Altered Neurotrophism in Diabetic Neuropathy: Spelunking the Caves of Peripheral Nerve

Abstract

Diabetic peripheral neuropathy (DPN) is a frequent and potentially traumatic complication in diabetic individuals. The chronic nature of diabetes and its associated hyperglycemic episodes initiate a complex and inter-related series of metabolic and vascular insults that contribute to the polygenic etiology of DPN. One contributing factor in DPN is an altered neurotrophism that results from changes in the synthesis and expression of neurotrophins, insulin-like growth factor, and various cytokine-like growth factors that can directly act upon distinct subpopulations of sensory and motor neurons. Although considerable effort has focused upon examining growth factor signaling in hyperglycemically stressed neurons, myelin-forming Schwann cells also undergo substantial degenerative changes in DPN. However, scant attention has been devoted to understanding the effect of hyperglycemia on the response of Schwann cells to growth factors critical to their function. Neuregulins are gliotrophic growth factors that signal through members of the Erb B receptor-tyrosine kinase family. The neuregulin/Erb B ligand-receptor cassette can differentially influence the response of Schwann cells throughout their development by regulating cell survival, mitogenesis, and differentiation. The activity of Erb B receptors may also be affected by their interaction with caveolin-1, a protein marker of caveolae ("little caves"). However, whether neuregulin signaling may be directly or indirectly altered under conditions of hyperglycemic stress and contribute to the physiological progression of DPN is unknown. This brief review will provide a perspective on a putative role of changes in the caveolar proteome of Schwann cells in contributing to an "altered neuregulinism" in DPN.

High glucose upregulates CYP24A1 expression which attenuates the ability of 1,25(OH)2D3 to increase NGF secretion in a rat Schwann cell line RSC96

“…As all know that the pathogenesis of DPN has been caused by a number of metabolic abnormalities including polyol pathway hyperactivity, increased advanced glycation end-point formation, alterations in the protein kinase C pathway and reduced supply of neurotrophic factors (Dobrowsky et al, 2005;Mizukami et al, 2011;Obrosova et al, 2007;Song et al, 2003). In particular, aldose reductase, the first enzyme in the polyol pathway, is localized in Schwann cells in the peripheral nervous system (Kern and Engerman, 1982).…”

Dual Delivery of bFGF- and NGF-Binding Coacervate Confers Neuroprotection by Promoting Neuronal Proliferation

“…bFGF and NGF have been extensively shown to promote the survival and maintainenance of neuronal function in neurological diseases [14,15]. A deficiency of these two GFs may cause neuron susceptibility to injury and death [16,17], suggesting that molecular therapy with exogenous bFGF and NGF may be a novel and challenging therapeutic strategy for neurodegenerative diseases.…”

Differential Effects of Myopathy-Associated Caveolin-3 Mutants on Growth Factor Signaling

“…Moreover, individual genetic differences caused by single nucleotide polymorphisms in genes for growth factor receptors or cholesterol-synthesis associated genes could play an additional role in the pathogenesis of caveolinopathies, 42 contributing to the puzzling differences between clinical phenotypes. 43 …”