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1.
J Biomed Nanotechnol ; 17(2): 291-302, 2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33785099

RESUMO

Schwann cells promote axonal regeneration following peripheral nerve injury. However, in terms of clinical treatment, the therapeutic effects of Schwann cells are limited by their source. The transmission of microvesicles from neuroglia cells to axons is a novel communication mechanism in axon regeneration.To evaluate the effect of microvesicles released from Schwann-like cells on axonal regeneration, neural stem cells derived from human embryonic stem cells differentiated into Schwann-like cells, which presented a typical morphology and characteristics similar to those of schwann cells. The glial markers like MBP, P0, P75NTR, PMP-22, GFAP, HNK-1 and S100 were upregulated, whereas the neural stem markers like NESTIN, SOX1 and SOX2 were significantly downregulated in schwann-like cells. Microvesicles enhanced axonal growth in dorsal root ganglia neurons and regulated GAP43 expression in neuron-like cells (N2A and PC12) through the PTEN/PI3 K/Akt signaling pathway. A 5 mm section of sciatic nerve was transected in Sprague-Dawley rats. With microvesicles transplantation, regenerative nerves were evaluated after 6 weeks. Microvesicles increased sciatic function index scores, delayed gastrocnemius muscle atrophy and elevated ßIII-tubulin-labeled axons in vivo. Schwann-like cells serve as a convenient source and promote axonal growth by secreting microvesicles, which may potentially be used as bioengineering materials for nerve tissue repair.


Assuntos
Axônios , Regeneração Nervosa , Animais , Materiais Biocompatíveis , Ratos , Ratos Sprague-Dawley , Células de Schwann , Nervo Isquiático
2.
Zhongguo Zhen Jiu ; 41(2): 183-8, 2021 Feb 12.
Artigo em Chinês | MEDLINE | ID: mdl-33788467

RESUMO

OBJECTIVE: To observe the effect of moxibustion at "Huantiao" (GB 30) on the expression of growth-associated protein-43 (GAP-43) in the sciatic nerve trunk and ventral horn of spinal cord (L4-L6) in rats with primary sciatica, and to explore the mechanism of moxibustion in improving primary sciatica. METHODS: A total of 48 healthy male SD rats were randomly divided into a normal group, a sham operation group, a model group and a moxibustion group, 12 rats in each group. The rat model of primary sciatic pain was established by chronic constriction injury (CCI) of the sciatic nerve in the model group and the moxibustion group. On the 8th day of the experiment, moxibustion was adopted at "Huantiao" (GB 30) in the moxibustion group for 5-10 min, once a day for 14 consecutive days. Sciatic nerve function index (SFI) was measured and compared in each group at day 1, 7, 14 and 21. On the 21st day of the experiment, HE staining was used to observe the morphology of ventral horn of rat spinal cord and sciatic nerve trunk. Immunohistochemical method and real-time PCR were used to detect mRNA and protein expressions of GAP-43 in the spinal cord and sciatic nerve trunk of rats. RESULTS: On day 7, 14 and 21, there was no statistical difference in SFI between the sham operation group and the normal group (P>0.05); compared with the sham operation group on day 7, 14 and 21, the SFI of the model group was reduced (P<0.01); compared with the model group on day 14 and 21, SFI in the moxibustion group was increased (P<0.01). In the normal group and the sham operation group, neuronal cells were in order in the ventral horn of the spinal cord, nissl bodies were spaced regularly, the myelin sheath structure of sciatic nerve axon was clearly visible. In the model group, neuronal cells were deformed and ruptured in the ventral horn of the spinal cord, the number of nissl bodies was less, and the demyelination of sciatic axons appeared. In the moxibustion group, neuronal cells were found in the ventral horn of spinal cord, and the number of nissl bodies was increased, and less demyelinating changes of axons appeared in sciatic nerve. Compared with the normal group, the expressions of GAP-43 mRNA and GAP-43 protein in the sciatic nerve trunk and GAP-43 protein in the ventral horn of spinal cord were increased in the sham operation group (P<0.01). Compared with the sham operation group, the expression of GAP-43 mRNA and GAP-43 protein in the spinal cord and sciatic nerve trunk of rats in the model group was increased. Compared with the model group, the expression of GAP-43 mRNA and GAP-43 protein in the spinal cord and sciatic nerve trunk of rats in the moxibustion group was increased (P<0.01). CONCLUSION: Moxibustion at "Huantiao" (GB 30) could improve the sciatic nerve function in rats with primary sciatica and its mechanism may be related to improving the expression of GAP-43 and enhancing the self-repair ability of the sciatic nerve after injury.


