Curcumin reduces blood-nerve barrier abnormalities and cytotoxicity to endothelial cells and pericytes induced by cisplatin.

BACKGROUND: Cisplatin is a platinum-based antineoplastic agent used to treat cancers of solid organs. Neuropathy is one of its major side effects, necessitating dose reduction or cessation. Previous studies suggested that cisplatin causes microvascular toxicity, including pericyte detachment. This study aimed to clarify whether these alterations occurred in the blood-nerve barrier (BNB) of capillaries after cisplatin treatment. MATERIALS AND METHODS AND RESULTS: Electron microscopic analysis of rat sciatic nerves with cisplatin neuropathy showed increased frequency and severity of pericyte detachment. Moreover, the vascular basement membrane did not tightly encircle around the endothelial cells and pericytes. Cultured human umbilical vein endothelial cells and human brain vascular pericytes showed reduced viability, increased caspase-3 activity and enhanced oxidative stress following cisplatin treatment. In addition, cisplatin decreased transendothelial electrical resistance (TEER) and the expression of the tight junction proteins occludin and zonula occludens-1. Curcumin, a polyphenol found in the root of Curcuma longa, had favourable effects on cisplatin neuropathy in previous work. Therefore, curcumin was tested to determine whether it had any effect on these abnormalities. Curcumin alleviated pericyte detachment, cytotoxicity, oxidative stress, TEER reduction and tight junction protein expression. CONCLUSIONS: These data indicate that cisplatin causes BNB disruption in the nerves and might result in neuropathy. Curcumin might improve neuropathy via the restoration of BNB. Whether alterations in the BNB occur and curcumin is effective in patients with cisplatin neuropathy remain to be investigated.

Preconditioning by voluntary wheel running attenuates later neuropathic pain via nuclear factor E2-related factor 2 antioxidant signaling in rats.

ABSTRACT: Animal and human studies have shown that exercise prior to nerve injury prevents later chronic pain, but the mechanisms of such preconditioning remain elusive. Given that exercise acutely increases the formation of free radicals, triggering antioxidant compensation, we hypothesized that voluntary running preconditioning would attenuate neuropathic pain by supporting redox homeostasis after sciatic nerve injury in male and female rats. We show that 6 weeks of voluntary wheel running suppresses neuropathic pain development induced by chronic constriction injury across both sexes. This attenuation was associated with reduced nitrotyrosine immunoreactivity-a marker for peroxynitrite-at the sciatic nerve injury site. Our data suggest that prior voluntary wheel running does not reduce the production of peroxynitrite precursors, as expression levels of inducible nitric oxide synthase and NADPH oxidase 2 were unchanged. Instead, voluntary wheel running increased superoxide scavenging by elevating expression of superoxide dismutases 1 and 2. Prevention of neuropathic pain was further associated with the activation of the master transcriptional regulator of the antioxidant response, nuclear factor E2-related factor 2 (Nrf2). Six weeks of prior voluntary wheel running increased Nrf2 nuclear translocation at the sciatic nerve injury site; in contrast, 3 weeks of prior wheel running, which failed to prevent neuropathic pain, had no effect on Nrf2 nuclear translocation. The protective effects of prior voluntary wheel running were mediated by Nrf2, as suppression was abolished across both sexes when Nrf2 activation was blocked during the 6-week running phase. This study provides insight into the mechanisms by which physical activity may prevent neuropathic pain. Preconditioning by voluntary wheel running, terminated prior to nerve injury, suppresses later neuropathic pain in both sexes, and it is modulated through the activation of Nrf2-antioxidant signaling.

Overexpression of miR-378 Alleviates Chronic Sciatic Nerve Injury by Targeting EZH2.

