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1.
Molecules ; 26(6)2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33804199

RESUMO

Neuropathic pain is described as the "most terrible of all tortures that a nerve wound may inflict." The aim of the present study was to demonstrate the antinociceptive effect of Symplocos chinensis f. pilosa Ohwi water extract (SCW) and synthesized derivatives of the isolated compound. The antinociceptive effect was tested using the acetic acid-induced writhing and 5% formalin tests. Antinociceptive effects on neuropathic pain were evaluated using the von Frey test with chronic constriction injury (CCI) and surgical nerve injury (SNI) models and tail-flick test with a vincristine-induced pain model. An Ames test was also conducted. 5-hydroxymethylfurfural (5-HMF) was isolated and derivatives were synthesized with various acid groups. Among the plant water extracts, SCW showed significantly effective activity. Additionally, SCW presented antinociceptive effects in the neuropathic pain models. The SCW water fraction resulted in fewer writhes than the other fractions, and isolated 5-HMF was identified as an effective compound. Because 5-HMF revealed a positive response in the Ames test, derivatives were synthesized. Among the synthesized derivations, 5-succinoxymethylfurfural (5-SMF) showed the best effect in the neuropathic pain model. Our data suggest that SCW and the synthesized compound, 5-SMF, possess effective antinociceptive activity against neuropathic pain.


Assuntos
Ericales/química , Neuralgia/tratamento farmacológico , Extratos Vegetais/farmacologia , Analgésicos/farmacologia , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos ICR , Nervo Isquiático/efeitos dos fármacos
2.
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
3.
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
4.
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
5.
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
6.
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
7.
Life Sci ; 256: 117959, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32531375

RESUMO

Resveratrol has the ability to promote functional recovery after sciatic nerve crush injury (SNCI), though the mechanism through which this occurs in not fully understood. Resveratrol can promote autophagy, a key process in Wallerian degeneration; thus, we hypothesized that resveratrol could promote recovery from SNCI by promoting Schwann cell autophagy and acceleration of Wallerian degeneration. Motor function recovery was assessed by calculating Sciatic Function Indexes (SFIs) at days 7, 14, 21, 28 post SNCI. Autophagy and myelin clearance were assessed by microtubule-associated protein light chain 3B (LC3B) and myelin protein zero (MPZ) immunofluorescence and Western blot analysis on the fourth day after SNCI. The autophagy of Schwann cells following resveratrol administration was quantified by immunofluorescence in RSC96 cells. Immunofluorescence and Transmission electron microscopy (TEM) were also used in Resveratrol treated sciatic nerve four days post-SNCI to find LC3B positive areas and typical double membrane structures represent for autophagy. The SNCI+resveratrol (crush+Res) groups recovered faster than the SNCI+vehicles (crush+V) group. On day four, almost all of the myelin had regenerated in the crush+Res rats, while the crush+V group's myelin remained intact and the expression levels of LC3-II/I was the highest. On day 28 post-injury, both the control and crush+Res groups' myelin neurofibers reached peak numbers as did the thickness of the myelin sheath. Both in vitro and in vivo immunofluorescence showed that LC3B was colocalized with Schwann cells. This is the first study to observe that resveratrol can promote recovery from SCNI by accelerating the myelin clearance process by promoting autophagy of Schwann cells.


Assuntos
Autofagia/efeitos dos fármacos , Lesões por Esmagamento/fisiopatologia , Compressão Nervosa , Recuperação de Função Fisiológica/efeitos dos fármacos , Resveratrol/farmacologia , Células de Schwann/patologia , Nervo Isquiático/patologia , Nervo Isquiático/fisiopatologia , Animais , Axônios/efeitos dos fármacos , Axônios/patologia , Lesões por Esmagamento/patologia , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Atividade Motora/efeitos dos fármacos , Proteína P0 da Mielina/metabolismo , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/metabolismo , Fibras Nervosas/efeitos dos fármacos , Fibras Nervosas/patologia , Regeneração Nervosa/efeitos dos fármacos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Células de Schwann/efeitos dos fármacos , Células de Schwann/metabolismo , Nervo Isquiático/efeitos dos fármacos
8.
Ideggyogy Sz ; 73(3-4): 113-120, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32364338

