(mentions CMT 1 & 2) The AGE/RAGE/NF-kappaB Pathway May Contribute to the Pathog

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Exp Clin Endocrinol Diabetes. 2005 May;113(5):288-91.

The AGE/RAGE/NF-kappaB Pathway May Contribute to the Pathogenesis of

Polyneuropathy in Impaired Glucose Tolerance (IGT).

Haslbeck KM, Schleicher E, Bierhaus A, Nawroth P, Haslbeck M,

Neundorfer B, Heuss D.

Department of Neurology, University of Erlangen-Nurnberg, Germany.

Binding of ligands to the receptor for advanced glycation end

products (RAGE) results in activation of the transcription factor

nuclear factor kappa B (NF-kappaB) and subsequent expression of NF-

kappaB-regulated cytokines. This has been shown to be a relevant

pathomechanism in diabetic polyneuropathies (PNP). To determine

whether this pathway may contribute to the pathogenesis of PNP due to

impaired glucose tolerance (IGT) we performed a pilot study to

demonstrate the presence of the RAGE ligand N (epsilon)-

(Carboxymethyl)lysine (CML), the receptor itself and NF-kappaB in

sural nerve biopsies of 4 patients with IGT-related PNP. Biopsies of

either 4 patients with diabetic PNP and with Charcot-Marie-Tooth

disease (CMT) I and II served as positive and negative controls,

respectively. In IGT-related PNP and diabetic PNP, CML, RAGE, and NF-

kappaB was found in the perineurium, epineurial vessels and in part

in endoneurial vessels. CMT patients showed, if any, only weak

staining for one or the other antigen. These data suggest that

activation of the RAGE pathway may be one of the first steps in the

pathogenesis of PNP even before chronic hyperglycemia occurs.