In numerous studies, microRNAs (miRNAs) have been authenticated to play vital roles in the pathophysiology of neuropathic pain and other neurological diseases. In our study, we focused on evaluating miR-378 and its potential effects in neuropathic pain development, as well as the underlying molecular mechanisms. Primarily, a chronic sciatic nerve injury (CCI) rat model was established. Next, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was employed to measure the expression levels of miR-378 and EZH2 mRNA; the EZH2 protein expression levels were detected by western blot. A luciferase activity assay monitored the interaction of miR-378 and EZH2. Mechanical and thermal hyperalgesia was also performed to quantitate the effects of overexpression of miR-378 or EZH2 on the CCI rats. We found that miR-378 was down-regulated in the CCI rats, and the overexpression of miR-378 produced significant relief in their pain management. EZH2 was the downstream gene of miR-378 and was negatively regulated by miR-378. The up-regulation of EZH2 reduced the inhibitory effects of miR-378 on the development of neuropathic pain in the CCI rats. miR-378 acts as an inhibitor in the progression of neuropathic pain via targeting EZH2; the miR-378/EZH2 axis may be a novel target for the diagnosis and therapy of neuropathic pain in clinical treatment.

The effect of gluteus maximus tenotomy in primary total hip arthroplasty with posterior approach: Kinematic analysis of hip extensor strength.

BACKGROUND: The posterior approach (PA) is the most commonly used surgical approach for total hip arthroplasty (THA), but the proximity of the sciatic nerve may increase the likelihood of sciatic nerve injury (SNI). Gluteus maximus tenotomy can be performed to prevent SNI because tenotomy increases the distance between the femoral neck and sciatic nerve and prevents compression of the sciatic nerve by the gluteus maximus tendon (GMT) during hip movements. We aimed to kinematically compare the postoperative hip extensor forces of patients who have and have not undergone gluteus maximus tenotomy to determine whether there is a difference in hip extensor strength. METHODS: Seventy-two patients who underwent gluteus maximus tenotomy during THA were included in the group 1, and 86 patients who did not undergo tenotomy were included in group 2. The Harris hip score, body mass index and hip extensor forces were measured both preoperatively, and 6 months after surgery with an isokinetic dynamometer and compared. RESULTS: The mean age was 64.6 ± 2.3 years in group 1 and 63.8 ± 2.1 in group 2. Mean body mass index was 25.7 ± 1.1 in group 1, and 25.5 ± 1.3 in group 2. Baseline Harris hip score (HHS) was 42.36 ± 12 in group 1 and 44.07 ± 9.4 in group 2 (p = 0.31), whereas it was 89.1 ± 7.8 and 88.4 ± 8.1 at 6 months after surgery, respectively. Baseline hip extensor force (HEF) was 2 ± 0.4 Nm/kg in group 1, and 2.1 ± 0.7 Nm/kg in group 2 (p = 0.28), while it was 2.4 ± 0.6 Nm/kg, and 2.5 ± 0.5 Nm/kg, respectively at 6 month follow-up (p = 0.87). Both groups had significantly improved HHS and HEF when comparing baseline and postoperative measurements (p < 0.0001). No cases of sciatic nerve palsy were noted in group 1, whereas there were two (2.32%) cases in group 2, postoperatively. CONCLUSION: The release of the GMT during primary hip arthroplasty performed with the PA did not lead to significant decrease in hip extension forces. Hip extensor strength improves after THA regardless of tenotomy. Gluteus maximus tenotomy with repair does not reduce muscle strength and may offer better visualization.

Umbelliprenin relieves paclitaxel-induced neuropathy.