RESUMO

Background and purpose: Peripheral nerve injury (PNI) is a frequent problem among young adults. Hopefully, regeneration can occur in PNI unlike central nervous system. If nerve cut is complete, gold standard treatment is surgery, but incomplete cuts have been tried to be treated by medicines. The aim of the study was to evaluate and compare clinical and histopathological outcomes of independent treatment of each of Vitamin B12 (B12) and Vitamin D3 (D3) and their combination on sciatic nerve injury in an experimental rat model. Methods: Experimental animal study was performed after the approval of BEH Ethics Committee No. 2015/10. 32 rats were grouped into four (n=8) according to treatment procedures, such as Group 1 (controls with no treatment), Group 2 (intraperitoneal 1 mg/kg/day B12), Group 3 (oral 3500 IU/kg/week D3), Group 4 (intraperitoneal 1 mg/kg/day B12+ oral 3500 IU/kg/week D3). Sciatic Functional Index (SFI) and histopathological analysis were performed. Results: SFIs of Group 2, 3, 4 were statistically significantly higher than controls. Group 2 and 3 were statistically not different, however Group 4 was statistically significantly higher than others according to SFI. Axonal degeneration (AD) in all treatment groups were statistically significantly lower than in Group 1. AD in Group 4 was significantly lower than in Group 2 and 3; there was no significant difference between Group 2 and 3. There was no significant difference between Group 1,2 and 3 in Axonolysis (A). But A of Group 4 was significantly very much lower than all others. Oedema- inflammation (OE-I) in all treatment groups were significantly lower than in Group 1; there was no significant difference between Group 2 and group 4. OE-I in Group 2 and 4 were significantly lower than in Group 3. There were no significant differences between Group 1, 2 and 3 in damage level scores; score of Group 4 was significantly lower than of Group 1. Conclusion: B12 and D3 were found effective with no statistically significant difference. But combined use of B12 and D3 improve nerve healing synergistically. We recommend combined use of B12 and D3 after PNI as soon as possible.


Assuntos
Colecalciferol/farmacologia , Fármacos Neuroprotetores/farmacologia , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Nervo Isquiático/efeitos dos fármacos , Vitamina B 12/farmacologia , Animais , Modelos Animais de Doenças , Humanos , Ratos , Adulto Jovem
9.
Life Sci ; 254: 117777, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32407839

RESUMO

AIM: Inflammatory cascade and oxidative stress play a central role in diabetic peripheral neuropathy via activation of inflammatory cytokines. Escin has potent antioxidant and anti-inflammatory properties. Hence, the present study was conducted to evaluate the effect of escin on diabetic peripheral neuropathy in streptozotocin (STZ) induced diabetes in rats. MAIN METHODS: Diabetes was induced in rats with streptozotocin (55 mg/kg). The animals with blood glucose above 250 mg/dl were randomized in different groups. Animals were treated with escin at a dose of 5, 10 and 20 mg/kg after six weeks of diabetes induction for the next four weeks. After completion of treatment, various parameters like glucose, thermal hyperalgesia, mechanical hyperalgesia, mechanical allodynia and nerve conduction velocities were evaluated. Oxidative stress parameters like malondialdehyde, catalase, reduced glutathione and superoxide dismutase were performed in sciatic nerves. Histopathology study of sciatic nerves was also studied. KEY FINDINGS: Escin treatment significantly reduced plasma glucose, thermal hyperalgesia, mechanical hyperalgesia and mechanical allodynia as compared to diabetic animals. The motor nerve conduction velocity and sensory nerve conduction velocities were significantly improved in diabetic animals treated with escin. Escin significantly normalized oxidative stress parameters. Escin treatment also prevented progression of neuronal damage by reducing demyelination, leukocytic infiltration in sciatic nerves as compared to diabetic animals. SIGNIFICANCE: From the results of study it can be concluded that escin can be a useful option for management of diabetic peripheral neuropathy.


Assuntos
Neuropatias Diabéticas/tratamento farmacológico , Escina/farmacologia , Animais , Antioxidantes/farmacologia , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Escina/metabolismo , Hiperalgesia/tratamento farmacológico , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/efeitos dos fármacos , Estreptozocina/farmacologia , Superóxido Dismutase/metabolismo
10.
Sci Rep ; 10(1): 6734, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32317735

