Unraveling the RAGE-NF-κB pathway: implications for modulating inflammation in diabetic neuropathy through photobiomodulation therapy.

Diabetic peripheral neuropathy (DPN) is a primary complication observed in diabetes that severely affects quality of life. Recent evidence suggests that photobiomodulation (PBM) is a promising therapy against painful conditions and nerve damage. However, the effects of PBM on DPN remains mostly unknown. In the present study, we investigated the efficacy of PBM therapy in modulating proinflammatory cytokine expression in both central and peripheral nervous systems of rats with Streptozotocin (STZ)-induced type 1 diabetes. Male Wistar rats were allocated into control (naïve), diabetic (STZ), and treatment (STZ + PBM) groups. A single intraperitoneal (i.p.) injection of STZ (85 mg/kg) was administered for the induction of diabetes. Animals were subjected to 10 treatment sessions, every other day. The results herein presented indicate that PBM treatment diminishes Receptor for Advanced Glycation End-products (RAGE) and Nuclear Factor Kappa B (NF-Ï°B) expression in peripheral nervous system and suppresses TNF-α expression in central nervous system tissues. Furthermore, PBM-therapy in diabetic rats also induces increased levels of the anti-inflammatory protein IL-10 in both peripheral and central nervous system. Collectively, our findings demonstrate compelling evidence that PBM-therapy modulates cytokine dynamics and influences RAGE/NF-Ï°B axis in a STZ-induced model of type 1 diabetes.

Electroacupuncture Alleviates Streptozotocin-Induced Diabetic Neuropathic Pain via the TRPV1-Mediated CaMKII/CREB Pathway in Rats.

Diabetic neuropathic pain (DNP) is a diabetic complication that causes severe pain and deeply impacts the quality of the sufferer's daily life. Currently, contemporary clinical treatments for DNP generally exhibit a deficiency in effectiveness. Electroacupuncture (EA) is recognized as a highly effective and safe treatment for DNP with few side effects. Regrettably, the processes via which EA alleviates DNP are still poorly characterized. Transient receptor potential vanilloid 1 (TRPV1) and phosphorylated calcium/calmodulin-dependent protein kinase II (p-CaMKII) are overexpressed on spinal cord dorsal horn (SCDH) in DNP rats, and co-localization is observed between them. Capsazepine, a TRPV1 antagonist, effectively reduced nociceptive hypersensitivity and downregulated the overexpression of phosphorylated CaMKIIα in rats with DNP. Conversely, the CaMKII inhibitor KN-93 did not have any impact on TRPV1. EA alleviated heightened sensitivity to pain caused by nociceptive stimuli and downregulated the level of TRPV1, p-CaMKIIα, and phosphorylated cyclic adenosine monophosphate response element-binding protein (p-CREB) in DNP rats. Intrathecal injection of capsaicin, on the other hand, reversed the above effects of EA. These findings indicated that the CaMKII/CREB pathway on SCDH is located downstream of TRPV1 and is affected by TRPV1. EA alleviates DNP through the TRPV1-mediated CaMKII/CREB pathway.

Exploring Mitochondrial Interactions with Pulsed Electromagnetic Fields: An Insightful Inquiry into Strategies for Addressing Neuroinflammation and Oxidative Stress in Diabetic Neuropathy.

Pulsed electromagnetic fields (PEMFs) are recognized for their potential in regenerative medicine, offering a non-invasive avenue for tissue rejuvenation. While prior research has mainly focused on their effects on bone and dermo-epidermal tissues, the impact of PEMFs on nervous tissue, particularly in the context of neuropathy associated with the diabetic foot, remains relatively unexplored. Addressing this gap, our preliminary in vitro study investigates the effects of complex magnetic fields (CMFs) on glial-like cells derived from mesenchymal cell differentiation, serving as a model for neuropathy of the diabetic foot. Through assessments of cellular proliferation, hemocompatibility, mutagenicity, and mitochondrial membrane potential, we have established the safety profile of the system. Furthermore, the analysis of microRNAs (miRNAs) suggests that CMFs may exert beneficial effects on cell cycle regulation, as evidenced by the upregulation of the miRNAs within the 121, 127, and 142 families, which are known to be associated with mitochondrial function and cell cycle control. This exploration holds promise for potential applications in mitigating neuropathic complications in diabetic foot conditions.

Expert opinion on screening, diagnosis and management of diabetic peripheral neuropathy: a multidisciplinary approach.