OBJECTIVES: Umbelliprenin (UMB) is a prenylated coumarin that acts as an in vitro antioxidant and inhibits lipoxygenase managing the inflammation pathways, while in vivo it exerts anti-inflammatory activities. METHODS: In this study, neuropathic pain was induced by four intraperitoneal doses of 2 mg/kg per day of paclitaxel (PTX) on days 1, 3, 5 and 7. Here, 49 male mice were randomly divided in the following groups: sham (not treated animals), negative control (PTX-treated receiving normal saline), single-dose UMB 6.25, 12.5 and 25 mg/kg groups (PTX-treated receiving UMB 6.25, 12.5 and 25 mg/kg, respectively), prevention (PTX-treated receiving PTX along with UMB 12.5 mg/kg on days 1, 3, 5 and 7) and positive control group (PTX-treated receiving imipramine 10 mg/kg as acute treatment). Hot-plate test was done to assess response to heat. Finally, interleukin (IL)-6 levels in the sciatic nerve and lipid peroxidation in sera were assessed. KEY FINDINGS: Umbelliprenin was found equally effective for acute treatment with imipramine, when comparing the prevention group and the positive control group. Single, 25 mg/kg UMB effectively attenuated hyperalgesia, lipid peroxidation and IL-6 levels. CONCLUSIONS: Umbelliprenin alleviated neuropathic pain, and decreased serum IL-6 levels and oxidative stress. UMB deserves further investigations, especially in clinical settings.

Lycopene protects against central and peripheral neuropathy by inhibiting oxaliplatin-induced ATF-6 pathway, apoptosis, inflammation and oxidative stress in brains and sciatic tissues of rats.

The fact that oxaliplatin (OXL), a platinum-based chemotherapeutic drug, causes severe neuropathy greatly limits its clinical use. This study investigated the effects of lycopene, a potent antioxidant, on OXL-induced central and peripheral neuropathy. In this study, 30 min after oral administration of LY at a dose of 2 mg/kg b.w./day and 4 mg/kg b.w./day on 1 st, 2nd, 4th and 5th days, rats were given 4 mg/kg b.w./day of OXL intraperitoneally. It was detected that LY decreased OXL-induced lipid peroxidation and increased the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) and the levels of glutathione (GSH) in brain tissue. LY showed anti-inflammatory effects by decreasing levels of mitogen-activated protein kinase-14 (MAPK14), nuclear factor kappa-B (NF-κB) and tumor necrosis factor-α (TNF-α) in brain and sciatic tissue. It was determined that OXL-induced endoplasmic reticulum stress (ERS) decreased because LY administration reduced the expressions of activating transcription factor-6 (ATF6), glucose-regulated protein-78 (GRP78), RNA-activated protein kinase (PKR)-like ER kinase and inositol-requiring enzyme-1 (IRE1). LY administration also reduced the damage of OXL-induced brain and sciatic tissue by increasing NCAM levels and decreasing GFAP levels. It was determined that caspase-3 immunopositivity markedly decreased by OXL and LY in combination. It was also observed that LY provided neuronal protection by increasing brain-derived neurotrophic factor (BDNF) levels, which decreased with OXL administration in sciatic tissue. The results demonstrate that LY can be beneficial in ameliorating OXL-induced central and peripheral nerve injuries by showing antioxidant, anti-inflammatory and anti-apoptotic properties in the brain and sciatic tissue.

Histopathological and Functional Evaluation of Radiation-Induced Sciatic Nerve Damage: Melatonin as Radioprotector.

Background and Objectives: Radiotherapy uses ionizing radiation for cancer treatment. One of the side effects of radiotherapy is peripheral neuropathy. After irradiation, the first stage of neuropathy involves electrophysiological, biochemical and histopathological variations, while the fibrosis of soft tissues surrounding the exposed nerve occurs in the second stage. The present study aimed to examine the radioprotective effects of melatonin against ionizing radiation-induced sciatic nerve damage. Materials and Methods: Sixty male Wistar rats were assigned to four groups: C (Control + Vehicle), M (Melatonin), R (Radiation + Vehicle), MR (Radiation + Melatonin). Their right legs were irradiated with a 30 Gy single dose of gamma rays. Then, 100 mg/kg melatonin was administered to the animals 30 min before irradiation once daily (5 mg/kg) until the day of rats' sacrifice. Their exposed nerve tissues were assessed using the sciatic functional index (SFI) and histological evaluation. Results: Four, 12 and 20 weeks post irradiation, the SFI results showed that irradiation led to partial loss of motor nerve function after 12 and 20 weeks. Histological evaluation showed the various stages of axonal degeneration and demyelination compared to the C and M groups. Scar-like tissues were detected around the irradiated nerves in the R group at 20 weeks, but were absent in the MR group. The SFI and histological results of the R group showed partial nerve lesion. However, in all cases, treatment with melatonin prevented these effects. Conclusions: Results showed that melatonin has the potential to improve functional and morphological features of exposed sciatic nerves. This could possibly improve the therapeutic window of radiotherapy.

