Degeneration Of Sensory Nerve Fibers Research Articles

Efficacy of radial shock wave therapy on rat models of adjuvant arthritis

BackgroundExtracorporeal shock wave therapy (ESWT) is an effective treatment for musculoskeletal pain, tendinopathy, and fasciitis with an anti-inflammatory effect. ESWT can be categorized into two groups: radial pressure wave (RPW) and focused shock wave (FSW). Although there have been several studies on the inflammation and pain-improvement mechanisms of FSW, there are few studies on the pain-improvement mechanisms of RPW. This study aimed to elucidate the efficacy of RPW in a rat model of adjuvant arthritis. MethodsNinety-six rats were randomly categorized into three groups: RPW, control, and sham as follows: (I) RPW group, which received RPW application after complete Freund's adjuvant (CFA) injection; (II) Control group, which received only CFA injection; and (III) Sham group, which received only saline injection. All rats were evaluated at 0, 4, 7, 14, 28, and 56 days post-RPW application based on foot circumference, von Frey test, and immunohistochemistry of nerve fibers for calcitonin gene-related peptide (CGRP) and protein gene product (PGP) 9.5 in plantar skins. ResultsThere were no significant differences in foot circumference between the RPW and control groups at any time point. The RPW group showed significant improvements in the von Frey test results on days 7 and 14. The total CGRP-immunoreactive (ir) and PGP9.5-ir nerve fiber lengths in the RPW group decreased on day 0; however, both were increased in the control group. The CGRP-ir and PGP9.5-ir nerve fibers in the RPW group were significantly shorter than those in the control group until day 14 after RPW. ConclusionsRPW improved the mechanical hypersensitivity between days 7 and 14 after application. Like FSW, RPW also induced the degeneration of sensory nerve fibers in the skin in the early period after irradiation, and reinnervation occurred between 14 and 28 days. Thus, our results demonstrate one of the pain relief mechanisms after RPW application.

Interactions between the 12/15‐lipoxygenase pathway and MAPK activation in diabetic peripheral neuropathy

Both MAPK activation and, recently, the 12/15-lipoxygenase (12/15-LO) pathway, have been implicated in the pathogenesis of diabetic peripheral neuropathy (DPN). We evaluated the relationship between the two mechanisms using the 12/15-LO inhibitor cinnamyl-3,4-dihydroxy-á-cyanocinnamate (CDC) and 12/15-LO−/− mice. Male wild-type (WT) and 12/15-LO−/− mice were made diabetic with streptozotocin. Wild-type mice with 12–14 wk duration of STZ diabetes displayed motor and sensory nerve conduction velocity deficits, thermal hypoalgesia, tactile allodynia, and intraepidermal nerve fiber loss. They also displayed 12/15-LO overexpression, 12(S)-HETE accumulation (a sign of increased 12/15-LO activity), and increased phosphorylation of p38, ERK, and SAP/JNK in the sciatic nerve. 12/15-LO inhibition with CDC (8 mgkg-1d-1, s.c., for 4 wks after initial 12 wks without treatment) or 12/15-LO gene deficiency alleviated peripheral nerve dysfunction and reduced p38 and ERK phosphorylation, without affecting SAP/JNK phosphorylation or intraepidermal nerve fiber loss, a sign of small sensory nerve fiber degeneration. In conclusion, the findings suggest interaction between the 12/15-LO pathway and p38 and ERK, but not SAP/JNK, in the development of peripheral nerve dysfunction characteristic for DPN. Neither 12/15-LO nor MAPK activation contribute to diabetes-induced intraepidermal nerve fiber loss.

