2013). In the present study, we found that in a normal, healthy human

nerve, RAGE is expressed in almost 30% of all nerve fibers and that number is higher in pathological states such as peripheral neuropathy. We also found that the expression level of RAGE was higher in neuropathic nerves as compared to the control nerve. Given that the Inhibitors,research,lifescience,medical disease was already established, it is not possible to discern if such expression changes were consequences of local traumatic or toxic events and/or whether those changes might have preceded or occurred concurrently with hyperglycemia-evoked peripheral nerve changes observed in diabetes. With respect to the ligands of RAGE in the nerve tissue, we found that the expression of two of the RAGE ligands, HMGB1 and CML, is also higher in the neuropathic nerves; however, their expression levels varied between the neuropathic specimens and controls. While the level of HMGB1 was similar in both idiopathic and diabetic neuropathic nerve, CML level was significantly different between the neuropathic

Inhibitors,research,lifescience,medical specimens. The observed differences might be explained by the fact that following injury, HMGB1 is not only secreted by immune cells Inhibitors,research,lifescience,medical but by PR-171 in vitro neurons as well, thus potentially promoting nerve repair by enhancing axonal sprouting and outgrowth (Lotze and Tracey 2005; Tian et al. 2009). Further, its expression might be unaffected by secondary, hyperglycemic, conditions observed in the diabetic peripheral neuropathy (Faraco et Inhibitors,research,lifescience,medical al. 2007; Shibasaki et al. 2010; Feldman et al. 2012; Juranek et al. 2013). In addition, it has been shown in vitro that blocking RAGE inhibits HMGB1-mediated neuronal development (Hori et al. 1995) indicating that RAGE-HMGB1 interaction might be crucial for repair mechanisms

in the neuropathic nerve. On the contrary, CML is thought to be one of the key molecules in the inflammatory, RAGE-NF-κB-dependent pathway in diabetes, but also, independently from RAGE, it plays an important role in cumulative oxidative stress-induced Inhibitors,research,lifescience,medical neuronal changes, (Haslbeck et al. 2007), contributing to the pathogenesis of neuropathy. Extensive study of CML expression in different types of peripheral neuropathies (Haslbeck et al. 2007) revealed that increased oxidative stress and/or CML-RAGE-NF-κB-activated pathway likely plays a role in diabetes, vitamin B12 deficiency related mafosfamide and chronic inflammatory demyelinating peripheral neuropathy, however, the authors did not observe either RAGE or CML increase in the idiopathic neuropathy. This discrepancy might be explained by the fact that the term “idiopathic neuropathy” comprises many different, unrelated, neuropathies caused by multiple factors and cannot be treated as one disease entity. Finally, we found that the expression of mDia1, a cytoplasmic actin-binding protein, described for the first time as an intracellular RAGE ligand in 2008 (Hudson et al.