Assuntos
Eletroacupuntura , Moxibustão , Ciática , Animais , Proteína GAP-43/genética , Masculino , Ratos , Ratos Sprague-Dawley , Nervo Isquiático , Ciática/terapia , Medula Espinal
3.
Georgian Med News ; (310): 165-169, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33658426

RESUMO

The article describes the results of studying the changes in peripheral nerves of a limb after a mechanically induced ischemia. It assessed myelinated nerve fibers in sciatic and tibial nerves after 6 hours of ischemia, simulated by a tourniquet on the level of a tibial, knee, and a lower third of a femur. Fasciculi of the sciatic nerve have shown no changes in the density of nerve fibers in 5th, 15th, and 30th days after the simulated ischemia, but we revealed the deformed fibers with the different thickness of myelin sheath. In a tibial nerve, myelin loss and deformations occurred on the 5th and 15th day, and atrophy of nerve fibers - on the 15th and 30th days. Neurolemmocytes of the injured myelin nerve fibers demonstrate the signs of dystrophic processes and autophagy. After the insertion of platelet-rich plasma, concentrated bone marrow aspirate, and homogenized adipose tissue in the ischemically damaged muscles, not a significant difference appeared between the extent of damage to the nerve. Consequently, the structural signs of the damage to peripheral nerves depend more on the level of injury to a limb than on therapy with autologous cellular technologies.


Assuntos
Doenças Vasculares Periféricas , Plasma Rico em Plaquetas , Humanos , Isquemia , Fibras Nervosas Mielinizadas , Nervos Periféricos , Nervo Isquiático
4.
Int J Mol Sci ; 22(3)2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33540826

RESUMO

Toll-like receptors (TLRs) are key receptors through which infectious and non-infectious challenges act with consequent activation of the inflammatory cascade that plays a critical function in various acute and chronic diseases, behaving as amplification and chronicization factors of the inflammatory response. Previous studies have shown that synthetic analogues of lipid A based on glucosamine with few chains of unsaturated and saturated fatty acids, bind MD-2 and inhibit TLR4 receptors. These synthetic compounds showed antagonistic activity against TLR4 activation in vitro by LPS, but little or no activity in vivo. This study aimed to show the potential use of N-palmitoyl-D-glucosamine (PGA), a bacterial molecule with structural similarity to the lipid A component of LPS, which could be useful for preventing LPS-induced tissue damage or even peripheral neuropathies. Molecular docking and molecular dynamics simulations showed that PGA stably binds MD-2 with a MD-2/(PGA)3 stoichiometry. Treatment with PGA resulted in the following effects: (i) it prevented the NF-kB activation in LPS stimulated RAW264.7 cells; (ii) it decreased LPS-induced keratitis and corneal pro-inflammatory cytokines, whilst increasing anti-inflammatory cytokines; (iii) it normalized LPS-induced miR-20a-5p and miR-106a-5p upregulation and increased miR-27a-3p levels in the inflamed corneas; (iv) it decreased allodynia in peripheral neuropathy induced by oxaliplatin or formalin, but not following spared nerve injury of the sciatic nerve (SNI); (v) it prevented the formalin- or oxaliplatin-induced myelino-axonal degeneration of sciatic nerve. SIGNIFICANCE STATEMENT We report that PGA acts as a TLR4 antagonist and this may be the basis of its potent anti-inflammatory activity. Being unique because of its potency and stability, as compared to other similar congeners, PGA can represent a tool for the optimization of new TLR4 modulating drugs directed against the cytokine storm and the chronization of inflammation.


Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Glicolipídeos/uso terapêutico , Hiperalgesia/prevenção & controle , Ceratite/tratamento farmacológico , Neuralgia/tratamento farmacológico , Receptor 4 Toll-Like/antagonistas & inibidores , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Citocinas/metabolismo , Avaliação Pré-Clínica de Medicamentos , Glicolipídeos/farmacologia , Células HEK293 , Humanos , Hiperalgesia/etiologia , Ceratite/induzido quimicamente , Ceratite/patologia , Lipopolissacarídeos/toxicidade , Antígeno 96 de Linfócito/metabolismo , Masculino , Camundongos , MicroRNAs/genética , Modelos Moleculares , Nociceptores/efeitos dos fármacos , Nociceptores/fisiologia , Conformação Proteica , Células RAW 264.7 , Distribuição Aleatória , Nervo Isquiático/lesões , Canal de Cátion TRPA1/metabolismo
5.
ACS Appl Mater Interfaces ; 13(1): 112-122, 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33397079

