Therapies For Nerve Regeneration

Neurotrophins

Neurotrophic factors are proteins that promote survival of neurons regulating gene expression through second messenger systems. These proteins may induce morphological changes, nerve differentiation, nerve cell proliferation, and induce neurotransmitter expression and release. Subsequently, reduction in levels of neurotrophic factors (97) can lead to neuronal loss, possibly through activation of apoptosis (98). Many proteins have properties and characteristics of neurotrophic factors, including cytokine-like growth factors, TGF-P, NT3, nerve growth factor (NGF), insulin-like growth factor (IGF)-1, and VEGF. Although only a few neurotrophic factors have been extensively investigated, there are number of proteins that have been identified as neurotrophic factors (31,99). Many of these proteins appear to have altered expression in nerves of patients with diabetes (77). For example, interleukin-6, a cytokine-like growth factor may play a role in cell proliferation (100). Although their function is not well understood, IGFs-I and -II have been shown to regulate growth and differentiation of neurons (101). IGF, NGF, and other neurotrophins have been shown to be members of a family of proteins supporting the growth and regeneration of neurons. Often these growth factors are associated with changes in nerve structure through apoptosis or proliferation. The laminin y gene is upregulated in normal animals undergoing postsection sciatic nerve regeneration (102,103). This process is impaired in diabetes. Other extracellular matrix proteins are also altered in neuropathic nerves (104). Therefore, understanding the role of neurotrophic factors has been the focus of much investigation.

Nerve Growth Factor

Neurons affected in diabetic neuropathy are developmentally dependent on NGF. Therefore, a decline in NGF synthesis in patients with diabetes plays a role in the pathogenesis of neuropathy, especially small fibers (105). More specifically, NGF has been shown to be trophic for sympathetic ganglion neurons and neural crest-derived system (99). Neurotrophins, including NGF, bind to high-affinity receptors, Trk (tropomyosin-related kinases) (106) or low-affinity receptors p75 (107); both receptors may activate different signaling cascades.

Neurotrophic proteins are reduced in patients with diabetes. NGF protein levels in the serum of patients with diabetes are suppressed (108). Additionally, diabetes might result in decreased serum IGF and increased IGF-I binding protein-I (109) thereby inhibiting the protein's downstream effects. Despite increasing evidence that growth factors are suppressed in patients with diabetes, there is no direct link between neurotrophic factors and the pathogenesis of diabetic neuropathy (99) and preliminary studies of both NGF and NT3 treatment have met with limited success.

There is now considerable evidence in animal models of diabetes that decreased expression of NGF and its high-affinity receptor, trk A, reduces retrograde axonal transport of NGF and diminishes support of small unmyelinated neurons and their neuropeptides, such as substance P and CGRP—both potent vasodilators (110-112). Furthermore, recombinant human NGF (rhNGF) administration restores these neuropeptide levels toward normal and prevents the manifestations of sensory neuropathy in animals (113). In a 15 center, double-blind, placebo-controlled study of the safety and efficacy of rhNGF in 250 subjects with symptomatic small fiber neuropathy (19), rhNGF improved the neurological impairment score of the lower limbs, and improved small nerve fiber function cooling threshold (A5-fibers) and the ability to perceive heat pain (C-fiber) compared with placebo (114). These results were consistent with the postulated actions of NGF on trk A receptors present on small fiber neurons. This led to two large multicenter studies conducted in the US and the rest of the world. Results of these two studies were presented at the ADA meetings in June 1999 (115). Regrettably, rhNGF was not found to have beneficial effects on and above placebo. The reason for this dichotomy has not been resolved, but this has somewhat dampened the enthusiasm for growth factor therapy of diabetic neuropathy.

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