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1.
Biomed Res Int ; 2019: 4252349, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30984781

RESUMO

Background: Local anesthetics are used in various purposes from topical and infiltration anesthesia to peripheral nerve or central neural blockade. Even though local anesthetics are relatively safe, they can have some toxic and adverse effects. Prolonged sensory and motor block is another example of an unwanted complication. The primary objective of this study was to determine whether insulin has a reversal effect on the peripheral (sciatic) nerve block with lidocaine or bupivacaine. Methods: The surgically exposed sciatic nerves in rats were blocked with lidocaine or bupivacaine, and then 0.1 ml of normal saline or 0.1 ml normal saline containing 0.1 IU a short-acting form of insulin was administrated per body in each group. Before and after sciatic nerve block, as well as until recovery from the nerve block after normal saline or insulin treatment, nerve conduction studies such as monitoring loss and recovery of the waveforms and amplitudes were performed to evaluate the status of motor nerve conduction. Results: Complete recovery time of nerve conduction status in lidocaine + normal saline group was 58 ± 16 min, whereas that in lidocaine + insulin group was 17 ± 3 min and the difference was statistically significant (p < 0.01). Complete recovery time of nerve conduction status in bupivacaine + normal saline group was 116 ± 16 min and that in bupivacaine + insulin group was 36 ± 4 min and the two groups were significantly different (p < 0.01). Conclusions: Insulin can reverse peripheral nerve block induced by lidocaine or bupivacaine.


Assuntos
Insulina/administração & dosagem , Bloqueio Nervoso/métodos , Nervo Isquiático/efeitos dos fármacos , Neuropatia Ciática/tratamento farmacológico , Anestesia Local/métodos , Animais , Bupivacaína/administração & dosagem , Modelos Animais de Doenças , Combinação de Medicamentos , Humanos , Lidocaína/administração & dosagem , Ratos , Nervo Isquiático/patologia , Neuropatia Ciática/patologia
2.
J Neuroinflammation ; 16(1): 83, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30975172

RESUMO

BACKGROUND: Neuropathic pain is a serious clinical problem that needs to be solved urgently. ASK1 is an upstream protein of p38 and JNK which plays important roles in neuroinflammation during the induction and maintenance of chronic pain. Therefore, inhibition of ASK1 may be a novel therapeutic approach for neuropathic pain. Here, we aim to investigate the effects of paeoniflorin on ASK1 and neuropathic pain. METHODS: The mechanical and thermal thresholds of rats were measured using the Von Frey test. Cell signaling was assayed using western blotting and immunohistochemistry. RESULTS: Chronic constrictive injury (CCI) surgery successfully decreased the mechanical and thermal thresholds of rats and decreased the phosphorylation of ASK1 in the rat spinal cord. ASK1 inhibitor NQDI1 attenuated neuropathic pain and decreased the expression of p-p38 and p-JNK. Paeoniflorin mimicked ASK1 inhibitor NQDI1 and inhibited ASK1 phosphorylation. Paeoniflorin decreased the expression of p-p38 and p-JNK, delayed the progress of neuropathic pain, and attenuated neuropathic pain. Paeoniflorin reduced the response of astrocytes and microglia to injury, decreased the expression of IL-1ß and TNF-α, and downregulated the expression of CGRP induced by CCI. CONCLUSIONS: Paeoniflorin is an effective drug for the treatment of neuropathic pain in rats via inhibiting the phosphorylation of ASK1, suggesting it may be effective in patients with neuropathic pain.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Apoptose/efeitos dos fármacos , Encefalite/tratamento farmacológico , Glucosídeos/uso terapêutico , MAP Quinase Quinase Quinase 5/metabolismo , Monoterpenos/uso terapêutico , Neuropatia Ciática/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Encefalite/complicações , Hidroxiquinolinas/uso terapêutico , Hiperalgesia/fisiopatologia , Interleucina-1beta/metabolismo , Masculino , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Neuropatia Ciática/complicações
3.
Behav Pharmacol ; 30(1): 79-88, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30633724

