Dystrophic Axonal Swellings Develop as a Function of Age and Diabetes in Human Dorsal Root Ganglia

Schmidt, Robert E.; Dorsey, Denise A.; Parvin, Curtis A.; Beaudet, Lucie N.; Plurad, Santiago B.; Roth, Kevin A.

doi:10.1097/00005072-199709000-00008

Cited by 63 publications

(60 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This was also observed to be the case in streptozotocin-induced type 1 diabetes in rats, in which there is no significant loss of DRG neurons for up to 12 months duration (3,36). There are also similar findings in human postmortem studies of type 2 diabetic patients (23,24). With HIV infection of cultured human DRG neurons, Hahn et al (7) also observed a differential effect on axons and cell bodies.…”

Section: Discussionmentioning

confidence: 65%

“…Vacuolation was also observed ultrastructurally with axons and presynaptic nerve endings. The involvement of ax- ons has a striking morphological similarity to the neurodegenerative changes that occur in diabetic sensory and autonomic neuropathy, in which a key feature is the presence of axonal swellings that are composed of accumulations of mitochondria and cytoskeletal proteins (e.g., neurofilaments) (12,24). Diabetes-induced oxidative stress in sensory neurons and peripheral nerves is demonstrated by increased production of reactive oxygen species (16,22,35), lipid peroxidation (19,35), and protein nitrosylation (18).…”

Section: Discussionmentioning

confidence: 99%

“…In this model, dendritic beading and axonal swellings were prominent, and neuronal process degeneration appeared to account for the severe clinical disease and fatal outcome. The axonal swellings exhibited striking morphological similarities to the neurodegenerative changes that occur in the axons of neurons in diabetic sensory and autonomic neuropathy and in human immunodeficiency virus (HIV) infection (4,12,24,35). Studies of cultured adult dorsal root ganglion (DRG) sensory neurons from type 1 diabetic rats have revealed that glucose-induced oxidative stress is a key instigator of axonal swellings (35).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Role of Oxidative Stress in Rabies Virus Infection of Adult Mouse Dorsal Root Ganglion Neurons

Jackson

Kammouni

Zherebitskaya

et al. 2010

J Virol

View full text Add to dashboard Cite

Rabies virus infection of dorsal root ganglia (DRG) was studied in vitro with cultured adult mouse DRG neurons. Recent in vivo studies of transgenic mice that express the yellow fluorescent protein indicate that neuronal process degeneration, involving both dendrites and axons, occurs in mice infected with the challenge virus standard (CVS) strain of rabies virus by footpad inoculation. Because of the similarities of the morphological changes in experimental rabies and in diabetic neuropathy and other diseases, we hypothesize that neuronal process degeneration occurs as a result of oxidative stress. DRG neurons were cultured from adult ICR mice. Two days after plating, they were infected with CVS. Immunostaining was evaluated with CVS-and mock-infected cultures for neuron specific ␤-tubulin, rabies virus antigen, and amino acid adducts of 4-hydroxy-2-nonenal (4-HNE) (marker of lipid peroxidation and hence oxidative stress). Neuronal viability (by trypan blue exclusion), terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining, and axonal growth were also assessed with the cultures. CVS infected 33 to 54% of cultured DRG neurons. Levels of neuronal viability and TUNEL staining were similar in CVS-and mock-infected DRG neurons. There were significantly more 4-HNE-labeled puncta at 2 and 3 days postinfection in CVS-infected cultures than in mock-infected cultures, and axonal outgrowth was reduced at these time points in CVS infection. Axonal swellings with 4-HNE-labeled puncta were also associated with aggregations of actively respiring mitochondria. We have found evidence that rabies virus infection in vitro causes axonal injury of DRG neurons through oxidative stress. Oxidative stress may be important in vivo in rabies and may explain previous observations of the degeneration of neuronal processes.Rabies is an acute viral infection of the central nervous system (CNS) that is usually fatal in humans and animals (10). Despite its lethality, under natural conditions only relatively mild histopathological lesions are typically found in association with a paucity of degenerative neuronal changes (9, 21). Li et al. (13) showed severe destruction and disorganization of axons and disruption of synaptic structures in silver-stained hippocampal sections from mice infected intracerebrally with the pathogenic N2C strain of rabies virus. Infection with the challenge virus standard (CVS) strain of rabies virus has recently been evaluated using hindlimb footpad inoculation in adult transgenic mice expressing yellow fluorescent protein (26). In this model, dendritic beading and axonal swellings were prominent, and neuronal process degeneration appeared to account for the severe clinical disease and fatal outcome. The axonal swellings exhibited striking morphological similarities to the neurodegenerative changes that occur in the axons of neurons in diabetic sensory and autonomic neuropathy and in human immunodeficiency virus (HIV) infection (4,12,24,35). Studies of cultured adult dorsal root ganglio...

show abstract

Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Role of Oxidative Stress in Rabies Virus Infection of Adult Mouse Dorsal Root Ganglion Neurons

Jackson

Kammouni

Zherebitskaya

et al. 2010

J Virol

View full text Add to dashboard Cite

show abstract

“…12 Accumulation of neurofilaments and microtubules, followed by their degradation into amorphous debris, can result in the formation of axonal swellings. 13,14,18,19 In healthy subjects, IENF typically showed tiny varicosity, which likely reflected the uneven distribution of cytoskeletal components. Normal IENF often ended with a single club-like enlargement, as previously described.…”