RESUMO

The gold standard treatment for peripheral nerve injuries (PNIs) is the autologous graft, while it is associated with the shortage of donors and results in major complications. In the present study, we engineer a graphene mesh-supported double-network (DN) hydrogel scaffold, loaded with netrin-1. Natural alginate and gelatin-methacryloyl entangled hydrogel that is synthesized via fast exchange of ions and ultraviolet irradiation provide proper mechanical strength and excellent biocompatibility and can also serve as a reservoir for netrin-1. Meanwhile, the graphene mesh can promote the proliferation of Schwann cells and guide their alignments. This approach allows scaffolds to have an acceptable Young's modulus of 725.8 ± 46.52 kPa, matching with peripheral nerves, as well as a satisfactory electrical conductivity of 6.8 ± 0.85 S/m. In addition, netrin-1 plays a dual role in directing axon pathfinding and neuronal migration that optimizes the tube formation ability at a concentration of 100 ng/mL. This netrin-1-loaded graphene mesh tube/DN hydrogel nerve scaffold can significantly promote the regeneration of peripheral nerves and the restoration of denervated muscle, which is even superior to autologous grafts. Our findings may provide an effective therapeutic strategy for PNI patients that can replace the scarce autologous graft.


Assuntos
Grafite/química , Hidrogéis/química , Regeneração Nervosa/efeitos dos fármacos , Netrina-1/uso terapêutico , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Nervo Isquiático/efeitos dos fármacos , Alginatos/química , Alginatos/toxicidade , Animais , Movimento Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Módulo de Elasticidade , Gelatina/química , Gelatina/toxicidade , Grafite/toxicidade , Células Endoteliais da Veia Umbilical Humana , Humanos , Hidrogéis/toxicidade , Masculino , Metacrilatos/química , Metacrilatos/toxicidade , Neovascularização Fisiológica/efeitos dos fármacos , Ratos Sprague-Dawley , Células de Schwann/efeitos dos fármacos , Nervo Isquiático/lesões , Tecidos Suporte/química
6.
Toxicol Lett ; 340: 67-76, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33429010

RESUMO

Vincristine (VCR) is commonly used to treat a variety of hematological malignancies and solid tumors in pediatric and adult patients. However, peripheral neuropathy is a dose-limiting side effect that leaves some patients with functional disability and long-term pain. Oxytocin (OT) has demonstrated analgesic and anti-inflammatory properties, but there is no evidence regarding its effects on VCR-induced neurotoxicity. Therefore, we evaluated the potential protective effects of OT on VCR-induced neurotoxicity. In vitro, VCR (0.005 ∼ 0.1 µmol/l) and OT (10-8 ∼ 10-5 mol/l) were added into cultured primary dorsal root ganglion (DRG) neurons of mice. The length of neurites was counted by using immunofluorescence. In vivo, neurotoxicity was induced in mice by administration of VCR (0.1 mg/kg, intraperitoneal injection for 14 days) with or without pretreatment of OT (0.1 mg/kg or 1 mg/kg). Atosiban, an OT receptor (OTR) antagonist and OTR knockout (KO) mice were used for evaluating effects of OTR. Mechanical hyperalgesia was measured by using von Frey filaments. Histology of plantar skin, sciatic nerve and DRG was observed by using transmission electron microscopy (TEM) and hematoxylin-eosin (HE) staining. Results indicated that OT alleviated VCR-induced neurite damage in cultured primary DRG neurons in vitro. In vivo, OT ameliorated VCR-induced hyperalgesia. Histologically, OT attenuated the VCR-induced damages of nerve endings, myelin sheaths and Schwann cells in sciatic nerve and DRG. These effects were antagonized by atosiban. In addition, OTR knockout mice exhibited more severe hyperalgesia than wild-type mice. Globally, these results indicated that OT may have neuroprotective effects on vincristine-induced neurotoxicity in mice.


Assuntos
Ocitócicos/toxicidade , Ocitocina/uso terapêutico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Vincristina/toxicidade , Animais , Antineoplásicos Fitogênicos/toxicidade , Hiperalgesia/induzido quimicamente , Camundongos , Camundongos Knockout , Síndromes Neurotóxicas/tratamento farmacológico , Receptores de Ocitocina/antagonistas & inibidores , Nervo Isquiático/efeitos dos fármacos , Vasotocina/análogos & derivados , Vasotocina/toxicidade
7.
Sensors (Basel) ; 21(2)2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33445808

RESUMO

Peripheral nerve interfaces (PNIs) allow us to extract motor, sensory, and autonomic information from the nervous system and use it as control signals in neuroprosthetic and neuromodulation applications. Recent efforts have aimed to improve the recording selectivity of PNIs, including by using spatiotemporal patterns from multi-contact nerve cuff electrodes as input to a convolutional neural network (CNN). Before such a methodology can be translated to humans, its performance in chronic implantation scenarios must be evaluated. In this simulation study, approaches were evaluated for maintaining selective recording performance in the presence of two chronic implantation challenges: the growth of encapsulation tissue and rotation of the nerve cuff electrode. Performance over time was examined in three conditions: training the CNN at baseline only, supervised re-training with explicitly labeled data at periodic intervals, and a semi-supervised self-learning approach. This study demonstrated that a selective recording algorithm trained at baseline will likely fail over time due to changes in signal characteristics resulting from the chronic challenges. Results further showed that periodically recalibrating the selective recording algorithm could maintain its performance over time, and that a self-learning approach has the potential to reduce the frequency of recalibration.