The miRNA biogenesis pathway prevents inappropriate expression of injury response genes in developing and adult Schwann cells.

Proper function of the nervous system depends on myelination. In peripheral nerves, Schwann cells (SCs) myelinate axons and the miRNA biogenesis pathway is required for developmental myelination and myelin maintenance. However, regulatory roles of this pathway at different stages of myelination are only partially understood. We addressed the requirement of the core miRNA biogenesis pathway components Dgcr8, Drosha, and Dicer in developing and adult SCs using mouse mutants with a comparative genetics and transcriptomics approach. We found that the microprocessor components Dgcr8 and Drosha are crucial for axonal radial sorting and to establish correct SC numbers upon myelination. Transcriptome analyses revealed a requirement of the microprocessor to prevent aberrantly increased expression of injury-response genes. Those genes are predicted targets of abundant miRNAs in sciatic nerves (SNs) during developmental myelination. In agreement, Dgcr8 and Dicer are required for proper maintenance of the myelinated SC state, where abundant miRNAs in adult SNs are predicted to target injury-response genes. We conclude that the miRNA biogenesis pathway in SCs is crucial for preventing inappropriate activity of injury-response genes in developing and adult SCs.

Novel technique for intraoperative sciatic nerve assessment in complex primary total hip arthroplasty: a pilot study.

INTRODUCTION: Sciatic nerve injury (SNI) is a potentially devastating complication after total hip arthroplasty (THA). Intraoperative neural monitoring has been found in several studies to be useful in preventing SNI, but can be difficult to implement. In this study, we examine the results of using a handheld nerve stimulator for intraoperative sciatic nerve (SN) monitoring during complex THA requiring limb lengthening and/or significant manipulation of the SN. METHODS: A consecutive series of 11 cases (9 patients, 11 hips) with either severe developmental dysplasia of the hip (Crowe 3-4) or other underlying conditions requiring complex hip reconstruction involving significant leg lengthening and/or nerve manipulation. SN function was monitored intraoperatively by obtaining pre- and post-reduction thresholds during component trialing. The results of nerve stimulation were then used to influence intraoperative decision-making. RESULTS: No permanent postoperative SN complications occurred, with an average increase of 28.5 mm in limb length, range (6-51 mm). In 2 out of 11 cases, a change in nerve response was identified after trial reduction, which resulted in an alternate surgical plan (femoral shortening osteotomy and downsizing femoral head). In the remaining cases, the stimulator demonstrated a response consistent with the baseline assessment, assuring that the appropriate lengthening was achieved without SNI. 1 patient had a transient motor and sensory peroneal nerve palsy, which resolved within 2 weeks. CONCLUSIONS: The intraoperative use of a handheld nerve stimulator facilitates surgical decision-making and can potentially prevent SNI. The real-time assessment of nerve function allows immediate corrective action to be taken before nerve injury occurs.

Epineural Sheath Jacket as a New Surgical Technique for Neuroma Prevention in the Rat Sciatic Nerve Model.

