Abstract

Diabetic neuropathy is the most common peripheral neuropathy in western countries. Although every effort has been made to clarify the pathogenic mechanism of diabetic neuropathy, thereby devising its ideal therapeutic drugs, neither convinced hypotheses nor unequivocally effective drugs have been established. In view of the pathologic basis for the treatment of diabetic neuropathy, it is important to enhance nerve regeneration as well as prevent nerve degeneration. Nerve regeneration or sprouting in diabetes may occur not only in the nerve trunk but also in the dermis and around dorsal root ganglion neurons, thereby being implicated in the generation of pain sensation. Thus, inadequate nerve regeneration unequivocally contributes to the pathophysiologic mechanism of diabetic neuropathy. In this context, the research on nerve regeneration in diabetes should be more accelerated. Indeed, nerve regenerative capacity has been shown to be decreased in diabetic patients as well as in diabetic animals. Disturbed nerve regeneration in diabetes has been ascribed at least in part to all or some of decreased levels of neurotrophic factors, decreased expression of their receptors, altered cellular signal pathways and/or abnormal expression of cell adhesion molecules, although the mechanisms of their changes remain almost unclear. In addition to their steady-state changes in diabetes, nerve injury induces injury-specific changes in individual neurotrophic factors, their receptors and their intracellular signal pathways, which are closely linked with altered neuronal function, varying from neuronal survival and neurite extension/nerve regeneration to apoptosis. Although it is essential to clarify those changes for understanding the mechanism of disturbed nerve regeneration in diabetes, very few data are now available. Rationally accepted replacement therapy with neurotrophic factors has not provided any success in treating diabetic neuropathy. Aside from adverse effects of those factors, more rigorous consideration for their delivery system may be needed for any possible success. Although conventional therapeutic drugs like aldose reductase (AR) inhibitors and vasodilators have been shown to enhance nerve regeneration, their efficacy should be strictly evaluated with respect to nerve regenerative capacity. For this purpose, especially clinically, skin biopsy, by which cutaneous nerve pathology including nerve regeneration can be morphometrically evaluated, might be a safe and useful examination.

Abbreviations: ABC, avidin-biotinylated enzyme complex; ALS, amyotrophic lateral sclerosis; AP-1, activator protein-1; AR, aldose reductase; ARI, aldose reductase inhibitor; ATF-2, activating transcription factor-2; BDNF, brain-derived neurotrophic factor; bFGF, basic fibroblast growth factor; Cdk5, cyclin-dependent kinase 5; CGRP, calcitonin gene-related protein; CMAP, compound muscle action potential; CNS, central nervous system; CNTF, ciliary neurotrophic factor; CRE, cAMP responsive element; CSF, cerebrospinal fluid; DRG, dorsal root ganglion; ELISA, enzyme-linked immunosorbent assay; ERK1, extracellular signal-related kinase 1 (42 kDa); ERK2, extracellular signal-related kinase 2 (44 kDa); GAP-43, growth-associated protein-43; GDC, granular disintegration of the cytoskeleton; GDNF, glial cell-derived neurotrophic factor; GFRα, GDNF family receptor α component; GPI, glycosylphosphatidylinositol; GSK-3β, glycogen synthase-3β; ICAM, intercellular cell adhesion molecule; IDDM, insulin-dependent diabetes mellitus; IGF, insulin-like growth factor; IGFBP, insulin-like growth factor binding protein; JNK, c-Jun N-terminal kinase; L1, L1-CAM (L1 cell adhesion molecule); LIF, leukemia inhibitory factor; MAG, myelin-associated glycoprotein; MAP, mitogen-activated protein; MAPK, MAP kinase; MAPKK, MAP kinase kinase; MMPs, matrix metalloproteinases; MNF, myelinated nerve fiber; NCAM, neural cell adhesion molecule; NF, neurofilament; NF-H, high molecular weight mass (200 kDa) neurofilament; NF-L, light molecular weight mass (68 kDa) neurofilament; NF-M, medium molecular weight mass (145 kDa) neurofilament; NGF, nerve growth factor; NIDDM, non-insulin-dependent diabetes mellitus; NPY, neuropeptide Y; NT-3, neurotrophin-3; NT-4/5, neurotrophin-4/5; p75NTR, p75 neurotrophin receptor; pak, p21-activated kinase; PGE1, prostaglandin E1; PGI2, prostaglandin I2; PGP 9.5, protein gene-product 9.5; PKC, protein kinase C; PNS, peripheral nervous system; RET, glial cell-derived neurotrophic factor receptor tyrosine kinase; rhNGF, recombinant human nerve growth factor; SAPK, stress-activated protein kinase; SCa, slow component a; SCb, slow component b; STZ, streptozocin; TNF-α, tumor necrosis factor-α; TrkA, tyrosine-receptor kinase A; TUNNEL, terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling; UMNF, unmyelinated nerve fiber; VEGF, vascular endothelial growth factor; VIP, vosoactive intestinal polypeptide