Assuntos
Algoritmos , Eletrodos Implantados , Nervos Periféricos/fisiologia , Processamento de Sinais Assistido por Computador , Animais , Simulação por Computador , Humanos , Aprendizado de Máquina , Modelos Biológicos , Redes Neurais de Computação , Ratos , Nervo Isquiático/fisiologia
8.
Psychopharmacology (Berl) ; 238(3): 877-886, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33404738

RESUMO

BACKGROUND: Memory deficit is a common cognitive comorbid in patients with neuropathic pain that need better treatment. Recent research revealed that nanocurcumin has an antinociceptive action and a protective effect against memory disorders, suggesting its possible effectiveness for the treatment of neuropathic pain and its comorbidity. METHODS: Adult male albino Wistar rats (n = 32) were randomly divided into four experimental groups: CCI+ nanocurcumin, CCI + vehicle, sham + nanocurcumin, and sham + vehicle. Neuropathic pain induced by a chronic constriction injury of the sciatic nerve. Nanocurcumin or vehicle was injected intraperitoneally for 10 days. Behavioral assessment achieved to evaluate pain threshold in the von Frey test and radiant heat test, also spatial learning and memory examined by the Morris water maze (MWM) test. To explore the possible relation, IL-1ß, and TNF-α levels of the hippocampus measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Our data showed that CCI caused neuropathic pain-related behaviors and spatial learning and memory disorders in rats. Chronic treatment with nanocurcumin significantly increased pain threshold (P < 0.001; F = 27.63, F = 20.58), improved spatial memory (P < 0.01; F = 47.37), and decreased the hippocampal levels of IL-1ß (P < 0.001; F = 33.57) and TNF-α (P < 0.01; F = 7.25) in CCI rats. CONCLUSION: Chronic nanocurcumin can ameliorate pain-related behavior, improve spatial learning and memory deficits, and is associated with the reduction of IL-1ß and TNF-α levels in the hippocampus in CCI rats. Nanocurcumin may be potentially providing a therapeutic alternative for the treatment of neuropathic pain and its memory impairment comorbidity.


Assuntos
Analgésicos/uso terapêutico , Curcumina/uso terapêutico , Hipocampo/efeitos dos fármacos , Interleucina-1beta/metabolismo , Neuralgia/tratamento farmacológico , Memória Espacial/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Analgésicos/administração & dosagem , Analgésicos/química , Animais , Comportamento Animal/efeitos dos fármacos , Constrição , Curcumina/administração & dosagem , Curcumina/química , Modelos Animais de Doenças , Hipocampo/metabolismo , Masculino , Transtornos da Memória/complicações , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Nanopartículas/administração & dosagem , Nanopartículas/química , Neuralgia/complicações , Neuralgia/metabolismo , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Wistar , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/lesões
9.
Molecules ; 26(1)2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33401491

RESUMO

7ß-(3-Ethyl-cis-crotonoyloxy)-1α-(2-methylbutyryloxy)-3,14-dehydro-Z-notonipetranone (ECN), a sesquiterpenoid obtained from a natural source has proved to be effective in minimizing various side effects associated with opioids and nonsteroidal anti-inflammatory drugs. The current study focused on investigating the effects of ECN on neuropathic pain induced by partial sciatic nerve ligation (PSNL) by mainly focusing on oxidative stress, inflammatory and apoptotic proteins expression in mice. ECN (1 and 10 mg/kg, i.p.), was administered once daily for 11 days, starting from the third day after surgery. ECN post-treatment was found to reduce hyperalgesia and allodynia in a dose-dependent manner. ECN remarkably reversed the histopathological abnormalities associated with oxidative stress, apoptosis and inflammation. Furthermore, ECN prevented the suppression of antioxidants (glutathione, glutathione-S-transferase, catalase, superoxide dismutase, NF-E2-related factor-2 (Nrf2), hemeoxygenase-1 and NAD(P)H: quinone oxidoreductase) by PSNL. Moreover, pro-inflammatory cytokines (tumor necrotic factor-alpha, interleukin 1 beta, interleukin 6, cyclooxygenase-2 and inducible nitric oxide synthase) expression was reduced by ECN administration. Treatment with ECN was successful in reducing the caspase-3 level consistent with the observed modulation of pro-apoptotic proteins. Additionally, ECN showed a protective effect on the lipid content of myelin sheath as evident from FTIR spectroscopy which showed the shift of lipid component bands to higher values. Thus, the anti-neuropathic potential of ECN might be due to the inhibition of oxidative stress, inflammatory mediators and pro-apoptotic proteins.