The proposed expert opinion aimed to address the current knowledge on conceptual, clinical, and therapeutic aspects of diabetic peripheral neuropathy (DPN) and to provide a guidance document to assist clinicians for the best practice in DPN care. The participating experts consider the suspicion of the disease by clinicians as a key factor in early recognition and diagnosis, emphasizing an improved awareness of the disease by the first-admission or referring physicians. The proposed "screening and diagnostic" algorithm involves the consideration of DPN in a patient with prediabetes or diabetes who presents with neuropathic symptoms and/or signs of neuropathy in the presence of DPN risk factors, with careful consideration of laboratory testing to rule out other causes of distal symmetric peripheral neuropathy and referral for a detailed neurological work-up for a confirmative test of either small or large nerve fiber dysfunction in atypical cases. Although, the first-line interventions for DPN are currently represented by optimized glycemic control (mainly for type 1 diabetes) and multifactorial intervention (mainly for type 2 diabetes), there is a need for individualized pathogenesis-directed treatment approaches for DPN. Alpha-lipoic acid (ALA) seems to be an important first-line pathogenesis-directed agent, given that it is a direct and indirect antioxidant that works with a strategy targeted directly against reactive oxygen species and indirectly in favor of endogenous antioxidant capacity for improving DPN conditions. There is still a gap in existing research in the field, necessitating well-designed, robust, multicenter clinical trials with sensitive endpoints and standardized protocols to facilitate the diagnosis of DPN via a simple and effective algorithm and to track progression of disease and treatment response. Identification of biomarkers/predictors that would allow an individualized approach from a potentially disease-modifying perspective may provide opportunities for novel treatments that would be efficacious in early stages of DPN, and may modify the natural course of the disease. This expert opinion document is expected to increase awareness among physicians about conceptual, clinical, and therapeutic aspects of DPN and to assist them in timely recognition of DPN and translating this information into their clinical practice for best practice in the management of patients with DPN.

Therapeutic Effect of Schwann Cell-Like Cells Differentiated from Human Tonsil-Derived Mesenchymal Stem Cells on Diabetic Neuropathy in db/db Mice.

BACKGROUND: Diabetic neuropathy (DN) is the most common complication of diabetes, and approximately 50% of patients with this disease suffer from peripheral neuropathy. Nerve fiber loss in DN occurs due to myelin defects and is characterized by symptoms of impaired nerve function. Schwann cells (SCs) are the main support cells of the peripheral nervous system and play important roles in several pathways contributing to the pathogenesis and development of DN. We previously reported that human tonsil-derived mesenchymal stem cells differentiated into SCs (TMSC-SCs), named neuronal regeneration-promoting cells (NRPCs), which cells promoted nerve regeneration in animal models with peripheral nerve injury or hereditary peripheral neuropathy. METHODS: In this study, NRPCs were injected into the thigh muscles of BKS-db/db mice, a commonly used type 2 diabetes model, and monitored for 26 weeks. Von Frey test, sensory nerve conduction study, and staining of sural nerve, hind foot pad, dorsal root ganglia (DRG) were performed after NRPCs treatment. RESULTS: Von Frey test results showed that the NRPC treatment group (NRPC group) showed faster responses to less force than the vehicle group. Additionally, remyelination of sural nerve fibers also increased in the NRPC group. After NRPCs treatment, an improvement in response to external stimuli and pain sensation was expected through increased expression of PGP9.5 in the sole and TRPV1 in the DRG. CONCLUSION: The NRPCs treatment may alleviate DN through the remyelination and the recovery of sensory neurons, could provide a better life for patients suffering from complications of this disease.

Exploring the Role of Mesenchymal Stem Cell-Derived Exosomes in Diabetic and Chemotherapy-Induced Peripheral Neuropathy.

Diabetic and chemotherapy-induced peripheral neuropathies are known for long-term complications that are associated with uncontrolled hyperglycemia and cancer treatment, respectively. Peripheral neuropathy often requires long-term therapy and could persist after treatment provoking detrimental effects on the patient's quality of life. Despite continuous drug discoveries, development of efficient therapies is still needed for the significant management of diabetic and chemotherapy-induced peripheral neuropathy. Exosomes are nanosized extracellular vesicles that show great promise recently in tissue regeneration and injury repair compared to their parent stem cells. Herein, we provided a summary for the use of mesenchymal stem cell-derived exosomes in diabetic and chemotherapy-induced peripheral neuropathy in addition to recent advancements and ways proposed for the enhancement of their efficacy in these diseases.

