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    • The present study demonstrates that SNAP exhibits

    2022-06-24

    The present study demonstrates that SNAP 37889 exhibits a toxic effect to these specific cell types, which is independent of endogenous expression of GAL receptor subtypes and leads to apoptosis. This conclusion is based on our findings that, although HMCB, HL-60 and SH-SY5Y cell lines differ in GAL receptor expression (Table 1), they are nonetheless equally affected by SNAP 37889 toxicity, suggesting that the toxicity is likely mediated by mechanisms not related to GAL receptors. Induction of apoptosis by DMSO (0.05–0.5%) in the vehicle is unlikely as several studies have shown that the apoptosis inducing concentrations of DMSO were above 1% (Banic et al., 2011, Galvao et al., 2014, Liu et al., 2001). In addition, we did not observe any difference between untreated KN-92 and vehicle control. Furthermore, SNAP 37889 seems to impair primarily proliferating cells at low densities, whereas confluent cells were more resistant to SNAP 37889. Interestingly, HepaRG cells, which are frequently used to access the toxicity of compounds, were not affected by SNAP 37889 (above 100μM) treatment even after 24h (data not shown). The apparent discordance between the affective concentrations of SNAP 37889 for light microscopy/apoptosis assays (10μM) and the viability assay could be explained by sustained ATP levels during the early apoptosis process (Denecker et al., 2001, Elmore, 2007). Interestingly, it has been reported that the GAL1–3 agonist galnon can penetrate across the plasma membrane of cells, activate intracellular G-proteins directly independent of receptor activation thereby triggering downstream signaling. Thus galnon is a ligand to other G-protein coupled receptors in addition to via GAL1–3 (Floren et al., 2005). Penetration of the cell membrane by SNAP 37889 and interference with intracellular signal transduction pathways could be one explanation for the toxicity of the compound observed in our studies. SNAP 37889 is a good tool to investigate GAL3-mediated functions in animal models and in in vitro studies. For example, Mansouri et al. (2013) demonstrated blockage of GAL3-effects using SNAP 37889 on neural stem cells at low doses, but they did not report toxic effects. In previous studies we were able to block galanin effects on plasma extravasation in mice by using SNAP 37889 (Schmidhuber et al., 2009). However, due to the short duration of treatment we did not observe nonspecific side effects. The concentration of SNAP 37889 used and the duration of the treatment are of paramount importance, especially in in vivo studies, because the cell-death-inducing effect of SNAP 37889 could be hidden by phagocytosis of dead cells and never be detected. Therefore, the results of previous studies may have been misinterpreted and their conclusions should be reviewed. The local concentrations reached by i.p. administration of SNAP 37889 (Ash et al., 2011, Ash et al., 2014, Swanson et al., 2005), should reach the mM range and therefore are 10-100-fold above the IC50 values of tested cell types shown in Fig 2. Toxic effects of antagonists have also been noted for other neuropeptides. For example telcagepant, an antagonist for calcitonin gene-related peptide receptor to treat acute migraine, exhibited liver toxicity and its clinical development was discontinued after completion of a phase III study (Edvinsson and Linde, 2010). We strongly recommend that the cytotoxicity of SNAP 37889 be taken into account when considering the compound as a therapeutic agent for anxiety and depression or for any other disease mediated by GAL3-interactions.
    Acknowledgments This research was supported by the Austrian Research Promotion Agency (822782/THERAPEP) and Paracelsus Medical University Salzburg (PMU-FFF E-10/11/059-LAN).
    Introduction Pain perception is a complex and externally inaccessible experience determined by the integration of complex neuronal processes. It is affected by neurotransmitter, neurohormone, sex, age, race/ethnicl and psychological states [5], [19], [59], [79]. A number of clinical and experimental studies addressed the effect of obesity on pain sensitivity, both decreased and increased, as described behind [2], [36], [56], [61], [80]. Although obesity may change the pain threshold via alteration of neuroendocrine, its precise mechanism is poorly understood as yet. The neuropeptide, galanin, may regulate food intake, obesity and nociception [17]. Whereas weight gain and injury pain may elevate plasma galanin level of subjects [18].