BACKGROUND: QR-333, a topical compound that contains quercetin, a flavonoid with aldose reductase inhibitor effects, ascorbyl palmitate, and vitamin D(3), was formulated to decrease the oxidative stress that contributes to peripheral diabetic neuropathy and thus alleviate its symptoms. This proof-of-principle study assessed the efficacy and safety of QR-333 against placebo in a small cohort of patients with diabetic neuropathy. METHODS: This randomized, placebo-controlled, double-blind trial included 34 men and women (21-71 years of age) with Type 1 or 2 diabetes and diabetic neuropathy who applied QR-333 or placebo (2:1 ratio), three times daily for 4 weeks, to each foot where symptoms were experienced. Five-point scales were used to determine changes from baseline to endpoint in symptoms and quality of life (efficacy). Safety was assessed through concomitant medications, adverse events, laboratory evaluations, and physical examinations. RESULTS: QR-333 reduced the severity of numbness, jolting pain, and irritation from baseline values. Improvements were also seen in overall and specific quality-of-life measures. QR-333 was well tolerated. Eleven patients in the QR-333 group reported 23 adverse events (all mild or moderate); 4 in the placebo group reported 5 events (all moderate). One patient who applied QR-333 noted a pricking sensation twice, the only adverse event considered possibly related to study treatment. CONCLUSIONS: From this preliminary safety study, it appears that QR-333 may safely offer relief of symptoms of diabetic neuropathy and improve quality of life. These findings warrant further investigation of this topical compound.

 Peripheral neurotoxicity is a major complication associated with the use of chemotherapeutic agents such as platinum compounds, taxanes and vinca alkaloids. The neurotoxicity of chemotherapy depends not only on the anticancer agent(s) used, the cumulative dose and the delivery method, but also on the capacity of the nerve to cope with the nerve-damaging process. The sensory and motor symptoms and signs of neurotoxicity are disabling, and have a significant impact on the quality of life of cancer patients. Moreover, the risk of cumulative toxicity may limit the use of highly effective chemotherapeutic agents. Therefore, prophylaxis and treatment of peripheral neurotoxicity secondary to chemotherapy are major clinical issues. Acetyl-L-carnitine (ALC), the acetyl ester of L-carnitine, plays an essential role in intermediary metabolism. Some of the properties exhibited by ALC include neuroprotective and neurotrophic actions, antioxidant activity, positive actions on mitochondrial metabolism, and stabilisation of intracellular membranes. ALC has demonstrated efficacy and high tolerability in the treatment of neuropathies of various aetiologies, including chemotherapy-induced peripheral neuropathy (CIPN). In several experimental settings, the prophylactic administration of ALC prevented the occurrence of peripheral neurotoxicity commonly induced by chemotherapeutic agents. In animal models of CIPN, ALC administration promoted the recovery of nerve conduction velocity, restored the mechanical nociceptive threshold, and induced analgesia by up-regulating the expression of type-2 metabotropic glutamate receptors in dorsal root ganglia. These results, plus the favourable safety profile of ALC in neuropathies of other aetiologies, have led to the effects of ALC on CIPN being investigated in cancer patients. Preliminary results have confirmed the reasonably good tolerability profile and the efficacy of ALC on CIPN. The present studies support the use of ALC in cancer patients with persisting neurotoxicity induced by paclitaxel or cisplatin treatment.

 Acetyl-L-carnitine (ALC) has gained clinical interest for its analgesic effect in different forms of neuropathies associated with chronic pain, such as diabetic and HIV-related peripheral neuropathies. The antinociceptive effect of ALC has been confirmed in several experimental models of neuropathic pain, including streptozotocin- and chemotherapy-induced neuropathy, and the sciatic nerve chronic constriction injury model. In these models, prophylactic administration of ALC has proven to be effective in preventing the development of neuropathic pain. In addition, ALC is known to produce a strong antinociceptive effect when given after neuropathic pain has been established. ALC can also improve the function of peripheral nerves by increasing nerve conduction velocity, reducing sensory neuronal loss, and promoting nerve regeneration. Analgesia requires repeated administrations of ALC, suggesting that the drug regulates neuroplasticity across the pain neuraxis. Recent evidence indicates that ALC regulates processes that go beyond its classical role in energy metabolism. These processes involve the activation of muscarinic cholinergic receptors in the forebrain, and an increased expression of type-2 metabotropic glutamate (mGlu2) receptors in dorsal root ganglia neurons. Induction of mGlu2 receptors is mediated by acetylation mechanisms that involve transcription factors of the nuclear factor (NF)-kappaB family.