Assuntos
Proteínas Reguladoras de Apoptose/biossíntese , Regulação da Expressão Gênica/efeitos dos fármacos , Neuralgia , Estresse Oxidativo/efeitos dos fármacos , Nervo Isquiático , Sesquiterpenos , Animais , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Neuralgia/patologia , Nervo Isquiático/metabolismo , Nervo Isquiático/patologia , Sesquiterpenos/química , Sesquiterpenos/farmacologia
10.
Int J Mol Sci ; 22(2)2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33430035

RESUMO

Traumatic peripheral nerve lesions affect hundreds of thousands of patients every year; their consequences are life-altering and often devastating and cause alterations in movement and sensitivity. Spontaneous peripheral nerve recovery is often inadequate. In this context, nowadays, cell therapy represents one of the most innovative approaches in the field of nerve repair therapies. The purpose of this systematic review is to discuss the features of different types of mesenchymal stem cells (MSCs) relevant for peripheral nerve regeneration after nerve injury. The published literature was reviewed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A combination of the keywords "nerve regeneration", "stem cells", "peripheral nerve injury", "rat", and "human" were used. Additionally, a "MeSH" research was performed in PubMed using the terms "stem cells" and "nerve regeneration". The characteristics of the most widely used MSCs, their paracrine potential, targeted stimulation, and differentiation potentials into Schwann-like and neuronal-like cells are described in this paper. Considering their ability to support and stimulate axonal growth, their remarkable paracrine activity, their presumed differentiation potential, their extremely low immunogenicity, and their high survival rate after transplantation, ADSCs appear to be the most suitable and promising MSCs for the recovery of peripheral nerve lesion. Clinical considerations are finally reported.


Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/fisiologia , Regeneração Nervosa/fisiologia , Nervos Periféricos/fisiologia , Animais , Diferenciação Celular , Humanos , Regeneração Nervosa/genética , Ratos , Células de Schwann/fisiologia , Nervo Isquiático/crescimento & desenvolvimento
11.
J Ethnopharmacol ; 266: 113461, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33039625

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Jinmaitong (JMT) is a prescription of Traditional Chinese Medicine, which is composed of ten herbal drugs and two animal drugs. It has long been used for the treatment of diabetic peripheral neuropathy (DPN). AIM OF STUDY: Wnt/ß-catenin pathway is considered as an essential and direct driver of myelinogenesis. This study aims to evaluate the protective effect of JMT against DPN dynamically during a 16-weeks' treatment, and to investigate the underlying mechanism in which the Wnt/ß-catenin pathway is involved. MATERIALS AND METHODS: Diabetic model was induced by single intraperitoneal injection of Streptozotocin (STZ) using male Sprague-Dawley rats. The model rats were divided into five groups and administrated with JMT at three doses (0.437, 0.875, and 1.75 g/kg per day), neurotropin (positive drug, 2.67 NU/kg per day), and placebo (deionized water), respectively, for continuous 8 weeks (n = 9-10), 12 weeks (n = 8-10), or 16 weeks (n = 7-9). Meanwhile, rats in control group were administrated with placebo (n = 10 for 8 weeks, n = 9 for 12 and 16 weeks, respectively). Blood glucose and body weight were monitored every four weeks. Mechanical allodynia was assessed using mechanical withdrawal threshold (MWT) test. The morphological change of sciatic nerves were observed by transmission electron microscope (TEM) and hematoxylin and eosin (HE) stain. The mRNA and protein levels of targeted genes were evaluated by quantitative real time-PCR and western bolt, respectively. Myelin protein zero (MPZ) and mediators involved in Wnt/ß-catenin pathway, such as ß-catenin, glycogen synthase kinase 3ß (GSK-3ß), and WNT inhibitory factor-1 (WIF-1), were compared among different groups after treatment of 8, 12, and 16 weeks, respectively. RESULTS: The mechanical allodynia and peripheral nerve morphology were degenerated in DPN rats over time, and notably improved after JMT-treatment of 12 and 16 weeks. The decreased MPZ level in DPN rats were also significantly amended by JMT. More importantly, we found that the suppressed Wnt/ß-catenin pathway in sciatic nerves of DPN rats was overtly up-regulated by JMT in a time-dependent manner. Among the three doses, JMT at the middle dose showed the best effect. CONCLUSIONS: JMT effectively ameliorated diabetic-induced peripheral neuropathy, which was mediated by the activation of Wnt/ß-catenin signaling pathway. This study provided new perspective to understand the neuroprotective mechanism of JMT.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Neuropatias Diabéticas/fisiopatologia , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/administração & dosagem , Masculino , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/metabolismo , Estreptozocina
12.
Biomed Pharmacother ; 133: 111062, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33378965