The Usefulness of Current Perception Threshold Test in Both Lower Extremities with Diabetic Patient

[Purpose] The purpose of this study was to investigate the differences of sensory nerve fiber degeneration rates with duration of diabetes mellitus, as well as the difference in the degeneration rate of nerve fibers by selectively providing stimulation to the A-beta, A-delta, C fibers and measuring the current perception threshold (CPT) of diabetic patients. [Subjects] The subjects of this study were diabetic patients complaining of significant neuropathy symptoms such as numbness, dullness and paraesthesia. [Methods] Stimulations of 5 Hz, 250 Hz, and 2,000 Hz of frequency were generated with a Neurometer CPT (Neurotron Inc., Baltimore, MD, U.S.A.) and delivered selectively to C fibers, A-delta fibers and A-beta fibers. The intensity of the stimulation of 5 Hz, 250 Hz and 2,000 Hz increased to 0.01 mA. The independent t-test was used to compare perception thresholds. [Results] In the case of the right lower limb, the threshold value of A-beta fibers varied with the duration of diabetes and was particularly higher in the group of patients with 10 years or longer duration. The threshold value of A-delta fibers also varied with diabetes duration. That of the group with diabetes duration from 5 years to less than 10 years was not significantly different from that group with diabetes of the duration of 10 years or longer. However, the threshold value of the group with diabetes duration of 10 years or longer was higher than that of the groups of other durations. [Conclusion] The perception thresholds varied with diabetes duration and showed that degeneration of A-beta fibers and A-delta fibers that have myelin was more rapid than that of C fibers that are without myelin. Therefore, therapeutic interventions should be applied at the early stage of neuropathy.

Different Roles of 12/15-Lipoxygenase in Diabetic Large and Small Fiber Peripheral and Autonomic Neuropathies

Up-regulation of 12/15-lipoxygenase, which converts arachidonic acid to 12(S)- and 15(S)-hydroxyeicosatetraenoic acids, causes impaired cell signaling, oxidative-nitrosative stress, and inflammation. This study evaluated the role for 12/15-lipoxygenase in diabetic large and small fiber peripheral and autonomic neuropathies. Control and streptozotocin-diabetic wild-type and 12/15-lipoxygenase-deficient mice were maintained for 14 to 16 weeks. 12/15-lipoxygenase gene deficiency did not affect weight gain or blood glucose concentrations. Diabetic wild-type mice displayed increased sciatic nerve 12/15-lipoxygenase and 12(S)-hydroxyeicosatetraenoic acid levels. 12/15-lipoxygenase deficiency prevented or alleviated diabetes-induced thermal hypoalgesia, tactile allodynia, motor and sensory nerve conduction velocity deficits, and reduction in tibial nerve myelinated fiber diameter, but not intraepidermal nerve fiber loss. The frequencies of superior mesenteric-celiac ganglion neuritic dystrophy, the hallmark of diabetic autonomic neuropathy in mouse prevertebral sympathetic ganglia, were increased 14.8-fold and 17.2-fold in diabetic wild-type and 12/15-lipoxygenase-deficient mice, respectively. In addition, both diabetic groups displayed small (<1%) numbers of degenerating sympathetic neurons. In conclusion, whereas 12/15-lipoxygenase up-regulation provides an important contribution to functional changes characteristic for both large and small fiber peripheral diabetic neuropathies and axonal atrophy of large myelinated fibers, its role in small sensory nerve fiber degeneration and neuritic dystrophy and neuronal degeneration characteristic for diabetic autonomic neuropathy is minor. This should be considered in the selection of endpoints for future clinical trials of 12/15-lipoxygenase inhibitors.

12/15‐LIPOXYGENASE: ROLES IN LARGE AND SMALL FIBER PERIPHERAL DIABETIC NEUROPATHY

Upregulation of 12/15‐lipoxygenase (12/15‐LO), responsible for the formation of 12(S)‐HETE, 15(S)‐HETE and their derivatives from arachidonic acid, causes oxidative stress, MAPK activation, and inflammation. We evaluated the role for 12/15‐LO in peripheral diabetic neuropathy (PDN). Wild‐type (WT) and 12/15‐LO−/− mice were made diabetic with streptozotocin and maintained for 14 wks. 12/15‐LO deficiency did not affect glycemia. Diabetic WT mice displayed increased 12/15‐LO expressions and 12(S)‐HETE levels in sciatic nerve and spinal cord. Thermal hypoalgesia, tactile allodynia, and nerve conduction slowing were clearly manifest in diabetic WT mice, and were prevented or alleviated in diabetic 12/15‐LO−/− mice. Diabetic WT mice displayed reductions in myelinated fiber diameter and myelin thickness, indicative of axonal atrophy of large myelinated fibers, as well as in intraepidermal nerve fiber density (INFD), a sign of small sensory nerve fiber degeneration. 12/15‐LO deficiency prevented diabetes‐induced axonal atrophy, but not a reduction in INFD. In conclusion, the 12/15‐LO mechanism provides an important contribution to peripheral nerve dysfunction and axonal atrophy of large myelinated fibers, whereas its role in small sensory nerve fiber degeneration is minor. The latter should be considered in selection of endpoints for future clinical trials of 12/15‐LO inhibitors.