RESUMO

Neuropathic pain is driven by abnormal peripheral and central processing, and treatments are insufficiently effective. Antibodies against nerve growth factor (anti-NGF) have been investigated as a potent analgesic treatment for numerous conditions. However, the peripheral and brain effects of anti-NGF in neuropathic pain remain unknown. We examined the effectiveness of anti-NGF in reducing chronic pain by local administration in a rat model of sciatic constriction injury (CCI). NGF and substance P in the dorsal root ganglion (DRG) and spinal cord were evaluated. Neuronal activation was measured using c-Fos in the anterior cingulate cortex and ventrolateral periaqueductal gray. At 14 days after CCI, anti-NGF promoted a significant dose-dependent improvement in mechanical threshold, thermal withdrawal latency, and cold sensitivity, lasting for 5 h. NGF upregulation in the DRG and spinal cord after CCI was decreased by anti-NGF, while substance P was increased only in the DRG, and the treatment reduced it. Anti-NGF induced a significant reduction of neuronal activation in the anterior cingulate cortex, but not in the ventrolateral periaqueductal gray. This study provides the first evidence of the anti-NGF effects on brain activity. Thus, our findings suggest that anti-NGF improves chronic neuropathic pain, acting directly on peripheral sensitization and indirectly on central sensitization.


Assuntos
Anticorpos/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Fator de Crescimento Neural/imunologia , Neuropatia Ciática/tratamento farmacológico , Neuropatia Ciática/patologia , Animais , Modelos Animais de Doenças , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Masculino , Medição da Dor , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Substância P/metabolismo , Fatores de Tempo , Regulação para Cima/efeitos dos fármacos
4.
Neurol Res ; 41(4): 326-334, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30638158

RESUMO

OBJECTIVE: To verify the action of sericin associated to swim exercise with overload, on sciatic nerve repair in Wistar rats, after 22 days of nerve compression. METHODS: Forty animals been composed of five groups: control, injury, injury-sericin, injury-swimming and injury-sericin-swimming. During the lesion procedure, sericin, in hydrolyzed form, applied directly to the injury in the injury-sericin and injury-sericin-swimming groups. Injury-swimming and injury-sericin-swimming groups underwent to 5 days per week for 3 weeks, with a 10% overload of the animal's body weight, and a weekly progressive evolution of swimming time, lasting 15, 20 and 25 min/day. Pre and throughout the treatment period the animals performed evaluation of sciatic functional index and pressure pain threshold with digital von Frey filament. Euthanasia was performed on the 22nd postoperative day, and two fragments of the nerve were collected and prepared for descriptive and quantitative analysis. RESULTS: The sciatic functional index assessment showed significant differences in the motor function of the control until the 14th day. Regarding the allodynia, there was revealed a significant improvement in injury-swimming performance relative to injury, injury-sericin and injury-sericin-swimming, and the number of viable and non-viable nerve fibers smaller than 4 µm in diameter was significantly higher in the injury-sericin-swimming. CONCLUSION: swimming showed a better evolution of the nociceptive threshold and allodynia. Sericin treatment had exacerbated pro-inflammatory characteristics. On the other hand, the association of sericine and swimming showed a possible regulatory effect by resting swimming exercise, with a significant increase of fibers of smaller diameter.


Assuntos
Condicionamento Físico Animal/métodos , Neuropatia Ciática/tratamento farmacológico , Neuropatia Ciática/reabilitação , Sericinas/uso terapêutico , Natação , Animais , Modelos Animais de Doenças , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Limiar da Dor/fisiologia , Ratos , Ratos Wistar , Nervo Isquiático/patologia , Neuropatia Ciática/fisiopatologia , Sericinas/metabolismo , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Resultado do Tratamento
5.
J Pharmacol Exp Ther ; 368(3): 490-502, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30591528

