Growth Factors as Therapeutics for Diabetic Neuropathy

Abstract

There has been a rapid growth in appreciation of the diverse array of neurotrophic factors, growth factors and other biological molecules that have the capacity to support adult neurons and direct reparative processes after injury to the nervous system. Understanding the mechanisms by which these factors operate offers the opportunity to use either the factors themselves or other agents that manipulate relevant signal transduction pathways as therapeutics for a wide range of neurodegenerative diseases, including diabetic neuropathy. In this review, we aim to summarize current knowledge of the extent to which loss of neurotrophic support contributes to the pathogenesis of diabetic neuropathy, present pre-clinical evidence that supports the potential efficacy of growth factors or their mimetics against indices of diabetic neuropathy and highlight the emerging approaches to manipulating neuronal support mechanisms that show potential for translation to clinical use. Recent advances in directly assessing the progression of nerve damage in diabetic patients will hopefully facilitate renewed clinical evaluation of treatments for degenerative diabetic neuropathy and provide the framework for advancing the potential of growth factors as a therapy for this widespread and currently untreatable condition.

Diabetic Peripheral Neuropathy: Should a Chaperone Accompany Our Therapeutic Approach?

“…Many excellent reviews have been published that 1) describe the various biochemical insults that contribute to the pathogenesis of DPN and 2) outline treatment strategies directed at blocking either causal mechanisms or treating neuropathic pain (Leinninger et al, 2004;Vincent et al, 2004Vincent et al, , 2009bPop-Busui et al, 2006;Calcutt and Backonja, 2007;Zochodne, 2007Zochodne, , 2008Calcutt et al, 2008Calcutt et al, , 2009Edwards et al, 2008;Tavakoli and Malik, 2008;Veves et al, 2008;Obrosova, 2009a;Fernyhough et al, 2010;Sivitz and Yorek, 2010;Malik et al, 2011). Thus, the intent of the current review is to briefly highlight and update many of these features and add to the discussion by proposing that both pharmaco-1 Abbreviations: AGE, advanced glycation end product; AR, aldose reductase; BDNF, brain-derived neurotrophic factor; COX, cyclooxygenase; DCCT, Diabetes Control and Complication Trial; DPN, diabetic peripheral neuropathy; DRG, dorsal root ganglia; F-6-P, fructose-6 phosphate; FDA, U.S. Food and Drug Administration; GDNF, glial cell-derived neurotrophic factor; GlcNAc, N-acetyl glucosamine; HETE, hydroxyeicosatetraenoic; HSF, heat-shock factor; Hsp, heat-shock protein; HSR, heat-shock response; 3R,4S,6-dimethyl-tetrahydro-2H-pyran-2-yloxy]-8-methyl-2-oxo-2H-chromen-3-yl}acetamide; LA, ␣-lipoic acid; MAPK, mitogen-activated protein kinase; MNCV, motor nerve conduction velocity; MnSOD, manganese superoxide dismutase; mtHsp70, mitochondrial paralog of Hsp70; NF-B, nuclear factor B; NGF, nerve growth factor; NT, neurotrophin; PARP, poly(ADP-ribose) polymerase; PKC, protein kinase C; PKI-166, 4-phenethylamino-6-(yderoxyl)phenyl-7H-pyrrolo(2,3-d)pyrimidine; RAGE, receptor for AGE; RBX, ruboxistaurin; ROS, reactive oxygen species; SNCV, sensory nerve conduction velocity; sRAGE, soluble RAGE; STZ, streptozotocin; TCA, tricyclic antidepressant; TNF, tumor necrosis factor.…”

Diabetic neuropathy: therapies on the horizon

“…These factors manipulate relevant signal transduction pathways and thus can be used as therapeutics for a wide range of neurodegenerative diseases, including diabetic neuropathy. [22] Recent advances in directly assessing the progression of nerve damage in diabetic patients will hopefully facilitate renewed clinical evaluation of treatments for degenerative DN and may provide the framework for advancing the potential of growth factors as therapy for currently untreatable conditions.…”

Muscle NT-3 levels increased by exercise training contribute to the improvement in caudal nerve conduction velocity in diabetic rats

“…Applying NT-3 to the spinal cord of rodents can compensate for induced damage, as shown by increased levels of axonal regeneration, reduced atrophy and increased levels of functional recovery (6,(27)(28)(29)(30). In this study, muscle NT-3 levels in the diabetic groups subjected to swimming training (D-Ex1 and D-Ex2 groups) significantly increased compared to the levels in the diabetic rats which had remained sedentary (D-Sed), and they were close to the levels of the 2 control groups (C-Ex1 and C-Sed).…”

“…NT-3 plays a crucial role in mediating central nervous system plasticity and regeneration in the spinal cord and muscle. Short-term STZ-induced diabetes causes a reduction in muscle NT-3 mRNA and protein expression, which leads to a decreased retrograde axonal transport of NT-3 to the neuronal cell body and consequent sub-optimal neurotrophic support (6). Previous studies have shown that the continuous production of NT-3 by the latency-associated promoter 2 (LAP2)-driven expression of the transgene from a herpes simplex virus (HSV) vector over a 6-month period protects against the progression of diabetic neuropathy in mice (7), and treatment with NT-3 improves the nerve conduction velocity (NCV) of both the large motor and sensory fibres in STZ-induced diabetic rodents (8).…”