OBJECTIVES:Neuropathy and its associated pain pose great therapeutic challenges. While there has been a recent surge in acupuncture use and research, little remains known about its effects on nerve function. This review aims to assess the efficacy of acupuncture in the treatment of neuropathy of various etiologies.

METHODS:The Medline, AMED, Cochrane, Scopus, CINAHL, and clintrials.gov databases were systematically searched from inception to July 2015. Randomized controlled trials (RCTs) assessing acupuncture's efficacy for poly- and mononeuropathy were reviewed. Parallel and crossover RCTs focused on acupuncture's efficacy were reviewed and screened for eligibility. The Scale for Assessing Scientific Quality of Investigations in Complementary and Alternative Medicine was used to assess RCT quality. RCTs with score of>9 and active control treatments such as sham acupuncture or medical therapy were included.

RESULTS:Fifteen studies were included: 13 original RCTs, a long-term follow-up, and a re-analysis of a prior RCT. The selected RCTs studied acupuncture for neuropathy caused by diabetes, Bell's palsy, carpal tunnel syndrome, human immunodeficiency virus (HIV), and idiopathic conditions. Acupuncture regimens, control conditions, and outcome measures differed among studies, and various methodological issues were identified. Still, the majority of RCTs showed benefit for acupuncture over control in the treatment of diabetic neuropathy, Bell's palsy, and carpal tunnel syndrome. Acupuncture is probably effective in the treatment of HIV-related neuropathy, and there is insufficient evidence for its benefits in idiopathic neuropathy. Acupuncture appears to improve nerve conduction study parameters in both sensory and motor nerves. Meta-analyses were conducted on all diabetic neuropathy and Bell's palsy individual subject data (six RCTs; a total of 680 subjects) using a summary estimate random effects model, which showed combined odds ratio of 4.23 (95% confidence interval 2.3-7.8; p < 0.001) favoring acupuncture over control for neuropathic symptoms.

CONCLUSIONS:Acupuncture is beneficial in some peripheral neuropathies, but more rigorously designed studies using sham-acupuncture control are needed to characterize its effect and optimal use better.

Oxidative stress and secondary excitotoxicity, due to cellular energy deficit, are major factors playing roles in 3-nitropropionic acid (3-NPA) induced mitochondrial dysfunction. Acute or chronic exposure to 3-NPA also leads to neuronal degeneration in different brain regions. The present study quantitatively assessed peripheral neuropathy induced by chronic exposure to 3-NPA in rats. The neuroprotective abilities of two antioxidants, acetyl-l-carnitine and resveratrol, were investigated as well. Rats were exposed for up to four weeks to 3-NPA alone or 3-NPA combined with acetyl-l-carnitine or resveratrol, administered peripherally. The experimental outcome was evaluated by neurophysiological, histological, and morphometric analyses. Rats exposed to 3-NPA developed hind limb paresis. Furthermore, a significant decrease in motor nerve conduction velocity (MCV) was detected in tail nerves and axonal degeneration in sciatic nerves (p<0.05). Treatment with resveratrol prevented the functional effects of 3-NPA exposure, whereas treatment with acetyl-l-carnitine, preventing paresis, was not effective to MCV and morphological changes. These data suggest that resveratrol is a good candidate for treatment of metabolic neuropathy. The experimental outcome of this study shows that chronic treatment with 3-NPA in rats is relevant in development of an experimental model of toxic neuropathy.

BACKGROUND: Complications in diabetes mellitus are partially mediated by enhanced formation of reactive oxygen species. Among the factors involved in reactive oxygen species formation, advanced glycation end products play a key role. Owing to a reduced activity of the enzyme transketolase, which requires diphosphorylated thiamine (vitamin B(1)) as cofactor, an accumulation of those deleterious glucose metabolites especially in diabetic patients can be observed. Benfotiamine, a lipophilic thiamine diphosphate prodrug, prevented early renal and retinal changes in animal studies, and reduced neuropathic pain in clinical studies. Several mechanisms for these activities have been described. We investigated for the first time direct antioxidant abilities of benfotiamine. Additionally, a potential DNA protective effect of benfotiamine was analysed. METHODS: Oxidative stress was detected by flow cytometry, antioxidative capacity was measured with the ferric reducing ability of plasma (FRAP) assay, two endpoints for genomic damage were assessed: the comet assay and the micronucleus test, and the expression and activity of transketolase was quantified. RESULTS: Benfotiamine prevented oxidative stress induced by the mutagen 4-nitroquinoline-1-oxide (NQO), the uremic toxin indoxyl sulfate, and the peptide hormone angiotensin II in three different kidney cell lines. Cell-free experiments showed a direct antioxidant effect of benfotiamine, which might account for the protective effect. Oxidative DNA damage, induced by angiotensin II, was completely prevented by benfotiamine. Incubation with benfotiamine increased transketolase expression and activity in the cells. CONCLUSIONS: Benfotiamine shows a direct antioxidant action. This effect of benfotiamine may be involved in the improvement of diabetic late complications, including peripheral neuropathy. Copyright (c) 2008 John Wiley & Sons, Ltd.