Poly(ADP-ribose) polymerase inhibition as a novel therapeutic approach against intraepidermal nerve fiber loss and neuropathic pain associated with advanced diabetic neuropathy: A commentary on “PARP Inhibition or gene deficiency counteracts intraepidermal nerve fiber loss and neuropathic pain in advanced diabetic neuropathy”

Poly(ADP-ribose) polymerase inhibition as a novel therapeutic approach against intraepidermal nerve fiber loss and neuropathic pain associated with advanced diabetic neuropathy: A commentary on “PARP Inhibition or gene deficiency counteracts intraepidermal nerve fiber loss and neuropathic pain in advanced diabetic neuropathy”

Nerve Regeneration after Radiofrequency Application

Background Many patients with chronic tendinosis have experienced early pain relief after application of bipolar radiofrequency treatment. It is hypothesized that the mechanism of action may be the acute degeneration and/or ablation of sensory nerve fibers. Hypothesis After ablation or degeneration by bipolar radiofrequency, nerve fibers will have the ability to regenerate with time. Study Design Controlled laboratory study. Methods Eighteen Sprague-Dawley rats were used in this study. These rats were divided into 3 groups (30, 60, and 90 days after bipolar radiofrequency). These rats were treated with 2 points of bipolar radiofrequency applications to the left hindpaws with the Topaz microdebrider device. Right hindpaws were used as the contralateral control. Tissues were processed for neural class III β-tubulin or calcitonin gene-related peptide immunohistochemistry by using the free-floating avidin biotin complex technique. The numbers of neural class III β-tubulin—immunoreactive and calcitonin gene-related peptide-immunoreactive nerve fibers in the epidermis were counted and compared with those in the contralateral control. Results Although the numbers of nerve fibers demonstrated by both the antibodies of neural class III β-tubulin and calcitonin gene-related peptide were significantly decreased (P < .0001) until 60 days after bipolar radiofrequency treatment, regeneration of the epidermal nerve fibers occurred 90 days after treatment. Conclusion Bipolar radiofrequency treatment induced degeneration of sensory nerve fibers immediately after treatment, but by 90 days posttreatment, there was evidence of complete regeneration. Clinical Relevance Early degeneration followed by later regeneration of nerve fibers after bipolar radiofrequency treatment may explain long-term postoperative pain relief after microtenotomy for tendinosis.

Role of nitrosative stress in early neuropathy and vascular dysfunction in streptozotocin-diabetic rats

Evidence for important roles of the highly reactive oxidant peroxynitrite in diabetic complications is emerging. We evaluated the role of peroxynitrite in early peripheral neuropathy and vascular dysfunction in STZ-diabetic rats. In the first dose-finding study, control and STZ-diabetic rats were maintained with or without the potent peroxynitrite decomposition catalyst Fe(III)tetrakis-2-(N-triethylene glycol monomethyl ether) pyridyl porphyrin (FP15) at 3, 5, or 10 mg.kg(-1).day(-1) in the drinking water for 4 wk after an initial 2 wk without treatment for assessment of early neuropathy. In the second study with similar experimental design, control and STZ-diabetic rats were maintained with or without FP15, 5 mg.kg(-1).day(-1), for vascular studies. Rats with 6-wk duration of diabetes developed motor and sensory nerve conduction velocity deficits, mechanical hyperalgesia, and tactile allodynia in the absence of small sensory nerve fiber degeneration. They also had increased nitrotyrosine and poly(ADP-ribose) immunofluorescence in the sciatic nerve and dorsal root ganglia. All these variables were dose-dependently corrected by FP15, with minimal differences between the 5 and 10 mg.kg(-1).day(-1) doses. FP15, 5 mg.kg(-1).day(-1), also corrected endoneurial nutritive blood flow and nitrotyrosine, but not superoxide, fluorescence in aorta and epineurial arterioles. Diabetes-induced decreases in acetylcholine-mediated relaxation by epineurial arterioles and coronary and mesenteric arteries, as well as bradykinin-induced relaxation by coronary and mesenteric arteries, were alleviated by FP15 treatment. The findings reveal the important role of nitrosative stress in early neuropathy and vasculopathy and provide the rationale for further studies of peroxynitrite decomposition catalysts in long-term diabetic models.