RESUMO

Diabetic peripheral neuropathy (DPN) is the common complication of diabetes mellitus. Histone deacetylase (HDAC) inhibitor trichostatin A (TSA) is reported to ameliorate the peripheral nerves degeneration of DPN. However, the exact mechanism is still not well elucidated. Here, we first revealed that TSA promoted nerve conduction and brain derived neurotrophic factor (BDNF) expression in the sciatic nerves of diabetic mice. In line, TSA also reversed high glucose-reduced mature BDNF expression in vitro cultured rat Schwann cells (RSC96). Then unexpectedly, the downstream targets of TSA HDAC1 and HDAC5 were not involved in TSA-improved BDNF expression. Furthermore, unfolded protein response (UPR) chaperone GRP78 was revealed to be downregulated with high glucose stimulation in RSC96 cells, which was avoided with TSA treatment. Also, GRP78 upregulation mediated TSA-improved mature BDNF expression in high glucose-cultured RSC96 cells by binding with BDNF. As well, TSA treatment enhanced the binding of GRP78 with BDNF in RSC96 cells. Again, UPR-associated transcription factors XBP-1s and ATF6 were involved in TSA-increased GRP78 expression in high glucose-stimulated RSC96 cells. Finally, conditioned medium from high glucose-cultured RSC96 cells delayed neuron SH-SY5Y differentiation and that from TSA-treated high glucose-cultured RSC96 cells promoted SH-SY5Y cell differentiation. Taken together, our findings suggested that TSA increased BDNF expression to ameliorate DPN by improving XBP-1s/ATF6/GRP78 axis in Schwann cells.


Assuntos
Fator 6 Ativador da Transcrição/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Neuropatias Diabéticas/tratamento farmacológico , Proteínas de Choque Térmico/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Células de Schwann/efeitos dos fármacos , Nervo Isquiático/efeitos dos fármacos , Proteína 1 de Ligação a X-Box/metabolismo , Fator 6 Ativador da Transcrição/genética , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Linhagem Celular Tumoral , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Neuropatias Diabéticas/etiologia , Neuropatias Diabéticas/metabolismo , Proteínas de Choque Térmico/genética , Humanos , Masculino , Camundongos Endogâmicos C57BL , Ratos , Células de Schwann/metabolismo , Nervo Isquiático/metabolismo , Transdução de Sinais , Regulação para Cima , Proteína 1 de Ligação a X-Box/genética
13.
Methods Mol Biol ; 2201: 71-82, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32975790

RESUMO

Immunohistochemical staining is widely used to identify opioid receptors in specific cell types throughout the nervous system. Opioid receptors are not restricted to the central nervous system, but are also present in peripheral sensory neurons, where their activation exerts analgesic effects without inducing centrally mediated side effects. Here, we describe immunohistochemical analysis of µ-opioid receptors in the peripheral sensory neuron cell bodies, along the axons and their peripheral endings in the hind paw skin, as well as in the spinal cord, under naïve and sciatic nerve damage conditions in mice. Importantly, we consider the ongoing debate on the specificity of antibodies.


Assuntos
Imuno-Histoquímica/métodos , Nervos Periféricos/metabolismo , Receptores Opioides mu/imunologia , Analgésicos Opioides/metabolismo , Animais , Axônios/metabolismo , Gânglios Espinais/citologia , Humanos , Camundongos , Nervos Periféricos/imunologia , Receptores Acoplados a Proteínas-G/metabolismo , Receptores Opioides/imunologia , Receptores Opioides/metabolismo , Receptores Opioides mu/metabolismo , Nervo Isquiático/citologia , Neuropatia Ciática , Células Receptoras Sensoriais/metabolismo , Medula Espinal/metabolismo
14.
Methods Mol Biol ; 2201: 83-95, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32975791

RESUMO

Real-time quantitative reverse transcription-PCR (qRT-PCR ) is a highly sensitive molecular biology method based on the amplification of the cDNA of mRNA to detect and quantify the levels of mRNA of interest. In this chapter, we describe real-time qRT-PCR to detect and quantify mRNA of opioid receptors in immune cells. Specifically, we analyze mouse immune cells isolated from the blood and sciatic nerves exposed to a chronic constriction injury, which represents a model of neuropathic pain. We describe in detail the requirements and techniques to induce the chronic constriction injury, to isolate immune cells from the blood and injured nerves, to isolate the total RNA from immune cells, to perform a cDNA reverse transcription from the total RNA, and to perform real-time qRT-PCR for µ-, δ-, and κ-opioid receptor mRNAs.