BACKGROUND: Terminal neuromas resulting from severe nerve injuries and traumatic or surgical limb amputations can become a source of pain, and significantly impair patients' quality of life. Recently, the number of patients with peripheral nerve injuries increased due to modern war conflicts, natural disasters, and traffic accidents. This study investigated the efficacy of the epineural sheath jacket (ESJ) as a novel technique for neuroma prevention in the rat sciatic nerve model. METHODS: A 20-mm segment of the right sciatic nerve was excised in 18 Lewis rats, and the animals were divided into 3 experimental groups (n = 6/group): group I-control, nerve stump without protection; group II-muscle burying group, nerve stump buried in the muscle; group III-ESJ group, nerve stump protected by ESJ. The ESJ was created from the excised sciatic nerve and applied as a "cap" over the proximal nerve stump. The presence of neuropathic pain was assessed weekly by pinprick test and Tinel sign, up to 24 weeks postsurgery. At 24 weeks, assessments, such as macroscopic evaluation, retrograde neuronal labeling analysis, histomorphometry, and neural/connective tissue ratio were performed. RESULTS: Epineural sheath jacket significantly reduced neuroma formation, which was associated with decreased Tinel sign (16.7%, P < 0.05) response compared with the nerve stump control. Moreover, ESJ reduced axonal sprouting, bulb-shaped nerve ending formation and perineural adhesions, as confirmed by macroscopic evaluation. Histological evaluation confirmed that nerve stumps protected with the ESJ showed less fibrosis and presented well-organized axonal structure. Neural/connective tissue ratio and retrograde neuronal labeling analysis revealed significantly improved results in the ESJ group compared to the control nerve stump group (P = 0.032 and P = 0.042, respectively). CONCLUSIONS: The protective effect of the ESJ against neuroma formation was confirmed by behavioral and histological analyses, showing outcomes comparable to the muscle burying technique-the criterion standard of neuroma management.

Effects of Low-Intensity Treadmill Exercise on Sciatic Nerve in Experimental Diabetic Neuropathy.

OBJECTIVE: To investigate the potential beneficial effects of low-intensity exercise on histopathological changes of sciatic nerves in streptozotocin (STZ)-induced diabetic rats. STUDY DESIGN: The rats were allotted randomly into 3 experimental groups: A (control), B (diabetic untreated), and C (diabetic treated with low-intensity exercise); each group contained 8 animals. Groups B and C received STZ. Diabetes was induced in 2 groups by a single intraperitoneal injection of STZ (40 mg/kg, freshly dissolved in 0.1 M citrate buffer, pH 4.2). Two days after STZ treatment, diabetes in 2 experimental groups was confirmed by measuring blood glucose levels. Rats with blood glucose levels ≥ 250 mg/dL were considered to be diabetic. Animals in the exercise group were made to run the treadmill once a day for 4 consecutive weeks. Exercise started 3 days prior to STZ administration. RESULTS: The treatment of low-intensity exercise caused a sharp decrease in the elevated serum glucose and an increase in the lowered serum insulin concentrations in STZ-induced diabetic rats. STZ induced a significant decrease in the area of insulin-immunoreactive ß cells. Low-intensity exercise treatment resulted in increased area of insulin-immunoreactive ß cells signficantly. Myelin breakdown decreased significantly after treatment with low intensity exercise. The ultrastructural features of degenerated axons also showed remarkable improvement. CONCLUSION: We believe that further preclinical research into low-intensity exercise may indicate its usefulness as a potential treatment for peripheral neuropathy in STZ-induced diabetic rats.

Prior voluntary wheel running attenuates neuropathic pain.