RESUMO

Oxaliplatin is a platinum-based antineoplastic drug commonly used for treating colorectal, gastric, and pancreatic cancer. However, it frequently causes peripheral neuropathy as dose-limiting toxicity and is lacking a strategy for prevention. Alogliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, is an oral antidiabetic drug. Previous studies have shown that DPP-4 inhibitors have pleiotropic effects, including neuroprotection. In this study, we investigated the effects of alogliptin on oxaliplatin-induced peripheral neuropathy using in vitro and in vivo models. In PC12 cells, alogliptin attenuated neurite disorders induced by oxaliplatin and cisplatin. The repeated injection of oxaliplatin caused mechanical allodynia and axonal degeneration of the sciatic nerve in rats. These neuropathies were ameliorated by co-administration of alogliptin. Moreover, alogliptin did not attenuate tumor cytotoxicity of oxaliplatin in the cultured colon, gastric, or pancreatic cancer cell lines and tumor-bearing mice. These findings suggest that alogliptin may be beneficial for preventing oxaliplatin-induced peripheral neuropathy.


Assuntos
Antineoplásicos/efeitos adversos , Cisplatino/efeitos adversos , Hiperalgesia/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Oxaliplatina/efeitos adversos , Doenças do Sistema Nervoso Periférico/prevenção & controle , Piperidinas/farmacologia , Uracila/análogos & derivados , Aloenxertos , Animais , Axônios/efeitos dos fármacos , Axônios/patologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Relação Dose-Resposta a Droga , Células HCT116 , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neuritos/efeitos dos fármacos , Neuritos/patologia , Células PC12 , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/fisiopatologia , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/fisiopatologia , Carga Tumoral/efeitos dos fármacos , Uracila/farmacologia
11.
Muscle Nerve ; 62(1): 119-127, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32243602

RESUMO

INTRODUCTION: Many reports have indicated that adipose-derived stem cells (ADSCs) are effective for nerve regeneration. We investigated nerve regeneration by combining a polyglycolic acid collagen (PGA-c) tube, which is approved for clinical use, and Schwann cell-like differentiated ADSCs (dADSCs). METHODS: Fifteen-millimeter-long gaps in the sciatic nerve of rats were bridged in each group using tubes (group I), with tubes injected with dADSCs (group II), or by resected nerve (group III). RESULTS: Axonal outgrowth was greater in group II than in group I. Tibialis anterior muscle weight revealed recovery only in group III. Latency in nerve conduction studies was equivalent in group II and III, but action potential was lower in group II. Transplanted dADSCs maintained Schwann cell marker expression. ATF3 expression level in the dorsal root ganglia was equivalent in groups II and III. DISCUSSION: dADSCs maintained their differentiated state in the tubes and are believed to have contributed to nerve regeneration.


Assuntos
Tecido Adiposo/fisiologia , Diferenciação Celular/fisiologia , Regeneração Nervosa/fisiologia , Células de Schwann/fisiologia , Nervo Isquiático/fisiologia , Transplante de Células-Tronco/métodos , Tecido Adiposo/citologia , Tecido Adiposo/transplante , Animais , Diferenciação Celular/efeitos dos fármacos , Colágeno/administração & dosagem , Feminino , Regeneração Nervosa/efeitos dos fármacos , Nervos Periféricos/efeitos dos fármacos , Nervos Periféricos/fisiologia , Ácido Poliglicólico/administração & dosagem , Ratos , Ratos Wistar , Células de Schwann/transplante , Nervo Isquiático/efeitos dos fármacos , Neuropatia Ciática/fisiopatologia , Neuropatia Ciática/terapia , Células-Tronco/fisiologia
12.
Wei Sheng Yan Jiu ; 49(1): 14-18, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-32290908

RESUMO

OBJECTIVE: To investigate the expression of S100ß protein and mRNA of Schwann cells(SC) in sciatic nerves of 2, 5-hexanedione(HD) intoxicated rats. METHODS: Nine-week old SPF male Wistar rats were administered at daily dosing of 100 and 300 mg/kg by intraperitoneal injection for continuous 8 weeks(five times every week). Age-matched control rats received an equivalent volume of normal saline. Ten rats in each group were sacrificed and sciatic nerves were excised for S100ß determination, with excised sciatic nerves from another three rats for morphological observation through electron microscope. At the end of the exposure, the other 8-week treated animals were allowed to naturally recover for 8 weeks and sciatic nerves were excised at the end of the test. S100ß protein contents were determined by immunohistochemistry method, and mRNA expression was observed by real-time quantitative polymerase chain reaction(PCR). RESULTS: HD intoxication with 300 mg/kg was associated with severe neurological deficits of paralysis in hindlimbs, accompanied with evident movement gait abnormalities for 100 mg/kg dosage. The morphological abnormalities in myelin sheath of sciatic nerves were observed through electron microscope after HD-exposure. The S100ß contents in 100 mg/kg and 300 mg/kg groups remained relatively unaffected with 92% and 79% of the control respectively after HD-intoxication, and a increase to 149%(P<0. 05) and 119% after a recovery of 8 weeks was accompanied with. As to S100ß mRNA, HD-intoxication was associated with decreased expression to 0. 65(P<0. 05) and 0. 56 times(P<0. 05) of the control, and 1. 46 and 0. 87 times for 8-week recovery individually. CONCLUSION: The S100ß protein and mRNA levels were influenced by HD exposure, and the result suggested that S100ß might be involved in HD-induced peripheral axonopathy.


