Kofler, 2011). Galanin's functions are mediated by three galanin receptors (GAL1, GAL2 and GAL3) with peculiar distributions in the CNS, PNS, and in other tissues of the body (Lang et al., 2007). The three receptors are members of the G-protein coupled receptor (GPCR) superfamily and show differences in functional coupling, which explains disparate physiological functions of galanin in the different parts of the body. GAL1 mRNA is found in Ceftazidime regions mainly involved in appetite control, addiction, nociception and memory, in both rodents and humans (Ash and Djouma, 2011). GAL2 is widely expressed throughout the CNS and PNS and has crucial roles in regulation of cardiovascular activity, neuroendocrine function, reproduction, digestion, and bone remodeling (Ash and Djouma, 2011). Studies on GAL3 distribution are limited but the receptor is known to be expressed in areas of the brain involved in feeding, reward, memory and emotions (Ash and Djouma, 2011). Therapeutic modulation of galanin functions in addiction and mood disorders is considered a possible treatment for these diseases (Ash and Djouma, 2011). Therefore, attempts are ongoing to develop chimeric peptides or non-peptidergic compounds to specifically stimulate or inhibit galanin (GAL) receptors. Swanson et al. (2005) developed two non-peptidergic GAL3 selective antagonists, 1-phenyl-3-[[3-(trifluoromethyl)phenyl]imino]-1H-indol-2-one (SNAP 37889) and (1-(3-(2-pyrrolidin-1-ylethoxy)phenyl)-3-(3-(trifluoromethyl)phenyl)iminoindol-2-one (SNAP 398299). The compounds were described as having high selectivity for GAL3 and low or no selectivity for GAL1 and GAL2 (Swanson et al., 2005). SNAP 37889 administrated intraperitoneal (i.p.) or orally was reported to significantly decrease anxiety and depression in rodents (Swanson et al., 2005). In addition, i.p. administration of SNAP 37889 has been shown to reduce alcohol consumption of rats (Ash et al., 2011, Ash et al., 2014). Furthermore, SNAP 37889 reduced inflammation in a model of acute pancreatitis and neurogenic skin inflammation (Barreto et al., 2011, Schmidhuber et al., 2009, Swanson et al., 2005). As SNAP 37889 could have potential as a therapeutic drug for several diseases, the present study evaluated possible toxic effects of SNAP 37889 on several cell types with differing patterns of endogenous expression of GAL receptors.
Materials and methods
Results
Discussion Mounting evidence has implicated GAL3 in several behavioral and mood disturbances (Lang et al., 2007). Swanson and colleagues proposed the use of SNAP 37889 as a new specific antagonist of GAL3 for treatment of anxiety- and depression-like disorders (Swanson et al., 2005). However, more recent studies have reported contradictory findings concerning the effect of SNAP 37889 on anxiety and depression symptoms. Both Lundstrom et al. (2008) and Ash et al. (2011) found that SNAP 37889 treatments administered to rats —using similar anxiety and depression behavioral testing paradigms and the same doses as used by Swanson et al. (2005) — had only a weak or even no anxiolytic effect. Furthermore, behavioral studies on GAL3 knockout mice revealed an anxiety-like phenotype (Brunner et al., 2014), which is the opposite of the anxiolytic effect reported by Swanson et al. (2005) after oral or i.p. administration of SNAP 37889 to rats. Recently, in silico investigations have demonstrated that SNAP 37889 has similar affinity for all three GAL receptor subtypes (Jurkowski et al., 2013).