RESUMO

The combination of decellularized nerve allograft and adipose-derived stromal cells (ASCs) represents a good alternative to nerve autograft for bridging peripheral nerve defects by providing physical guidance and biologic cues. However, the regeneration outcome of acellular nerve allograft (ANA) is often inferior to autograft. Therefore, we hypothesized that acetyl-l-carnitine (ALCAR) treatment and implantation of ASC-embedded ANA would work synergistically to promote nerve regeneration. Seventy rats were randomly allocated into seven experimental groups (n = 10), including the healthy control group, sham surgery group, autograft group, ANA group, ANA + ASCs group, ANA + ALCAR group (50 mg/kg for 2 weeks), and ANA + ASCs + ALCAR (50 mg/kg for 2 weeks) group. All grafts were implanted to bridge long-gap (10-mm) sciatic nerve defects. Functional, electrophysiological, and morphologic analysis was conducted during the experimental period. We found that ALCAR potentiated the survival and retention of transplanted ASCs and upregulated the expression of neurotrophic factor mRNAs in transplanted grafts. Sixteen weeks following implantation in the rat, the ANA supplemented by ASCs was capable of supporting reinnervation across a 10-mm sciatic nerve gap, with results close to that of the autografts in terms of functional, electrophysiological, and histologic assessments. Results demonstrated that ALCAR treatment improved regenerative effects of ANA combined with ASCs on reconstruction of a 10-mm sciatic nerve defect in rat comparable to those of autograft.


Assuntos
Acetilcarnitina/administração & dosagem , Tecido Adiposo/transplante , Aloenxertos/transplante , Regeneração Nervosa/fisiologia , Neuropatia Ciática/terapia , Células Estromais/transplante , Derme Acelular/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/fisiologia , Aloenxertos/efeitos dos fármacos , Aloenxertos/fisiologia , Animais , Masculino , Regeneração Nervosa/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Wistar , Neuropatia Ciática/tratamento farmacológico , Neuropatia Ciática/patologia , Células Estromais/efeitos dos fármacos , Células Estromais/patologia , Complexo Vitamínico B/administração & dosagem
6.
Neurochem Res ; 43(12): 2404-2422, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30367337

RESUMO

Neuropathic pain is an intractable disease with few definitive therapeutic options. Anethole (AN) has been confirmed to possess potent anti-inflammatory and neuroprotective properties, but its effect on neuropathic pain has not been reported. The present study was designed to investigate the antinociceptive effect of AN on chronic constriction injury (CCI)-induced neuropathic pain in mice. AN (125, 250, and 500 mg/kg) and pregabalin (40 mg/kg) were intragastric administered for 8 consecutive days from the 7th day post-surgery. Behavioral parameters were measured on different days, namely, 0, 7, 8, 10, 12, and 14, from CCI operation. Additionally, electrophysiological and histopathological changes were analyzed on the 14th day. Afterward, immunofluorescence and Western blot were utilized to examine the activation of glial cells and the expression of inflammatory cytokines, respectively. AN treatment of CCI mice considerably alleviated hyperalgesia and allodynia, ameliorated abnormal sciatic nerve conduction, and restored injured sciatic nerves in a dose-dependent manner. Furthermore, AN suppressed the activation of glial cells, down-regulated pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin (IL-6, and IL-1ß), and up-regulated the anti-inflammatory cytokine (IL-10). These assays first indicated that AN exerted an antinociceptive effect on CCI-induced neuropathic pain, and might be attributed to the anti-inflammatory and neuroprotective activities of AN.


Assuntos
Anisóis/uso terapêutico , Neuralgia/patologia , Neuralgia/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Neuropatia Ciática/tratamento farmacológico , Neuropatia Ciática/patologia , Animais , Constrição , Masculino , Camundongos , Camundongos Endogâmicos ICR , Neuralgia/etiologia , Neuropatia Ciática/complicações
7.
Biomed Pharmacother ; 105: 907-914, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30021384