Assuntos
Reação em Cadeia da Polimerase em Tempo Real/métodos , Receptores Opioides mu/genética , Animais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuralgia , RNA Mensageiro/genética , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Receptores Opioides/genética , Receptores Opioides/imunologia , Receptores Opioides/metabolismo , Receptores Opioides delta/genética , Receptores Opioides kappa/genética , Receptores Opioides mu/imunologia , Receptores Opioides mu/metabolismo , Transcrição Reversa , Nervo Isquiático/lesões
15.
Methods Mol Biol ; 2201: 127-137, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32975795

RESUMO

Patch clamp is an electrophysiological technique that allows to analyze the activity of ion channels in neurons. In this chapter, we provide a detailed description of patch clamp protocol to measure the effect of a µ-opioid receptor agonist on the activity of G protein-coupled inwardly rectifying potassium (GIRK or Kir3) channels. This is performed in peripheral sensory neurons isolated from dorsal root ganglia (DRG) of mice without or with a chronic constriction injury (CCI) of the sciatic nerve, which models neuropathic pain. We describe the induction of the CCI , isolation and culture of DRG neurons, performance of the patch clamp recordings, and identification of opioid-responding neurons.


Assuntos
Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/análise , Técnicas de Patch-Clamp/métodos , Células Receptoras Sensoriais/fisiologia , Animais , Modelos Animais de Doenças , Eletrofisiologia , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Gânglios Espinais/lesões , Gânglios Espinais/metabolismo , Hiperalgesia , Masculino , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Neuralgia , Traumatismos dos Nervos Periféricos/metabolismo , Nervo Isquiático/lesões
16.
Nat Commun ; 11(1): 6425, 2020 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-33349630

RESUMO

Overcoming the restricted axonal regenerative ability that limits functional repair following a central nervous system injury remains a challenge. Here we report a regenerative paradigm that we call enriched conditioning, which combines environmental enrichment (EE) followed by a conditioning sciatic nerve axotomy that precedes a spinal cord injury (SCI). Enriched conditioning significantly increases the regenerative ability of dorsal root ganglia (DRG) sensory neurons compared to EE or a conditioning injury alone, propelling axon growth well beyond the spinal injury site. Mechanistically, we established that enriched conditioning relies on the unique neuronal intrinsic signaling axis PKC-STAT3-NADPH oxidase 2 (NOX2), enhancing redox signaling as shown by redox proteomics in DRG. Finally, NOX2 conditional deletion or overexpression respectively blocked or phenocopied enriched conditioning-dependent axon regeneration after SCI leading to improved functional recovery. These studies provide a paradigm that drives the regenerative ability of sensory neurons offering a potential redox-dependent regenerative model for mechanistic and therapeutic discoveries.


Assuntos
Regeneração Nervosa , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/patologia , Transdução de Sinais , Traumatismos da Medula Espinal/fisiopatologia , Animais , Axônios/patologia , Axotomia , Gânglios Espinais/patologia , Camundongos Endogâmicos C57BL , NADPH Oxidase 2/metabolismo , Crescimento Neuronal , Plasticidade Neuronal , Oxirredução , Fosforilação , Regiões Promotoras Genéticas/genética , Proteína Quinase C/metabolismo , Subunidades Proteicas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/metabolismo , Nervo Isquiático/fisiopatologia , Regulação para Cima
17.
PLoS One ; 15(12): e0244301, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33338083

RESUMO

Adhesion and scarring after neural surgery are detrimental to nerve regeneration and functional recovery. Amniotic membranes have been used in tissue repair due to their immunogenicity and richness in cytokines. In this study, an electrospun polycaprolactone (PCL)-amnion nanofibrous membrane was prepared for the treatment of sciatic nerve compression in a rat model. The effects of the PCL-amnion nanofibrous membrane on the prevention of adhesion formation and nerve regeneration were evaluated using electrophysiology and histological analyses. Compared with the medical chitosan hydrogel dressing, the PCL-amnion nanofibrous membrane significantly reduced peripheral nerve adhesion and promoted the rapid recovery of nerve conduction. Moreover, the immunohistochemical analysis identified more Schwann cells and less pro-inflammatory M1 macrophages in the PCL-amnion group. Western blot and RT-PCR results showed that the expression levels of type-Ⅰ and Ⅲ collagen in the PCL-treated rats were half of those in the control group after 12 weeks, while the expression level of nerve growth factor was approximately 3.5 times that found in the rats treated with medical chitosan hydrogel. In summary, electrospun PCL-amnion nanofibrous membranes can effectively reduce adhesion after neural surgery and promote nerve repair and regeneration. The long-term retention in vivo and sustained release of cytokines make PCL-amnion a promising biomaterial for clinical application.