Effect of cold application versus transcutaneous nerve stimulation on chemotherapy induced diabetic peripheral neuropathy post mastectomy.

BACKGROUND: The adverse effects of chemotherapy-induced diabetic peripheral neuropathy (CIDPN) are rather prevalent. There is no known pharmaceutical treatment that can stop CIDPN. OBJECTIVE: This study compared the effects of cold application and transcutaneous nerve stimulation (Transcutaneous electrical nerve stimulation (TENS)) on individuals who had undergone mastectomy following CIDPN. SUBJECTS AND METHODS: Between Mars 2021 and September 2021, a randomised controlled experiment was carried out at physical therapy clinics at the Modern University for Technology and Information. 30 patients were randomly split into two equal groups (A and B). Both lower limbs received cold application (Group A) three times per week for 12 weeks and TENS application (Group B) three times each week for 12 weeks. The Visual Analogue Scale and nerve conduction velocity for the sural nerve were used to assess patients before and after 12 weeks of therapy. RESULTS: The results showed that Group A significantly (p < 0.05) decreased pain intensity after treatment by 70.83% compared with Group B by 55.17%. Moreover, Group A improved significantly (p < 0.05) the sural nerve amplitude by 44.12% compared with group B which recorded 26.87%. After treatment, both pain intensity and sural nerve amplitude significantly (p < 0.05) changed between Group A versus Group B. CONCLUSION: Cold application has a better effect on pain in CIDPN post mastectomy.

Effect of 10.6 µm laser moxibustion on inflammation in diabetic peripheral neuropathy rats.

Diabetic peripheral neuropathy (DPN) is the main cause of disability in diabetes patients but the efficacy of available drugs is poor. Moxibustion is an adjunctive treatment for DPN that can reduce symptoms. The peak value of the far infrared wavelength of 10.6 µm laser moxibustion is close to the infrared radiation spectrum of traditional moxibustion. Its effect is similar to that of moxibustion and does not cause pain, infection or produce irritating smoke. Twenty-four male SD rats were divided into control (Con), DPN, laser moxibustion (LM), and pyrrolidine dithiocarbamate (PDTC) groups (n=6/group). The DPN, LM and PDTC group rats were intraperitoneally injected with 1% streptozotocin (STZ) to induce a model of DPN. LM group rats were irradiated with a laser at bilateral ST36 acupoints for 15 min, once every other day, for 14 days. PDTC group rats were intraperitoneally injected with PDTC once a day. Body weight, blood glucose, and paw withdrawal mechanical threshold (PWMT) were measured and laser speckle imaging (LSI) performed before and after modeling and at 1 and 2 weeks after intervention. Two weeks after intervention, changes in serum interleukin 1ß (IL1ß), interleukin 6 (IL6), tumor necrosis factor α (TNFα) and nerve growth factor (NGF) were analyzed, and the abundance of NF-κB and IκB-α proteins and levels of NF-κB and IκB-α mRNAs in the sciatic nerve were observed. The results showed that 10.6 µm laser moxibustion can relieve pain, improve microcirculation, and alleviate inflammation in DPN rats, possibly via the NF-κB inflammatory pathway.

Effects of Mindfulness Training Combined with Tai Chi in Patients with Diabetic Peripheral Neuropathy.

Diabetic peripheral neuropathy (DPN) is one of the most prevalent chronic complications of diabetes. One of its crucial therapy approaches is mind-body exercise. Recently, various exercise modalities, including stepping, resistance, aerobics, balance, and whole-body vibration, were investigated to construct the most suitable form of exercise for patients with DPN. The purpose of this study is to describe a standard protocol for mindfulness training combined with Tai Chi. The convenience sampling method was used to select 90 patients with DPN who met the inclusion and exclusion criteria from three communities. The three communities were randomly divided into the control group (CG), the Tai Chi group (TCG), and the mindfulness training combined with the Tai Chi group (MTCG). The CG was given routine health education guidance once a month, a total of three times. Based on the CG, the TCG practiced Tai Chi three times; the MTCG received mindfulness training combined with Tai Chi exercise a week for a total of 12 weeks. Before the intervention and 12 weeks after the intervention, the clinical symptoms, neurological function, attention awareness level, pain, and quality of life of the subjects were evaluated by Toronto Clinical Scoring System (TCSS), Mindful Attention Awareness Scale (MAAS), Visual analog scale (VAS), Diabetes Specificity Quality of life Scale (DSQL) and tumor necrosis factor-α. Overall, the addition of mindfulness training to Tai Chi effectively enhances the exercise effects of Tai Chi. Therefore, mindfulness training combined with Tai Chi is worthy of promotion and application.