Exercise is known to exert a systemic anti-inflammatory influence, but whether its effects are sufficient to protect against subsequent neuropathic pain is underinvestigated. We report that 6 weeks of voluntary wheel running terminating before chronic constriction injury (CCI) prevented the full development of allodynia for the ∼3-month duration of the injury. Neuroimmune signaling was assessed at 3 and 14 days after CCI. Prior exercise normalized ipsilateral dorsal spinal cord expression of neuroexcitatory interleukin (IL)-1ß production and the attendant glutamate transporter GLT-1 decrease, as well as expression of the disinhibitory P2X4R-BDNF axis. The expression of the macrophage marker Iba1 and the chemokine CCL2 (MCP-1), and a neuronal injury marker (activating transcription factor 3), was attenuated by prior running in the ipsilateral lumbar dorsal root ganglia. Prior exercise suppressed macrophage infiltration and/or injury site proliferation, given decreased presence of macrophage markers Iba1, iNOS (M1), and Arg-1 (M2; expression was time dependent). Chronic constriction injury-driven increases in serum proinflammatory chemokines were suppressed by prior running, whereas IL-10 was increased. Peripheral blood mononuclear cells were also stimulated with lipopolysaccharide ex vivo, wherein CCI-induced increases in IL-1ß, nitrite, and IL-10 were suppressed by prior exercise. Last, unrestricted voluntary wheel running, beginning either the day of, or 2 weeks after, CCI, progressively reversed neuropathic pain. This study is the first to investigate the behavioral and neuroimmune consequences of regular exercise terminating before nerve injury. This study suggests that chronic pain should be considered a component of "the diseasome of physical inactivity," and that an active lifestyle may prevent neuropathic pain.

Increase of neurofilament-H protein in sensory neurons in antiretroviral neuropathy: Evidence for a neuroprotective response mediated by the RNA-binding protein HuD.

Nucleoside reverse transcriptase inhibitors (NRTIs) are key components of HIV/AIDS treatment to reduce viral load. However, antiretroviral toxic neuropathy has become a common peripheral neuropathy among HIV/AIDS patients leading to discontinuation of antiretroviral therapy, for which the underlying pathogenesis is uncertain. This study examines the role of neurofilament (NF) proteins in the spinal dorsal horn, DRG and sciatic nerve after NRTI neurotoxicity in mice treated with zalcitabine (2',3'-dideoxycitidine; ddC). ddC administration up-regulated NF-M and pNF-H proteins with no effect on NF-L. The increase of pNF-H levels was counteracted by the silencing of HuD, an RNA binding protein involved in neuronal development and differentiation. Sciatic nerve sections of ddC exposed mice showed an increased axonal caliber, concomitantly to a pNF-H up-regulation. Both events were prevented by HuD silencing. pNF-H and HuD colocalize in DRG and spinal dorsal horn axons. However, the capability of HuD to bind NF mRNA was not demonstrated, indicating the presence of an indirect mechanism of control of NF expression by HuD. RNA immunoprecipitation experiments showed the capability of HuD to bind the BDNF mRNA and the administration of an anti-BDNF antibody prevented pNF-H increase. These data indicate the presence of a HuD - BDNF - NF-H pathway activated as a regenerative response to the axonal damage induced by ddC treatment to counteract the antiretroviral neurotoxicity. Since analgesics clinically used to treat neuropathic pain are ineffective on antiretroviral neuropathy, a neuroregenerative strategy might represent a new therapeutic opportunity to counteract neurotoxicity and avoid discontinuation or abandon of NRTI therapy.

Detection of Position-Related Sciatic Nerve Dysfunction by Somatosensory Evoked Potentials During Spinal Surgery.