Biotin in high doses was given for 1-2 years to three diabetic patients suffering from severe diabetic peripheral neuropathy. Within 4-8 weeks there was a marked improvement in clinical and laboratory findings. It is suggested that in diabetes may exist a deficiency, inactivity or unavailability of Biotin, resulting in disordered activity of biotin-dependent enzyme, pyruvate carboxylase, leading to accumulation of pyruvate and/or depletion of aspartate, both of which play a significant role in nervous system metabolism. Based on our good results, regular biotin administration could be suggested for every diabetic patient for the prevention and management of peripheral neuropathy although extensive randomised clinical trials are required

Diabetic peripheral neuropathy (DPN) is associated with peripheral arterial disease and endothelial dysfunction. We investigated the effect of exercise training on the measures of superficial femoral artery (SFA) and neuropathic symptoms in patients with DPN. In a randomized-controlled trial, 31 volunteers with established DPN were randomly assigned to experimental or control groups. Experimental group performed cycling exercise training (50%-70% of heart rate reserve, 30-45 min, 3 sessions/week) over 12 weeks. Before and 48 h after the experimental period a 5-min flow mediated dilation (FMD) response in SFA using Color Doppler Ultrasonography, fasting glucose level, HbA1c and neuropathic score were assessed. FMD% significantly increased in the experimental group (from 3.2 ± 1.1% to 5.7 ± 1.2%) compared to the control condition (P = 0.0001). However, no significant alteration occurred in baseline membrane diameter and intima media thickness (P > 0.05). We also observed a significant improvement in fasting glucose, HbA1c and Michigan Diabetic Neuropathy Score (MDNS) following exercise intervention (all P < 0.05). Linear regression analysis indicated that the change in MDNS was significantly associated with the change in HbA1c (R Square = 0.34, standardized coefficients Beta = -0.58, P = .001) and FMD (R Square = 0.37, standardized coefficients Beta = 0.61, P = .001). This finding may beclinically of considerable importance as metabolic and vascular factors have been indicated to be involved in the development of DPN.

AIMS: To evaluate the effectiveness of transcutaneous electrical nerve stimulation (TENS) on diabetic peripheral neuropathy (DPN). METHODS: Randomized controlled trials (RCTs) comparing TENS with routine care, pharmacological interventions or placebo devices on patients with symptomatic DPN, were identified by electronic and manual searches. Studies were selected and available data were extracted independently by two investigators. Meta-analysis was performed by RevMan 4.2.8 software. RESULTS: Three RCTs involving 78 patients were included in this study. The reductions in mean pain score were significantly greater in TENS group than in placebo TENS group in 4 weeks and 6 weeks follow-up [4 weeks, SMD-5.37, 95% CI (-6.97, -3.77); 6 weeks, SMD-1.01, 95% CI (-2.01, -0.01)], but not in 12 weeks follow-up [SMD-1.65, 95% CI (-4.02, 0.73)]. TENS therapy was associated with significantly subjective improvement in overall neuropathic symptoms in 12 weeks follow-up [WMD-0.18, 95% CI (-0.32, -0.051)]. No TENS-related adverse events were registered in TENS group. CONCLUSIONS: TENS therapy may be an effective and safe strategy in treatment of symptomatic DPN. Due to small sample and short-term treatment duration, large multi-centre RCTs are needed to further evaluate the long-term effect of TENS on DPN.

OBJECTIVE:This pilot double-blind randomized study evaluated the efficacy of 780-nm laser phototherapy on the acceleration of axonal growth and regeneration after peripheral nerve reconstruction by polyglycolic acid (PGA) neurotube.