Section: (Pgp) (A C E and G) And ␤-Tubulin (B) Microtubule-associmentioning

confidence: 99%

Axonal swellings predict the degeneration of epidermal nerve fibers in painful neuropathies

et al. 2003

View full text Add to dashboard Cite

Abstract-Objective:To correlate the density of swellings in intraepidermal nerve fibers (IENF) with the longitudinal measurement of the epidermal innervation density in patients with painful neuropathy and to assess the predictive value of IENF swelling to progression of neuropathy. Methods: Fifteen patients with persistent pain in the feet underwent neurologic examination, nerve conduction studies, quantitative sensory examination, and skin biopsies at proximal thigh and distal leg. In all patients and in 15 healthy subjects, IENF density and swelling ratio (no. swellings/no. IENF) were quantified at distal leg. Follow-up study, including IENF density and swelling ratio quantification, was performed a mean of 19.2 months later. Double staining confocal microscope studies using anti-human protein-gene-product 9.5, anti-tubule, anti-neurofilament, and anti-synaptophysin antibodies were performed to assess specific accumulation within swellings. Ultrastructural investigation of IENF was also carried out. Results: Patients with neuropathy had lower density of IENF and higher swelling ratio than healthy subjects (p Ͻ 0.01) at distal leg. At follow-up, patients showed a parallel decrease in both IENF density (p ϭ 0.02) and swelling ratio (p ϭ 0.002). However, swelling ratio remained higher (p ϭ 0.03) than in controls. Progression of neuropathy was confirmed by the decay in sural nerve sensory nerve action potential amplitude. Double immunostaining studies suggest accumulation of tubules and ubiquitin-associated proteins within swellings. Swollen and vacuolated IENF were identified in patients with neuropathy by conventional and immuno-electron microscopy. Conclusions: Increased swelling ratio predicted the decrease in IENF density in patients with painful neuropathy. Its quantification could support earlier diagnosis of sensory axonopathy.

show abstract

“…There is good evidence that the persistent activation of JNK causes phosphorylation of inappropriate substrates, in particular non-nuclear substrates such as neurofilaments, where it could be the direct cause of hyperphosphorylation [96]. Hyperphosphorylation of neurofilaments is associated with filamentous tangles, axodendritic swell-ing and neurodegeneration associated and is present in a range of diseases, including human diabetic neuropathy [139,140]. It is, therefore, possible that JNK activation could be pathogenic through neurofilament phosphorylation in several disease states.…”

Section: Diabetic Neuropathymentioning

confidence: 99%

Mitogen-activated protein kinases as glucose transducers for diabetic complications

1999

View full text Add to dashboard Cite

The results of the Diabetes Control and Complications Trial [1] emphatically confirmed the heroic studies of Jean Pirart [2±4], showing that poor control of glycaemia in Type I (insulin-dependent) diabetes mellitus predisposes patients to chronic complications. This has led to the tacit assumption that glucose, at supranormal concentrations, is the agent of damage. Participation of hypoinsulinaemia or other manifestations of poor control cannot be discounted but glucose itself certainly has the capacity to disturb biosystems. It can do this in a variety of ways, so that hypotheses to explain specific complications ± retinopathy, nephropathy and neuropathy ± starting from high glucose are tenable, testable and, therefore, useful.Figure 1 presents a simple generic plan by which complications develop. It usefully discriminates between metabolic effects of glucose on the target cells showing the complication and the exacerbating effect of independent accelerators, such as arterial hypertension in diabetic nephropathy. Not all independent accelerators have, however, as clearly defined a rela- Diabetologia (1999) AbstractThe damaging effects of glucose on the cells which contribute to the development of diabetic complications are ill-understood. There are three major hypotheses ± the sorbitol pathway, non-enzymatic glycation of proteins and increased oxidative stress ± and many examples illustrate inter-connections between the three. It is suggested that these pathways, together with other biochemical anomalies arising from hyperglycaemia, can synergise by sharing the capacity to activate mitogen-activated protein kinases (MAP kinases) and that these enzymes in actual fact form glucose transducers. The more recent hypothesis, namely that activation of a specific isoform of protein kinase C (PKC) underpin damaging changes in retinopathy and neuropathy, can also be related because protein kinase C is an effective activator of mitogen-activated protein kinases. These latter kinases phosphorylate transcription factors, which in turn alter the balance of gene expression. In this way they can alter cellular phenotype, promote division or increase production of extracellular material. In short, mitogen-activated protein kinases have the capacity to trigger all the cellular events necessary for the development of diabetic nephropathy, retinopathy and neuropathy and it is suggested that their pharmacological modulation might provide therapeutic control of these conditions. [Diabetologia (1999

show abstract

Dystrophic Axonal Swellings Develop as a Function of Age and Diabetes in Human Dorsal Root Ganglia

Cited by 63 publications

References 0 publications

Role of Oxidative Stress in Rabies Virus Infection of Adult Mouse Dorsal Root Ganglion Neurons

Role of Oxidative Stress in Rabies Virus Infection of Adult Mouse Dorsal Root Ganglion Neurons

Axonal swellings predict the degeneration of epidermal nerve fibers in painful neuropathies

Mitogen-activated protein kinases as glucose transducers for diabetic complications

Contact Info

Product

Resources

About