Assuntos
Hexanonas/toxicidade , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Células de Schwann/efeitos dos fármacos , Nervo Isquiático/efeitos dos fármacos , Animais , Masculino , Ratos , Ratos Wistar , Células de Schwann/metabolismo , Nervo Isquiático/patologia , Testes de Toxicidade
13.
PLoS One ; 15(4): e0231194, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32271817

RESUMO

Various injuries to the neural tissues can cause irreversible damage to multiple functions of the nervous system ranging from motor control to cognitive function. The limited treatment options available for patients have led to extensive interest in studying the mechanisms of neuronal regeneration and recovery from injury. Since many neurons are terminally differentiated, by increasing cell survival following injury it may be possible to minimize the impact of these injuries and provide translational potential for treatment of neuronal diseases. While several cell types are known to survive injury through plasma membrane repair mechanisms, there has been little investigation of membrane repair in neurons and even fewer efforts to target membrane repair as a therapy in neurons. Studies from our laboratory group and others demonstrated that mitsugumin 53 (MG53), a muscle-enriched tripartite motif (TRIM) family protein also known as TRIM72, is an essential component of the cell membrane repair machinery in skeletal muscle. Interestingly, recombinant human MG53 (rhMG53) can be applied exogenously to increase membrane repair capacity both in vitro and in vivo. Increasing the membrane repair capacity of neurons could potentially minimize the death of these cells and affect the progression of various neuronal diseases. In this study we assess the therapeutic potential of rhMG53 to increase membrane repair in cultured neurons and in an in vivo mouse model of neurotrauma. We found that a robust repair response exists in various neuronal cells and that rhMG53 can increase neuronal membrane repair both in vitro and in vivo. These findings provide direct evidence of conserved membrane repair responses in neurons and that these repair mechanisms can be targeted as a potential therapeutic approach for neuronal injury.


Assuntos
Regeneração Nervosa , Nervo Isquiático/lesões , Nervo Isquiático/fisiopatologia , Cicatrização , Animais , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Lesões por Esmagamento/patologia , Lesões por Esmagamento/fisiopatologia , Modelos Animais de Doenças , Humanos , Proteínas de Membrana/metabolismo , Membranas , Camundongos Endogâmicos C57BL , Regeneração Nervosa/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Proteínas Recombinantes/farmacologia , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia , Proteínas com Motivo Tripartido/farmacologia , Cicatrização/efeitos dos fármacos
14.
Eur J Histochem ; 64(2)2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32236088

RESUMO

Schwann cells (SC) are characterized by a remarkable plasticity that enables them to promptly respond to nerve injury promoting axonal regeneration. In peripheral nerves after damage SC convert to a repair-promoting phenotype activating a sequence of supportive functions that drive myelin clearance, prevent neuronal death, and help axon growth and guidance. Regeneration of peripheral nerves after damage correlates inversely with thrombin levels. Thrombin is not only the key regulator of the coagulation cascade but also a protease with hormone-like activities that affects various cells of the central and peripheral nervous system mainly through the protease-activated receptor 1 (PAR1). Aim of the present study was to investigate if and how thrombin could affect the axon supportive functions of SC. In particular, our results show that the activation of PAR1 in rat SC cultures with low levels of thrombin or PAR1 agonist peptides induces the release of molecules, which favor neuronal survival and neurite elongation. Conversely, the stimulation of SC with high levels of thrombin or PAR1 agonist peptides drives an opposite effect inducing SC to release factors that inhibit the extension of neurites. Moreover, high levels of thrombin administered to sciatic nerve ex vivo explants induce a dramatic change in SC morphology causing disappearance of the Cajal bands, enlargement of the Schmidt-Lanterman incisures and calcium-mediated demyelination of the paranodes. Our results indicate thrombin as a novel modulator of SC plasticity potentially able to favor or inhibit SC pro-regenerative properties according to its level at the site of lesion.