BACKGROUND DATA:The use of a guiding tube for the reconstruction of segmental loss of injured peripheral nerve has some advantages over the regular nerve grafting procedure. Experimental studies have shown that laser phototherapy is effective in influencing nerve regeneration.

METHODS:The right sciatic nerve was transected, and a 0.5-cm nerve segment was removed in 20 rats. A neurotube was placed between the proximal and the distal parts of the nerve for reconnection of nerve defect. Ten of 20 rats received post-operative, transcutaneous, 200-mW, 780-nm laser irradiation for 14 consecutive days to the corresponding segments of the spinal cord (15 min) and to the reconstructed nerve (15 min).

RESULTS:At 3 months after surgery, positive somato-sensory evoked responses were found in 70% of the irradiated rats (p = 0.015), compared to 30% of the non-irradiated rats. The Sciatic Functional Index in the irradiated group was higher than in the non-irradiated group (p<0.05). Morphologically, the nerves were completely reconnected in both groups, but the laser-treated group showed an increased total number of myelinated axons.

CONCLUSION:The results of this study suggest that postoperative 780-nm laser phototherapy enhances the regenerative process of the peripheral nerve after reconnection of the nerve defect using a PGA neurotube.

Diabetic neuropathy (DN) is the highly occurred complication of diabetes mellitus; it has been defined as an event of peripheral nerve dysfunction characterized by pain, allodynia, hyperalgesia, and paraesthesia. The current study was conducted to evaluate the efficacy of low-level laser therapy (LLLT) in the management of neuropathy in diabetic rats. The used animals were divided into the following groups: negative control, streptozotocin-induced diabetic rats, and diabetic rats with peripheral neuropathy (DNP) and DNP treated with gabapentin or with LLLT. Behavioral tests were carried out through hotplate test for the determination of pain sensations and the Morris water maze test for spatial reference memory evaluation. Blood samples were collected at the end of treatment for biochemical determinations. In the current study, the latency of hind-paw lick decreased significantly when DNP are treated with gabapentin or LLLT. The Morris water maze test showed that LLLT treatment improved memory that deteriorated in DNP more than gabapentin do. The results of the biochemical study revealed that LLLT could not affect the level of beta-endorphin that decreased in DNP but significantly decreased S100B that rose in DNP. PGE2 and cytokines IL-1β, IL-10, and TNF-α showed significant increase in DNP compared with control group. The gabapentin administration or LLLT application significantly reversed the levels of the mentioned markers towards the normal values of the controls. Levels of serum MDA and nitric oxide increased significantly in the DNP but rGSH showed significant decrease. These markers were improved significantly when the DNP were treated with gabapentin or LLLT. The treatment with gabapentin or LLLT significantly decreased the raised level in total cholesterol in DNP but could not decrease the elevated level of triglycerides, while LDL cholesterol decreased significantly in DNP treated with gabapentin but not affected by LLLT. Values of serum alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), urea, and creatinine increased significantly in the DPN and diabetic rats without peripheral neuropathy (PN) compared with control group. The treatment of DNP with gabapentin induced significant increases in ALAT and ASAT activities but LLLT treatment induced significant decreases in ALAT and ASAT activities as compared with DNP group. Neither gabapentin nor LLLT could improve the elevated levels of serum urea and creatinine in the DNP. It could be concluded that LLLT is more safe and effective than gabapentin in the management of neuropathy in diabetic rats.

Our study aimed to investigate the effects of acupuncture on diabetic peripheral neuropathy. We compared 42 cases treated with acupuncture with 21 cases exposed to sham acupuncture and observed the effects on nerve conduction velocity and a variety of subjective symptoms associated with diabetic peripheral neuropathy. Three of the six measures of motor nerves, and two measures of sensory function, demonstrated significant improvement (p<0.05) over the 15-day treatment period in the acupuncture group, while no motor or sensory function significantly improved in the sham acupuncture group. There were also significant differences in vibration perception threshold between the groups (p<0.05) and when compared to the baseline levels (p<0.01) in the acupuncture group. Acupuncture was significantly more effective than sham for treatment of numbness of the lower extremities, spontaneous pain in the lower extremities, rigidity in the upper extremities and alterations in temperature perception in the lower extremities after therapy. Our pilot study has, therefore, provided evidence that acupuncture may be clinically useful for the radical treatment of diabetic peripheral neuropathy.