Conventional, high frequency and differential targeted multiplexed spinal cord stimulation in experimental painful diabetic peripheral neuropathy: Pain behavior and role of the central inflammatory balance.

Spinal cord stimulation (SCS) is a last resort treatment for pain relief in painful diabetic peripheral neuropathy (PDPN) patients. However, the effectivity of SCS in PDPN is limited. New SCS paradigms such as high frequency (HF) and differential target multiplexed (DTM) might improve responder rates and efficacy of SCS-induced analgesia in PDPN patients, and are suggested to modulate the inflammatory balance and glial response in the spinal dorsal horn. The aim of this study was to research the effects of Con-, HF- and DTM-SCS on pain behavior and the spinal inflammatory balance in an animal model of PDPN. Streptozotocin-induced PDPN animals were stimulated for 48 hours with either Con-SCS (50Hz), HF-SCS (1200Hz) or DTM-SCS (combination of Con- and HF-SCS). Mechanical hypersensitivity was assessed using Von Frey (VF) test and the motivational aspects of pain were assessed using the mechanical conflict avoidance system (MCAS). The inflammatory balance and glial response were analyzed in the dorsal spinal cord based on RNA expression of pro- and anti-inflammatory cytokines (Tnf-α, Il-1ß, Il-4, Il-10), a microglia marker (Itgam), an astrocyte marker (Gfap), a T-cell marker (Cd3d), microglia proliferation markers (Irf8, Adgre1) and P2X4, p13-MAPK, BDNF signaling markers (P2x4, Mapk14, Bdnf). The results show that Con-, HF-, and DTM-SCS significantly decreased hypersensitivity after 48 hours of stimulation compared to Sham-SCS in PDPN animals, but at the same time did not affect escape latency in the MCAS. At the molecular level, Con-SCS resulted in a significant increase in spinal pro-inflammatory cytokine Tnf-α after 48 hours compared to DTM-SCS and Sham-SCS. In summary, Con-SCS showed a shift of the inflammatory balance towards a pro-inflammatory state whilst HF- and DTM-SCS shifted the balance towards an anti-inflammatory state. These findings suggest that the underlying mechanism of Con-SCS induced pain relief in PDPN differs from that induced by HF- and DTM-SCS.

Synergistic role of resveratrol and exercise training in management of diabetic neuropathy and myopathy via SIRT1/NGF/GAP43 linkage.

AIMS: Oxidative stress also plays an important role in the pathogenesis of diabetic neuropathy (DN). Both resveratrol (RES) and exercise (EX) have potent anti-oxidative benefits. Low levels of nerve growth factor (NGF) and SIRT1 (a member of sirtuin family) have been reported in patients with DN. The current study has been designed to investigate the role of serum NGF and SIRT1 on DN-induced hyperalgesia and motor incoordination and to evaluate the possible protective role of RES and/or EX. MAIN METHODS: A total of 40 male adult albino rats divided into five groups; control, DN, DN + RES, DN + EX, and DN + RES and EX. DN was confirmed by sensorimotor disturbance and diminished nerve conduction velocity (NCV). NGF and SIRT1 levels were measured by western blot. Calcitonin gene-related peptide (CGRP) was measured by PCR. Myofibrillar degeneration and inflammation scores were revealed via H&E microscopic analysis of the gastrocnemius muscle. Immunohistochemical evaluation of caspase3 and TNF-α was performed in the lumber segment of spinal cord and gastrocnemius muscle sections. Ultrastructural evaluation of sciatic nerve axonal degeneration has also been assessed. KEY FINDINGS: DN group showed decreased SIRT1 level, decreased NGF level and correlated with CGRP level and Na+/K+ ATPase. Treatment with RES and/or EX resulted in improvement of sensorimotor disturbance. DN characterized by reduced SOD level, whereas RES and/or EX could limit oxidative damage by up-regulation Bcl2, Akt and GAP-43 and down-regulation of caspase3 and TNF-α. In conclusion, increased level of SIRT1and NGF by incorporation of RES (natural supplementation) and EX (life style modification) could improve the neuroinflammatory state in DN.

