Expression of transcription factor ATF3 in sensory neurons in dorsal root ganglion and in Schwann cells in sciatic nerve of diabetic (BB and Goto-Kakizaki rats; experimental models of types 1 and 2 diabetes, respectively) and healthy rats were examined by immunocytochemistry after nerve compression (silicone tube) for 3, 6 or 14 days. ATF3-stained sensory neurons in dorsal root ganglia and Schwann cells at compression site were more frequent in diabetic BB rats. Decompression of nerves in Goto-Kakizaki rats did not reduce number of ATF3-stained cells. Diabetes (BB; i.e. type 1) confers on the peripheral nerve an increased susceptibility to nerve compression indicated by an increased expression of stained ATF3 neurons and Schwann cells.
"Furthermore, animal experiments have shown that the Schwann cells around the axons also are affected by the compression. Experimental studies have shown that the response is more pronounced in both neurons and Schwann cells in diabetic animals than in healthy ones . The intracellular transport in the axon, i.e. axonal transport, provides the distal part of the nerve with essential substances as well as conveying information from the periphery up to the nerve-cell body. "
[Show abstract][Hide abstract] ABSTRACT: Prolonged exposure to hand-held vibrating tools may cause a hand-arm vibration syndrome (HAVS), sometimes with individual susceptibility. The neurological symptoms seen in HAVS are similar to symptoms seen in patients with carpal tunnel syndrome (CTS) and there is a strong relationship between CTS and the use of vibrating tools. Vibration exposure to the hand is known to induce demyelination of nerve fibres and to reduce the density of myelinated nerve fibres in the nerve trunks. In view of current knowledge regarding the clinical effects of low nerve-fibre density in patients with neuropathies of varying aetiologies, such as diabetes, and that such a low density may lead to nerve entrapment symptoms, a reduction in myelinated nerve fibres may be a key factor behind the symptoms also seen in patients with HAVS and CTS. Furthermore, a reduced nerve-fibre density may result in a changed afferent signal pattern, resulting in turn in alterations in the brain, further prompting the symptoms seen in patients with HAVS and CTS. We conclude that a low nerve-fibre density lead to symptoms associated with nerve entrapment, such as CTS, in some patients with HAVS.
Journal of Occupational Medicine and Toxicology 03/2014; 9(1):7. DOI:10.1186/1745-6673-9-7 · 1.62 Impact Factor
"ATF3 is strongly upregulated in peripheral glia following various types of injury. Schwann cells in the distal stump of injured sciatic nerves in rats and mice upregulate ATF3 (Hunt et al., 2004; Isacsson et al., 2005; Kataoka et al., 2007; Dahlin et al., 2008; Saito and Dahlin, 2008) in addition to c-Jun. Glial cells including Schwann and satellite cells in the superior cervical ganglion expressed ATF3 after decentralization (section of the cervical sympathetic trunk); this procedure induces the anterograde degeneration of preganglionic fibers and some of the ATF3 expression was probably around degenerating fibers (Zigmond and Vaccariello, 2007). "
[Show abstract][Hide abstract] ABSTRACT: Activating transcription factor 3 (ATF3) belongs to the ATF/cyclic AMP responsive element binding family of transcription factors and is often described as an adaptive response gene whose activity is usually regulated by stressful stimuli. Although expressed in a number of splice variants and generally recognized as a transcriptional repressor, ATF3 has the ability to interact with a number of other transcription factors including c-Jun to form complexes which not only repress, but can also activate various genes. ATF3 expression is modulated mainly at the transcriptional level and has markedly different effects in different types of cell. The levels of ATF3 mRNA and protein are normally very low in neurons and glia but their expression is rapidly upregulated in response to injury. ATF3 expression in neurons is closely linked to their survival and the regeneration of their axons following axotomy, and that in peripheral nerves correlates with the generation of a Schwann cell phenotype that is conducive to axonal regeneration. ATF3 is also induced by Toll-like receptor (TLR) ligands but acts as a negative regulator of TLR signaling, suppressing the innate immune response which is involved in immuno-surveillance and can enhance or reduce the survival of injured neurons and promote the regeneration of their axons.
"In contrast with Wright et al,42 a study by Dahlin et al44 concluded that diabetes does not in itself cause an increase in ATF3 expression, but it does enhance the expression of ATF3 in response to nerve injury. To investigate whether the higher ATF3 expression seen in DRG cultures from diabetic rats is not just due to a higher vulnerability of the neurons to the isolation procedure, we undertook an RT-PCR analysis of whole-mounted DRGs for the stress-related genes, ATF3, c-jun, and c-fos. "
[Show abstract][Hide abstract] ABSTRACT: Diabetic neuropathy is a complication of diabetes mellitus that develops in about 50% of people with diabetes. Despite its widespread occurrence and devastating effects, this complication is still not fully understood, and there is no treatment available to prevent its development.
In this study, immunocytochemistry for activating transcription factor 3, a marker for cell injury, was used to investigate the stress response in dorsal root ganglion neurons in both in vitro and ex vivo models of diabetic neuropathy.
Our findings showed increased activating transcription factor 3 expression in hyperglycemic culture conditions and in dorsal root ganglion neurons isolated from diabetic rats. Glial cell line-derived neurotrophic factor, a substance with known neuroprotective properties, was able to reduce diabetes mellitus-induced neuronal stress in vitro, while gabapentin and carbamazepine, currently used to treat neuropathic pain, showed only limited effects.
Growth factors may have a therapeutic benefit as neurotrophic agents in the treatment of diabetic peripheral neuropathy, but gabapentin and carbamazepine have no direct protective effect on sensory neurons. This research also indicates that immunocytochemistry for activating transcription factor 3 is a valuable tool for evaluation of pharmacological substances in dorsal root ganglion cultures.
Journal of Pain Research 02/2011; 4:55-65. DOI:10.2147/JPR.S15452
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