Our study aimed to investigate the effects of acupuncture on diabetic peripheral neuropathy. We compared 42 cases treated with acupuncture with 21 cases exposed to sham acupuncture and observed the effects on nerve conduction velocity and a variety of subjective symptoms associated with diabetic peripheral neuropathy. Three of the six measures of motor nerves, and two measures of sensory function, demonstrated significant improvement (p<0.05) over the 15-day treatment period in the acupuncture group, while no motor or sensory function significantly improved in the sham acupuncture group. There were also significant differences in vibration perception threshold between the groups (p<0.05) and when compared to the baseline levels (p<0.01) in the acupuncture group. Acupuncture was significantly more effective than sham for treatment of numbness of the lower extremities, spontaneous pain in the lower extremities, rigidity in the upper extremities and alterations in temperature perception in the lower extremities after therapy. Our pilot study has, therefore, provided evidence that acupuncture may be clinically useful for the radical treatment of diabetic peripheral neuropathy.

OBJECT:This review summarizes the continuous study of low-power laser radiation treatment of a severely injured peripheral nerve. Laser phototherapy was applied as a supportive factor for accelerating and enhancing axonal growth and regeneration after injury or a reconstructive peripheral nerve procedure. In nerve cell cultures, laser phototherapy was used to stimulate activation of nerve cells.

METHODS:Low-power laser radiation was used for treatment of peripheral nerve injury using a rat sciatic nerve model after crush injury, neurorrhaphy, or neurotube reconstruction. Nerve cell growth and axonal sprouting were investigated using laser phototherapy on embryonic rat brain cultures. The outcome in animal studies facilitated a clinical double-blind, placebo-controlled, randomized study that measured the effectiveness of 780-nm laser phototherapy on patients suffering from incomplete peripheral nerve injuries for 6 months to several years.

RESULTS:Animal studies showed that laser phototherapy has an immediate protective effect, maintains functional activity of the injured nerve, decreases scar tissue formation at the injury site, decreases degeneration in corresponding motor neurons of the spinal cord, and significantly increases axonal growth and myelinization. In cell cultures, laser irradiation accelerates migration, nerve cell growth, and fiber sprouting. A pilot clinical double-blind, placebocontrolled, randomized study showed that in patients with incomplete long-term peripheral nerve injury, 780-nm laser radiation can progressively improve peripheral nerve function, which leads to significant functional recovery.

CONCLUSIONS:Using 780-nm laser phototherapy accelerates and enhances axonal growth and regeneration after injury or a reconstructive peripheral nerve procedure. Laser activation of nerve cells, their growth, and axonal sprouting can be considered as potential treatment of neuronal injury. Animal and clinical studies show the promoting action of phototherapy on peripheral nerve regeneration, making it possible to suggest that the time for broader clinical trials has arrived.

BACKGROUND:Although evidence suggests that therapeutic ultrasound (TU) in combination with treadmill training (TT) suppresses nerve injury-associated pain, the molecular mechanisms for this action are not clear.

OBJECTIVE:The purpose of this research was to study the possible beneficial effects of TU and TT, alone and in combination, on two clinical indicators of neuropathic pain and to correlate these findings with changes in inflammatory mediators within the spinal cord. Our experimental model used the well-known chronic constriction injury (CCI) of the rat sciatic nerve.

DESIGN:An experimental study.

METHODS:Each group contained 10 rats. Group 1 underwent only the CCI procedure. Group 2 underwent a sham-operation where the sciatic nerve was exposed but not ligated. Group 3 had the sham-operation followed by both TT and TU. Groups 4, 5, and 6 underwent the CCI procedure followed by TT alone, TU alone, and both the TT and TU interventions, respectively. Heat and mechanical sensitivity, interleukin-6 (IL-6), IL-10, and ionized calcium binding adaptor molecule 1 (iba-1) were evaluated.

RESULTS:Compared to Group 1 animals, TT and/or TU produced smaller decreases in mechanical withdrawal threshold and heat withdrawal latencies. The combination of TT and TU was more effective than either treatment alone. In addition, rats who received these treatments did not express the upregulation of IL-6 and iba-1 in their spinal cords on postoperative days 14 and 28, as was found in the Group 1 animals.

LIMITATIONS:These experimental findings may not be generalizable to humans.

CONCLUSIONS:The combination of TU + TT reduces neuropathic pain more than either modality alone. This beneficial effect appears related to down-regulation of pro-inflammatory IL-6 and iba-1, while up-regulating the anti-inflammatory IL-10.