Assuntos
Regeneração Nervosa/efeitos dos fármacos , Poliésteres/farmacologia , Aderências Teciduais/prevenção & controle , Âmnio/patologia , Animais , Materiais Biocompatíveis , Quitosana/farmacologia , Colágeno/farmacologia , Modelos Animais de Doenças , Hidrogéis/farmacologia , Masculino , Nanofibras/química , Ratos , Ratos Sprague-Dawley , Células de Schwann/patologia , Nervo Isquiático/patologia , Neuropatia Ciática/fisiopatologia , Aderências Teciduais/tratamento farmacológico , Engenharia Tecidual/métodos , Tecidos Suporte
18.
An Acad Bras Cienc ; 92(4): e20191155, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33331440

RESUMO

Gabapentin has antihyperalgesic action, decreasing central sensitization in neuropathic pain models; this effect depends on the mobilization of endogenous pain control pathways. This study aims to investigate the contribution of the endocannabinoid system to the antihyperalgesic action of gabapentin. Mus musculus Swiss, male, were submitted to PSL. On the 7th and 14th days post PSL, different groups were treated with CB1 receptor antagonist, AM281 via i.t. (2 µg/5 µl) or i.pl. (10 µg/20 µl) or CB2, AM630 via i.t. (5 µL i.t.) or (20 µL i.p.) and 15 min after gabapentin (30 mg / kg orally). Mechanical hyperalgesia was measured by the frequency of paw removal by the von Frey monofilament. Gabapentin demonstrated antihypernociceptive action, which was attenuated in animals pretreated with AM281 in both the i.t. and i.pl routes on the 7th and 14th days, differently from animals pretreated with AM630 that did not achieve a significant reduction with administration i.t. only on the 14th day with administration i.pl. The results show that endocannabinoid system contributes to the antihyperalgesic action of gabapetin in neuropathic pain by PSL, suggesting participation in the medullary and peripheral levels of CB1 receptors, and the peripheral performance of CB2 receptors.


Assuntos
Endocanabinoides , Neuralgia , Analgésicos/uso terapêutico , Animais , Modelos Animais de Doenças , Gabapentina , Hiperalgesia/tratamento farmacológico , Masculino , Camundongos , Neuralgia/tratamento farmacológico , Nervo Isquiático
19.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 3379-3383, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018729

RESUMO

This paper presents a neurosurgical device called NEIT 2 (Nerve Electrode Insertion Tool) to implant a 3D microelectrode array into a peripheral nervous system. Using an elastomer-made nerve holder, the device is able to stable target a flexible nerve, and then safely inserts an electrode array into the fixed nerve. Finally, a nerve containment assembly is made at once. We conducted animal experiments to evaluate the proposed scenario using a 3D printed prototype and commercial microelectrodes. The results show that microelectrodes are successfully implanted into sciatic nerves of rats and neural signals are recorded through the chronically implanted electrodes.


Assuntos
Nervo Isquiático , Animais , Eletrodos Implantados , Microeletrodos , Ratos
20.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 3407-3410, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018735

RESUMO

Chronic stability of functional performance is a significant challenge to the success of implantable devices for neural stimulation and recording. Integrating wireless technology with typical microelectrode array designs is one approach that may reduce instances of mechanical failure and improve the long-term performance of neural devices. We have investigated the long-term stability of Wireless Floating Microelectrode Arrays (WMFAs) implanted in rat sciatic nerve, and their ability to selectively recruit muscles in the hind limb via neural stimulation. Thresholds as low as 4.1 µA were able to generate visible motion of the rear paw. Each implanted device (n=6) was able to selectively recruit plantar flexion and dorsiflexion of the rear paw, and selective stimulation of both movements was achieved throughout the study period. The evoked limb motion was electrode specific and was dependent on location within the fascicular structure of the nerve. Motor thresholds and movement patterns remained stable for more than 8 weeks after device implantation. No major changes in limb function were observed between the implanted and contralateral limb, or between implanted animals and control group animals. The results of this study show that WFMAs with intrafascicular electrodes implanted in a healthy peripheral nerve can provide stable and selective motor recruitment, without altering overall limb function.


Assuntos
Nervo Isquiático , Tecnologia sem Fio , Animais , Membro Posterior , Microeletrodos , Movimento , Ratos
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