It is well established that intraoperative somatosensory evoked potentials (SSEPs) are sensitive to plexus and peripheral nerve dysfunction related to malpositioning of patients during spinal surgery. While most reports focus on upper extremity nerve or brachial plexus effects, there is very little on detection of sciatic nerve compromise. Recording of the SSEP at the popliteal fossa is a common strategy to aid in troubleshooting stimulus-related problems or distal peripheral tibial nerve failure; yet position-related sciatic nerve effects may not be realized by changes in the popliteal fossa response. Three posterior lumbar surgeries are reviewed in which there was evidence of proximal lower extremity peripheral nerve dysfunction related to positioning. Loss of posterior tibial nerve SSEPs with preservation of the peripheral popliteal fossa response recording occurred in the absence of critical surgical manipulations. Efforts at repositioning and release of tension on the lower limbs promptly resulted in recovey of lost responses. Two of the three cases involved patients in a kneeling position with a tight strap across the posterior thigh. Standard SSEP recordings used in intraoperative neuromonitoring do not specifically localize intraoperative changes to the sciatic nerve; thus, such changes affecting SSEPs above the popliteal fossa mimic iatrogenic changes occurring at the surgical site. These case reports show that when the stage of surgery does not support iatrogenic changes, malpositioning affecting sciatic nerve should be considered, especially for patients placed in a kneeling position on an Andrews frame.

The Effect of Coumaric Acid on Ischemia-Reperfusion Injury of Sciatic Nerve in Rats.

The aim of the study was to determine the effect of coumaric acid on sciatic nerve ischemia/reperfusion (SNI) injury in rats. The rats were randomly divided into four groups: control group (no medication or surgical procedure), SNI group, SNI + coumaric acid (CA) group, and SNI + methylprednisolone (MP) group. Ischemia was achieved by abdominal aorta clamping, and all animals were sacrificed 24 h after ischemia. Harvested sciatic nerve segments were investigated histopathologically and for tissue biochemistry. A significant decrease in MDA, an increase in NRF1 levels, and increase in SOD activity were observed in the groups which received coumaric acid and methylprednisolone when compared to the corresponding untreated group (p < 0.05). Ischemic fiber degeneration significantly reduced in the SNI + CA and SNI + MP groups, especially in the SNI + MP group, compared to the SNI group (p < 0.05). Beta amyloid protein expressions were significantly decreased in the SNI + CA group compared to the SNI group (p < 0.05). Our study revealed that coumaric acid treatment after ischemia/reperfusion in rat sciatic nerves reduced oxidative stress and axonal degeneration. Therefore, coumaric acid may play a role in the treatment of peripheral nerve injuries due to ischemia/reperfusion.

Effects of histidine and n-acetylcysteine on experimental lesions induced by doxorubicin in sciatic nerve of rats.

In this study, the effect of separate and combined intraperitoneal (i.p.) injections of histidine and n-acetylcysteine were investigated on experimental damage induced by doxorubicin (DOX) in sciatic nerve of rats. DOX was i.p. injected at a dose of 4 mg/kg once weekly for four weeks. Histidine and n-acetylcysteine were i.p. injected at a same dose of 20 mg/kg. Cold and mechanical allodynia were recorded using acetone spray and von Frey filaments tests, respectively. The sciatic nerve damage was evaluated by light microscopy. Plasma levels of malondialdehyde (MDA) and total antioxidant capacity (TAC) were measured. Histidine and especially n-acetylcysteine at a same dose of 20 mg/kg suppressed cold and mechanical allodynia, improved sciatic nerve lesions and reversed MDA and TAC levels in DOX-treated groups. Combination treatment with histidine and n-acetylcysteine showed better responses when compared with them used alone. The results of the present study showed peripheral neuroprotective effects for histidine and n-acetylcysteine. Reduction of free radical-induced toxic effects may have a role in neuroprotective properties of histidine and n-acetylcysteine.

Sciatic nerve injection injury.

Nerve injury is a common complication following intramuscular injection and the sciatic nerve is the most frequently affected nerve, especially in children, the elderly and underweight patients. The neurological presentation may range from minor transient pain to severe sensory disturbance and motor loss with poor recovery. Management of nerve injection injury includes drug treatment of pain, physiotherapy, use of assistive devices and surgical exploration. Early recognition of nerve injection injury and appropriate management are crucial in order to reduce neurological deficit and to maximize recovery. Sciatic nerve injection injury is a preventable event. Total avoidance of intramuscular injection is recommended if other administration routes can be used. If the injection has to be administered into the gluteal muscle, the ventrogluteal region (gluteal triangle) has a more favourable safety profile than the dorsogluteal region (the upper outer quadrant of the buttock).