Physiotherapy interventions for pain relief in individuals with peripheral neuropathic pain: A systematic review and meta-analyses of randomized controlled trials.

OBJECTIVE: To evaluate the effectiveness of physiotherapy interventions on peripheral neuropathic pain (pNeP) due to any underlying cause. METHODS: Multiple databases were searched from database inception until Dec 2021. Studies on physiotherapy interventions for pain relief assessed using the visual analogue scale among individuals with pNeP of any underlying cause were included. Methodological quality was assessed using the PEDro scale and the quality of the evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tool. RESULTS: The searches yielded 1498 articles. Seventeen studies met the inclusion criteria and were included in the review. Meta-analysis revealed a significant benefit for laser therapy compared to sham laser on pNeP (weighted mean difference [WMD] -1.27; 95% CI: -2.29 to -0.25; p = 0.01) in people with carpal tunnel syndrome. The pooled analyses revealed a significant effect of spinal cord stimulation compared to control for failed back syndrome (standardised mean difference [SMD; Hedges'g] -0.73; 95% CI: -1.17 to -0.30; p = 0.001) and diabetic neuropathy (SMD -1.63; 95% CI -2.06--1.21; p < 0.001). The effect of acupuncture on chemotherapy-induced pain (SMD - 2.09; 95% CI: -4.27-0.09; p = 0.06) and electromagnetic stimulation on diabetic neuropathic pain (Hedges' g - 0.77; 95% CI: -1.82-0.27; p = 0.15) were insignificant. CONCLUSION: Evidence supports the use of spinal cord stimulation for the treatment of pNeP secondary to failed back surgery syndrome and diabetic neuropathy. Laser therapy was more effective than sham laser for alleviating pain due to carpal tunnel syndrome. The efficacy of acupuncture and electromagnetic therapy for chemotherapy-induced pain and diabetic neuropathy, respectively remains inconclusive.

Diabetes Mellitus: An Overview in Relationship to Charcot Neuroarthropathy.

Diabetes mellitus with the lack of glycemic control increases risks for developing comorbidities affecting organ systems responsible for critical function. The development of diabetic neuropathy predisposes patients to the onset of Charcot neuroarthropathy (CN). There is significant complexity with treatment of diabetic-induced CN, which can have an often delayed or missed diagnosis. Supervision and treatment from trained specialists are required to provide care for this multifaceted disease process. It is essential for patients to partner with glucose control, comorbidity prevention and care, as well as lower extremity management. Ultimately, CN can result in significant lower extremity deformity placing patients at risk of limb and life.

Effects of Neural Mobilization on Sensory Dysfunction and Peripheral Nerve Degeneration in Rats With Painful Diabetic Neuropathy.

OBJECTIVE: This study aims to evaluate the effectiveness of neural mobilization (NM) in the management of sensory dysfunction and nerve degeneration related to experimental painful diabetic neuropathy (PDN). METHODS: This is a pre-clinical animal study performed in the streptozocin-induced diabetic rat model. Three groups were included: a treatment group of rats with PDN receiving NM under anesthesia (PDN-NM, n = 10), a sham treatment group of rats with PDN that received only anesthesia (PDN-Sham, n = 9), and a vehicle control group with nondiabetic animals (Vehicle, n = 10). Rats in the PDN-NM and PDN-Sham groups received 1 treatment session on days 10, 12, and 14 after streptozocin injection, with a 48-hour rest period between sessions. Behavioral tests were performed using von Frey and Plantar tests. Evaluation for peripheral nerve degeneration was performed through measuring protein gene product 9.5-positive intra-epidermal nerve fiber density in hind-paw skin biopsies. All measurements were performed by a blinded investigator. RESULTS: The behavioral tests showed that a single NM session could reduce hyperalgesia, which was maintained for 48 hours. The second treatment session further improved this treatment effect, and the third session maintained it. These results suggest that it requires multiple treatment sessions to produce and maintain hypoalgesic effects. Skin biopsy analysis showed that the protein gene product 9.5-positive intra-epidermal nerve fiber density was higher on the experimental side of the PDN-NM group compared with the PDN-Sham group, suggesting NM may mitigate the degeneration of peripheral nerves. CONCLUSION: This study demonstrated that NM may be an effective method to manage experimentally induced PDN, potentially through mitigation of nerve degeneration. Further studies are needed to develop standardized protocols for clinical use. IMPACT: These findings provide neurophysiological evidence for the use of NM in PDN and can form the basis for the development of physical therapy-based programs in clinics.