Nitrosative stress and peripheral diabetic neuropathy in leptin-deficient ( ob/ob) mice

Nitrosative stress contributes to nerve conduction slowing, thermal hypoalgesia, and impaired nitrergic innervation in animal models of Type 1 diabetes. The role for reactive nitrogen species in Type 2 diabetes-associated neuropathy remains unexplored. This study evaluated the role for nitrosative stress in functional and structural neuropathic changes in ob/ob mice, a model of Type 2 diabetes with mild hyperglycemia and obesity. Two structurally diverse peroxynitrite decomposition catalysts, Fe(III) tetrakis-2-( N-triethylene glycol monomethyl ether)-pyridyl porphyrin (FP15) and Fe(III) tetra-mesitylporphyrin octasulfonate (FeTMPS), were administered to control and 8-week-old ob/ob mice for 3 weeks at the doses of 5 mg kg − 1 day − 1 (FP15) and 5 and 10 mg kg − 1 day − 1 (FeTMPS). The 11-week-old ob/ob mice developed motor nerve conduction velocity (MNCV) and hind-limb digital sensory nerve conduction velocity (SNCV) deficits, thermal hypoalgesia, tactile allodynia, and a remarkable (∼ 78%) loss of intraepidermal nerve fibers. They also had increased nitrotyrosine and poly(ADP-ribose) immunofluorescence in the sciatic nerve, spinal cord, and dorsal root ganglion neurons. Treatment with two structurally diverse peroxynitrite decomposition catalysts was associated with restoration of normal MNCV and SNCV, and alleviation of thermal hypoalgesia. Tactile response thresholds increased in response to peroxynitrite decomposition catalyst treatment, but still remained ∼ 2.7- to 3.2-fold lower compared with non-diabetic controls. Intraepidermal nerve fiber loss was not alleviated by either FP15 or FeTMPS. Nitrotyrosine and poly(ADP-ribose) immunofluorescence in sciatic nerve, spinal cord, and dorsal root ganglia of peroxynitrite decomposition catalyst-treated ob/ob mice were essentially normal. In conclusion, nitrosative stress plays an important role in functional abnormalities associated with large motor, large sensory, and small sensory fiber neuropathy, but not in small sensory nerve fiber degeneration, in this animal model. Peroxynitrite decomposition catalysts alleviate Type 2 diabetes-associated sensory nerve dysfunction, likely by mechanism(s) not involving arrest of degenerative changes or enhanced regeneration of small sensory nerve fibers.

Morphologic effects of denervation on the taste buds of the catfish barbel

The morphological effects of sectioning the gustatory nerves were studied in the taste buds of the catfish mandibular barbel. Gross observations as well as scanning electron microscope studies showed a proximal-distal degeneration of the taste buds. Serial histologic sections of the denervated barbel illustrated the progressive breakdown of the taste buds as early as 2 days after nerve section. The centrifugal sweep in bud degeneration was completed in 9 to 10 days at 22°C but occurred in stepwise alterations in individual buds and not by overnight disappearance of all buds simultaneously as heretofore reported. Silver impregnation and transmission electron microscope studies of the main nerves showed rapid wallerian degeneration of sensory nerve fibers occurring within a few days. The results are compared with similar studies in tetrapods.