TGF-ß1 attenuates spinal neuroinflammation and the excitatory amino acid system in rats with neuropathic pain.

UNLABELLED: Previous studies have reported that the intrathecal (i.t.) administration of transforming growth factor ß1 (TGF-ß1) prevents and reverses neuropathic pain. However, only limited information is available regarding the possible role and effects of spinal TGF-ß1 in neuropathic pain. We aimed to investigate the antinociceptive effects of exogenous TGF-ß1 on chronic constriction injury (CCI)-induced neuropathic pain in rats. We demonstrated that sciatic nerve injury caused a downregulation of endogenous TGF-ß1 levels on the ipsilateral side of the lumbar spinal dorsal gray matter, and that the i.t. administration of TGF-ß1 (.01-10 ng) significantly attenuated CCI-induced thermal hyperalgesia in neuropathic rats. TGF-ß1 significantly inhibited CCI-induced spinal neuroinflammation, microglial and astrocytic activation, and upregulation of tumor necrosis factor-α. Moreover, i.t. TGF-ß1 significantly attenuated the CCI-induced downregulation of glutamate transporter 1, the glutamate aspartate transporter, and the excitatory amino acid carrier 1 on the ipsilateral side. Furthermore, i.t. TGF-ß1 significantly decreased the concentrations of 2 excitatory amino acids, aspartate and glutamate, in the spinal dialysates in CCI rats. In summary, we conclude that the mechanisms of the antinociceptive effects of i.t. TGF-ß1 in neuropathy may include attenuation of spinal neuroinflammation, attenuation, or upregulation of glutamate transporter downregulation, and a decrease of spinal extracellular excitatory amino acids. PERSPECTIVE: Clinically, medical treatment is usually initiated after the onset of intractable pain. Therefore, in the present study, i.t. TGF-ß1 was designed to be administered 2 weeks after the establishment of CCI pain. Compared to the continuous TGF-ß1 infusion mode, single-dose administration seems more convenient and practical to use.

Lipomatosis of the sciatic nerve secondary to compression by a desmoid tumor.

Lipomatosis of nerve is a rare benign tumor-like process characterized by infiltration of the epineurium by adipose and fibrous tissue leading to nerve enlargement. We describe a case of lipomatosis of the sciatic nerve compressed by an adjacent desmoid tumor. This case supports the hypothesis that lipomatosis of nerve may form as a result of irritation or compression by adjacent structures.

Peripherally injected linalool and bergamot essential oil attenuate mechanical allodynia via inhibiting spinal ERK phosphorylation.

Bergamot essential oil (BEO) is one of the most common essential oil containing linalool and linalyl acetate as major volatile components. This study investigated the effect of intraplantar (i.pl.) bergamot essential oil (BEO) or linalool on neuropathic hypersensitivity induced by partial sciatic nerve ligation (PSNL) in mice. The i.pl. injection of BEO or linalool into the ipsilateral hindpaw to PSNL reduced PSNL-induced mechanical allodynia in a dose-dependent manner. Peripheral (i.pl.) injection of BEO or linalool into the contralateral hindpaw did not yield anti-allodynic effects, suggesting a local anti-mechanical allodynic effect of BEO or linalool in PSNL mice. Anti-mechanical hypersensitivity of morphine was enhanced by the combined injection of BEO or linalool at an ineffective dose when injected alone. We also examined the possible involvement of spinal extracellular signal-regulated protein kinase (ERK) in BEO or linalool-induced anti-mechanical allodynia. In western blotting analysis, i.pl. injection of BEO or linalool resulted in a significant blockade of spinal ERK activation induced by PSNL. These results suggest that i.pl. injection of BEO or linalool may reduce PSNL-induced mechanical allodynia followed by decreasing spinal ERK activation.