Assuntos
Neurogênese/efeitos dos fármacos , Nós Neurofibrosos/efeitos dos fármacos , Células de Schwann/efeitos dos fármacos , Trombina/farmacologia , Animais , Cálcio/metabolismo , Feminino , Masculino , Neuritos/efeitos dos fármacos , Células PC12 , Pirróis/farmacologia , Quinazolinas/farmacologia , Ratos , Ratos Wistar , Receptor PAR-1/metabolismo , Nervo Isquiático/efeitos dos fármacos , Tapsigargina/farmacologia
15.
Oxid Med Cell Longev ; 2020: 6431459, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32184918

RESUMO

Oxidative stress has been recognized as the contributor to diabetic peripheral neuropathy (DPN). Antioxidant strategies have been most widely explored; nevertheless, whether antioxidants alone prevent DPN still remains inconclusive. In the present study, we established an in vitro DPN cell model for drug screening using Schwann RSC96 cells under high glucose (HG) stimulation, and we found that salvianolic acid A (SalA) mitigated HG-induced injury evidenced by cell viability and myelination. Mechanistically, SalA exhibited strong antioxidative effects by inhibiting 1,1-diphenyl-2-picrylhydrazyl (DPPH) and reducing reactive oxygen species (ROS), malondialdehyde (MDA), and oxidized glutathione (GSSG) content, as well as upregulating antioxidative enzyme mRNA expression. In addition, SalA significantly extenuated neuroinflammation with downregulated inflammatory factor mRNA expression. Furthermore, SalA improved the mitochondrial function of HG-injured Schwann cells by scavenging mitochondrial ROS, decreasing mitochondrial membrane potential (MMP), and enhancing ATP production, as well as upregulating oxidative phosphorylation gene expression. More importantly, we identified nuclear factor-E2-related factor 2 (Nrf2) as the upstream regulator which mediated protective effects of SalA on DPN. SalA directly bound to the Kelch domain of Kelch-like ECH-associated protein 1 (Keap1) and thus disrupted the interaction of Nrf2 and Keap1 predicted by LibDock of Discovery Studio. Additionally, SalA significantly inhibited Nrf2 promoter activity and downregulated Nrf2 mRNA expression but without affecting Nrf2 protein expression. Interestingly, SalA upregulated the nuclear Nrf2 expression and promoted Nrf2 nuclear translocation by high content screening assay, which was confirmed to be involved in its antiglucotoxicity effect by the knockdown of Nrf2 in RSC96 cells. In KK-Ay mice, we demonstrated that SalA could effectively improve the abnormal glucose and lipid metabolism and significantly protect against DPN by increasing the mechanical withdrawal threshold and sciatic nerve conduction velocity and restoring the ultrastructural impairment of the injured sciatic nerve induced by diabetes. Hence, SalA protected against DPN by antioxidative stress, attenuating neuroinflammation, and improving mitochondrial function via Nrf2. SalA may be prospective therapeutics for treating DPN.


Assuntos
Ácidos Cafeicos/uso terapêutico , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/metabolismo , Lactatos/uso terapêutico , Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/metabolismo , Animais , Ácidos Cafeicos/química , Ácidos Cafeicos/farmacologia , Linhagem Celular , Neuropatias Diabéticas/patologia , Glucose/toxicidade , Inflamação/patologia , Lactatos/química , Lactatos/farmacologia , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Doenças do Sistema Nervoso Periférico/patologia , Ratos , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia , Nervo Isquiático/ultraestrutura
16.
J Orthop Surg Res ; 15(1): 41, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32028972

