Increased CML Deposition, Rage Expression, And NF‐κB Activation In Diabetic Neuropathy

There is growing evidence that upregulation of NF ‐ κB‐controlled adhesion molecules and cytokines contributes to neuropathic pain and diabetic neuropathy. Since AGE/RAGE‐interactions activate NF ‐ κB, we asked whether deposition of the defined AGE‐adduct CML, upregulation of RAGE, and NF ‐ κB activation is evident in peripheral nerves in human and animal models of diabetes mellitus. When immunohistology was performed on sural nerve biopsies from diabetic patients, local accumulation of CML, prominent upregulation of RAGE and strong activation of NF ‐ κB was observed in the perineurium and the vascular endothelium. This colocalisation was not observed in control patients. Schwann cells also demonstrated increased RAGE expression, but no staining for CML and NF ‐ κB. In mouse models of diabetes mellitus, histological examination confirmed upregulation of NF ‐ κB in the perineurium, but was also evident in Schwann cells. In the mouse model, NF ‐ κB activation could be reversed by the antioxidant α‐lipoic acid. These data demonstrate that NF ‐ κB activation occurs in hyperglycemia, but affects different neuronal cells in human and mice. Hyperglycemia dependent activation of NF‐κB results in enhanced NF ‐ κB dependent gene expression in transgenic mice, carrying a β‐globin reporter transgene controlled by NF ‐ κB. Infusion of AGE‐albumin also led to induction of the β‐globin‐gene and could be blocked in the presence of soluble RAGE, neutralizing anti‐RAGE‐antibodies and α‐lipoic acid. These studies provide evidence that the AGE‐RAGE‐NF‐κB axis is upregulated in diabetic neuropathy. NF ‐ κB‐activation and subsequent induction of NF ‐ κB‐dependent gene expression can be reduced by treatment with α‐lipoic acid.