10.6-µm infrared laser as adjuvant therapy for diabetic peripheral neuropathy: study protocol for a double-blind, randomized controlled trial.

BACKGROUND: Diabetic peripheral neuropathy (DPN) is the most common chronic neurological complication. It is the main cause of disability in diabetes mellitus (DM) patients and seriously affects the quality of life of patients. Pharmacological treatments always associate with limited efficacy and adverse effects. Moxibustion has been recommended to treat DPN as an adjuvant therapy to conventional medical treatment to accelerate alleviation of the symptoms of DPN. 10.6-µm laser moxibustion (LM), whose wavelength is close to the peak of infrared radiation spectrum of the traditional moxibustion as well as human acupoints, produces the thermal effect similar with moxibustion but with no smoke or smell. The purpose of this sham controlled clinical trial is to determine the effect and safety of 10.6-µm LM as adjuvant therapy in patients with DPN. METHODS: This is a protocol for a randomized, double-blind, sham-controlled trial. One hundred fourteen patients meeting the inclusion and exclusion criteria will be recruited and randomly assigned to the LM group or the sham LM group with a 1:1 allocation ratio. Patients in both groups will receive a basic integrated treatment of Chinese and Western medicine and a total of 12 sessions of true or sham LM treatments over 4 weeks with 3 sessions a week. The primary outcome is nerve conduction velocity (NCV), and the secondary outcomes include Michigan Neuropathy Screening Instrument (MNSI) scores, Diabetes-Specific Quality of Life (DSQL) scores, blood rheology parameters, and assessments of safety and blinding. Outcome measures will be collected at baseline, 2 weeks after treatment, the end of LM treatments (4 weeks), and 4, 8 weeks after the end of LM treatment (8, 12weeks). DISCUSSION: This study will be conducted to compare the efficacy of LM versus sham LM combined with medical treatment. 10.6-µm LM may alleviate symptoms, improve quality of life, and reduce the dosage of drugs as well as avoid causing serious side effects. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2000029329 . Registered on 25 January 2020.

Carpal Tunnel Syndrome in Diabetes Mellitus.

The aim of the present brief review was to discuss carpal tunnel syndrome (CTS) in diabetes mellitus (DM). Generally, CTS is more common in DM, especially in subjects with coexisting diabetic polyneuropathy (DPN) and/or long DM duration. There is no agreement if it is more frequent in type 1 or type 2 DM. The precise underlying mechanisms are not entirely clear but appear to involve hyperglycaemia-induced median nerve oedema, increased sensitivity to exogenous trauma and nerve myelin ischaemia and axonal degeneration. More recently, increased vascular endothelial growth factor (VEGF) and advanced glycation endproducts (AGEs) appear to also play an important role. Median nerve conduction study remains the cornerstone of CTS diagnosis in DM, being more sensitive than clinical examination. CTS can be treated medically or surgically. The latter appears now to be equally effective in subjects with vs. without DM in terms of recurrence rates and quality of life.

The neuro-restorative effect of adipose-derived mesenchymal stem cell transplantation on a mouse model of diabetic neuropathy.

Diabetic neuropathy (DN) is the most common degenerative complication associated with Diabetes Mellitus. Despite widespread awareness about DN, the only effective treatments are blood glucose control and pain management. The aim of the current study was to determine the effect of intramuscular adipose-derived mesenchymal stem cell (AMSC) transplantation on sciatic nerves in DN using EMG and histological analyses. A total of 27 mice were randomly divided into three groups: control group, DN group and AMSC group. In EMG, CMAP amplitude in the sciatic nerves was lower, but distal latency was higher in the DN group compared with the control group. CMAP amplitude in the sciatic nerves was higher in the AMSC group compared with the DN group. Distal latency in the sciatic nerve was lower in the AMSC group compared with the DN group. Histologic examination of the tissues in the animals treated with AMSC showed a remarkable improvement in microscopic morphology. Fluorescence microscopy analyses demonstrated that intramuscularly transplanted AMSC was selectively localized in the sciatic nerves. Transplantation of AMSC increased protein expression of S100, cdk2, NGF and DHH, all of which, interfered with DN onset in sciatic nerves. The findings of the present study suggest that AMSC transplantation improved DN through a signal-regulatory effect on Schwann cells, neurotrophic actions and restoration of myelination.