RESUMO

BACKGROUND: Total knee arthroplasty (TKA) is usually associated with moderate to severe postoperative pain. Peripheral nerve block (PNB) and local infiltration analgesia (LIA) are two major methods for postoperative analgesia. Femoral nerve block (FNB) leads to residual posterior knee pain; thus, currently sciatic nerve block (SNB) and LIA are two major options for supplementing FNB. However, the efficacy and safety of LIA compared with combined femoral and sciatic nerve block still remain controversial. Here, we conducted a study to analyze the postoperative analgesic efficacy of these two methods. METHOD: Two hundred six patients undergoing TKA were enrolled in a retrospective cohort study. The patients received either PNB or LIA. All patients in PNB group were conducted combined femoral and sciatic nerve block. All patients were encouraged to use patient-controlled analgesia (PCA) after surgery. The postoperative visual analog scale (VAS) at rest or with movement during the first 24 h and 48 h was recorded. We analyzed the VAS of 24 h, VAS of 48 h, opioid consumption, and adverse effects between PNB group and LIA group. Chi-square test and nonparametric test were used in this study. RESULTS: There were 82 patients in the PNB group and 124 patients in the LIA group. The patients' characteristics such as age, height, weight, and ASA showed no significant difference (P > 0.05). No significant differences were found (P > 0.05) between the two groups regarding VAS score at rest or with movement. The LIA group had less opioid consumption than the PNB group but without significant difference (P > 0.05). In both groups, the most common side effect was nausea, and the side effects showed no significant differences between groups (P > 0.05). CONCLUSION: Local infiltration analgesia provided a similar analgesic effect and complications compared with combined femoral and sciatic nerve block in the short term. Considering less opioid consumption with local infiltration analgesia though without significant difference and its convenience, local infiltration analgesia provided better postoperative analgesia.


Assuntos
Anestesia Local/métodos , Artroplastia do Joelho/efeitos adversos , Bloqueio Nervoso Autônomo/métodos , Manejo da Dor/métodos , Dor Pós-Operatória/prevenção & controle , Idoso , Artroplastia do Joelho/tendências , Estudos de Coortes , Terapia Combinada/métodos , Feminino , Nervo Femoral/efeitos dos fármacos , Nervo Femoral/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Dor Pós-Operatória/etiologia , Estudos Retrospectivos , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/fisiologia
17.
Food Chem Toxicol ; 137: 111167, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32007468

RESUMO

Chronic exposure to n-hexane could induced serious peripheral nerve impairments. It has been well documented that the metabolic activation from n-hexane to 2,5-hexanedione (2,5-HD) is vital in the pathogenesis. Diallyl sulfide (DAS) is an extract of garlic and able to block the bioactivation of xenobiotic. The current study was designed to investigate whether DAS can attenuate n-hexane induced neuropathy. Male Wistar rats were pretreated with DAS (50 or 100 mg/kg.bw) and then n-hexane (3 g/kg.bw) for 7 weeks. Behavioral performance, biomarker measurement and toxicokinetic studies were performed. Enzymatic methods and western blotting analyses were also conducted to investigate the hepatic phase I enzymes (including cytochrome P450(CYP)2E1, CYP1A1 and CYP2B1) and phase II enzymes (including glutathione S transferase theta 1 (GSTT1) and NA(D)PH dehydrogenase quinone 1 (NQO1)). The results showed that DAS improved the behavioral performance while reducing the toxic metabolite: 2,5-HD and pyrrole adducts. Besides, DAS reduced the expression of CYP2E1 with a proportional decrease in activity, which largely decreased the bioactivation of n-hexane in vivo. The results suggested that DAS decreased the toxic metabolites of n-hexane to attenuate n-hexane-induced peripheral neuropathy.


Assuntos
Compostos Alílicos/farmacologia , Hexanos/toxicidade , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/prevenção & controle , Nervo Isquiático/efeitos dos fármacos , Sulfetos/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Cabelo/química , Hexanos/metabolismo , Hexanonas/análise , Masculino , Pirróis/análise , Ratos Wistar
18.
Eur J Med Chem ; 191: 112144, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32087465

RESUMO

We designed and synthesized a novel series of piperidine propionamide derivatives as potent sigma-1 (σ1) receptor antagonists and mu (µ) opioid receptor agonists, and measured their affinity for σ1 and µ receptors in vitro through binding assays. The basic scaffold of the new compounds contained a 4-substituted piperidine ring and N-aryl propionamide. Compound 44, N-(2-(4-(4-fluorobenzyl) piperidin-1-yl) ethyl)-N-(4-methoxy-phenyl) propionamide, showed the highest affinity for σ1 receptor (Ki σ1 = 1.86 nM) and µ receptor (Ki µ = 2.1 nM). It exhibited potent analgesic activity in the formalin test (ED50 = 15.1 ± 1.67 mg/kg) and had equivalent analgesic effects to S1RA (σ1 antagonist) in a CCI model. Therefore, Compound 44, which has mixed σ1/µ receptor profiles, may be a potential candidate for treating neuropathic pain.