Article Outline

1. Introduction: aims and scope of review

2. Intrinsic and extrinsic factors associated with nerve regeneration

2.1. Intrinsic neuronal regenerating activity

2.1.1. Growth-associated protein-43 (GAP-43)

2.1.2. Tubulin

2.2. Growth factors

2.2.1. Neurotrophins

2.2.1.1. Nerve growth factor (NGF)

2.2.1.2. Brain-derived neurotrophic factor (BDNF)

2.2.1.3. Neurotrophin-3 (NT-3)

2.2.1.4. Neurotrophin-4/5 (NT-4/5)

2.2.2. Insulin-like growth factors

2.2.2.1. Insulin-like growth factor-I and -II (IGF-I/II)

2.2.2.2. Insulin-like growth factor binding protein (IGFBP)

2.2.3. Hematopoietic cytokines

2.2.3.1. Ciliary neurotrophic factor (CNTF)

2.2.3.2. Tumor necrosis factor-α (TNF-α)

2.2.3.3. Interleukin-6 (IL-6)

2.2.4. Glial cell line-derived neurotrophic factor (GDNF)

2.3. Extracellular matrix

2.3.1. Laminin

2.3.2. Fibronectin

2.3.3. Collagen

2.3.4. Matrix metalloproteinases (MMPs)

2.4. Cell adhesion molecules

2.4.1. Neural cell adhesion molecule (NCAM)

2.4.2. L1 cell adhesion molecule (L1)

2.4.3. Myelin-associated glycoprotein (MAG)

2.4.4. Others

2.5. Cell signal messengers

2.5.1. cAMP

2.5.2. Protein kinase C (PKC)

2.5.3. Mitogen-activated protein kinases (MAPKs)

2.5.3.1. c-Jun N-terminal protein kinase (JNK)

2.5.3.2. Extracellular signal-related kinase 1/2 (ERK1/2)

2.5.4. Cyclin-dependent kinases and small GTPases

2.6. Immediate early genes

2.6.1. c-Jun

2.6.2. c-Fos

2.6.3. Activating transcription factor-2 (ATF-2)

2.7. Endoneurial microenvironment including vascularization

3. Experimental studies

3.1. Relevance of examining nerve regeneration in experimental diabetic models

3.2. Evaluation of nerve regeneration in animal models

3.3. Degeneration and regeneration of the peripheral nerve

3.3.1. Cellular events in Wallerian degeneration

3.3.2. Early axonal changes

3.3.3. Schwann cell responses

3.3.4. Macrophage responses

3.3.5. Nerve regeneration

3.3.6. Axonal sprouting

3.3.7. Growth cone and axonal elongation

3.3.8. Cell body reaction

3.3.9. Maturation of regenerating nerve fibers

3.4. Wallerian degeneration in experimental diabetes

3.4.1. Axonal degeneration and pathway clearance in diabetes

3.4.2. Degradation of cytoskeletal proteins in diabetes

3.4.3. Macrophage responses in diabetes

3.4.4. Schwann cell response in diabetes

3.5. Nerve regeneration in experimental diabetes

3.5.1. Axonal sprouting, elongation and maturation in diabetes

3.5.2. Cell body reaction in diabetes

3.5.3. Partial denervation in diabetes

4. Clinical observation

4.1. Pathological findings suggesting nerve regeneration in diabetic nerves

4.2. Rationale for using neurotrophic factors for diabetic patients

4.3. Clinical trials: current state

4.3.1. Lessens from other trials: amyotrophic lateral sclerosis and toxic neuropathies

4.3.2. Nerve growth factor

4.3.3. Other neurotrophic factors

4.3.4. Aldose reductase inhibitors

4.4. Specific problems for the use of neurotrophic factors

5. Regenerating nerve fibers with special reference to pain generation

6. Evaluation of nerve pathology including regeneration by skin biopsy

6.1. Morphometric analysis of cutaneous nerves by immunohistochemistry

6.2. Morphometric analysis of cutaneous nerves by ultrastructural examination

6.3. Neurotrophins and cutaneous innervation

6.4. Evaluation of therapeutic compounds for diabetic neuropathy by skin biopsy

7. Neuronal cell death

7.1. Apoptosis induced by the sera from diabetic patients

7.2. Apoptosis is induced under high glucose or hyperglycemia

7.3. Apoptosis and neurotrophins/MAP kinase/cAMP in hyperglycemia

7.3.1. Neurotrophins and their receptors

7.3.2. MAP kinases

7.3.3. cAMP

8. Conclusion

References