Assuntos
Amidas/farmacologia , Neuralgia/tratamento farmacológico , Piperidinas/farmacologia , Receptores Opioides mu/agonistas , Receptores sigma/antagonistas & inibidores , Amidas/administração & dosagem , Amidas/química , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Formaldeído , Cobaias , Injeções Subcutâneas , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Neuralgia/induzido quimicamente , Neuralgia/patologia , Piperidinas/administração & dosagem , Piperidinas/química , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia , Relação Estrutura-Atividade
19.
Anesthesiology ; 133(1): 185-194, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31977524

RESUMO

BACKGROUND: Postoperative pain caused by trauma to nerves and tissue around the surgical site is a major problem. Perioperative steps to reduce postoperative pain include local anesthetics and opioids, the latter of which are addictive and have contributed to the opioid epidemic. Cryoneurolysis is a nonopioid and long-lasting treatment for reducing postoperative pain. However, current methods of cryoneurolysis are invasive, technically demanding, and are not tissue-selective. This project aims to determine whether ice slurry can be used as a novel, injectable, drug-free, and tissue-selective method of cryoneurolysis and resulting analgesia. METHODS: The authors developed an injectable and selective method of cryoneurolysis using biocompatible ice slurry, using rat sciatic nerve to investigate the effect of slurry injection on the structure and function of the nerve. Sixty-two naïve, male Sprague-Dawley rats were used in this study. Advanced Coherent anti-Stokes Raman Scattering microscopy, light, and fluorescent microscopy imaging were used at baseline and at various time points after treatment for evaluation and quantification of myelin sheath and axon structural integrity. Validated motor and sensory testing were used for evaluating the sciatic nerve function in response to ice slurry treatment. RESULTS: Ice slurry injection can selectively target the rat sciatic nerve. Being injectable, it can infiltrate around the nerve. The authors demonstrate that a single injection is safe and selective for reversibly disrupting the myelin sheaths and axon density, with complete structural recovery by day 112. This leads to decreased nocifensive function for up to 60 days, with complete recovery by day 112. There was up to median [interquartile range]: 68% [60 to 94%] reduction in mechanical pain response after treatment. CONCLUSIONS: Ice slurry injection selectively targets the rat sciatic nerve, causing no damage to surrounding tissue. Injection of ice slurry around the rat sciatic nerve induced decreased nociceptive response from the baseline through neural selective cryoneurolysis.


Assuntos
Crioterapia/métodos , Gelo , Bloqueio Nervoso/métodos , Nervo Isquiático , Analgesia , Animais , Axônios/efeitos dos fármacos , Axônios/ultraestrutura , Injeções , Masculino , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/ultraestrutura , Nociceptividade , Medição da Dor , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/ultraestrutura , Caminhada
20.
Nutrients ; 12(1)2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31947713

RESUMO

Neuropathic pain is generally characterized by sensory abnormalities such as sensory disorders, hyperalgesia, and allodynia. Recent studies have reported that TRPV1 activation is essential for establishing of inflammation in the neuropathy pain models, showing that the expression of this receptor is increased, and contributing to enhanced thermal sensitivity. Nypa fruticans Wurmb (NF), which was used as a folk remedy, is a plant that is gaining attention due to its various effects. In this study, we investigated the antinociceptive and anti-inflammatory effects of NFE (Nypa fruticans Wurmb extracts) by controlling the neurological function of TRPV1. In sciatic crush injury rat models, a significant level of antinociceptive effect was observed in the thermal hyperalgesia test in which NF extracts (NFE 500 mg/kg) were orally administered, daily. Protein quantification of the sciatic nerve and the of the L4-L6 spinal cord showed a decrease of the TRPV1 expression, the inflammatory expression factor, COX2, and proinflammatory factors in the NFE treated groups. Our results indicate that NFE affects antinociceptive and anti-inflammatory by controlling TRPV1 in sciatic neuropathic pain models.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Arecaceae , Neuralgia/tratamento farmacológico , Extratos Vegetais/farmacologia , Neuropatia Ciática/tratamento farmacológico , Animais , Modelos Animais de Doenças , Ratos , Nervo Isquiático/efeitos dos fármacos , Canais de Cátion TRPV/efeitos dos fármacos
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