RESUMO

Type 1 diabetes (T1DM) affects approximately 1 in 500 children. Diabetic peripheral neuropathy (DPN) is the most common form of peripheral neuropathy in diabetes and is a significant risk factor for serious pathological change. It is difficult and costly to treat DPN and although there have been several pivotal trials. The development of new drugs to treat DPN remains a high priority. Trehalose is a naturally occurring disaccharide, which is indicated to prevent maternal type 1 diabetes-induced neural tube defects. Thus, the primary aim of this study is to determine whether trehalose ameliorates DPN-induced sciatic nerve injury in TIDM. To establish a T1DM mouse model, wild-type (WT) male C57BL/6 J mice were injected with streptozotocin (STZ). WT mice, T1DM mice, and mice fed with trehalose were assayed for myelin-related gene expression and with behavioral tests. To mimic high glucose in vivo, Schwann cells were cultured under high glucose conditions with or without trehalose. In addition, oxidative damage, apoptosis, and mitochondrial translocation of the pro-apoptotic B-cell lymphoma-2 (Bcl-2) family members were assessed in Schwann cells. Results showed that treatment by trehalose prevented DPN and preserved diabetes-decreased expression of myelin-related genes in T1DM mice. Furthermore, trehalose abolished diabetes-suppressed regeneration of the sciatic nerve. More importantly, trehalose suppressed high glucose-induced oxidative damage and apoptosis in Schwann cells. In summary, trehalose ameliorates DPN-induced sciatic nerve injury in T1DM by preventing apoptosis, which makes it a promising candidate for the treatment of DPN.


Assuntos
Apoptose/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Células de Schwann/efeitos dos fármacos , Neuropatia Ciática/tratamento farmacológico , Trealose/uso terapêutico , Animais , Apoptose/fisiologia , Células Cultivadas , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/patologia , Neuropatias Diabéticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células de Schwann/patologia , Neuropatia Ciática/patologia , Estreptozocina/toxicidade , Trealose/farmacologia
8.
J Neuroinflammation ; 15(1): 187, 2018 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-29929563

RESUMO

BACKGROUND: Management of neuropathic pain is a real clinical challenge. Despite intense investigation, the mechanisms of neuropathic pain remain substantially unidentified. Matrix metalloproteinase (MMP)-9 and MMP-2 have been reported to contribute to the development and maintenance of neuropathic pain. Therefore, inhibition of MMP-9/2 may provide a novel therapeutic approach for the treatment of neuropathic pain. In this study, we aim to investigate the effect of procyanidins (PC), clinically used health product, on MMP-9/2 in neuropathic pain. METHODS: The nociception was assessed by measuring the incidence of foot withdrawal in response to mechanical indentation in mice. Cell signaling was assayed using gelatin zymography, western blotting, and immunohistochemistry. The BV2 cells were cultured to investigate the effects of PC on microglia. RESULTS: Both in vitro and in vivo administration of PC significantly suppresses the activity of MMP-9/2. Oral administration of PC relieves neuropathic pain behaviors induced by chronic constriction sciatic nerve injury (CCI) in mice. Additionally, PC blocks the maturation of interleukin-1ß, which is a critical substrate of MMPs, and markedly suppresses CCI-induced MAPK phosphorylation and neuronal and microglia activation, including the reduced phosphorylation of protein kinase C γ and NMDAR1. Furthermore, PC decreases the phosphorylation of p38 mitogen-activated protein kinase and inhibits the translocation of nuclear factor-κB (NF-κB) in microglia. CONCLUSIONS: PC is an effective and safe approach to alleviate neuropathic pain via a powerful inhibition on the activation of MMP-9/2.


Assuntos
Anti-Inflamatórios/uso terapêutico , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Proantocianidinas/uso terapêutico , Neuropatia Ciática/tratamento farmacológico , Análise de Variância , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Linhagem Celular Transformada , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Proteínas dos Microfilamentos/metabolismo , Microglia/efeitos dos fármacos , NF-kappa B/metabolismo , Medição da Dor , Transdução de Sinais/efeitos dos fármacos
9.
Biomed Pharmacother ; 103: 1146-1153, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29715758

RESUMO

OBJECTIVE: It has been reported that sciatic nerve injury (SNI) leads to degeneration, damage, and apoptosis of motor neurons. Nerve growth factor (NGF) plays a pivotal role in regeneration and reestablishment of neuronal function via activating PI3K/Akt survival signaling pathways. Curcumin owns neuroprotective effect following brain injury. In the present study, we attempt to investigate underlying mechanism of neuroprotective effect of curcumin through elucidating its correlation with NGF and PI3K/Akt signaling pathways in vitro and in vivo. METHODS: PC-12 cells were exposed H2O2 in order to induce neuron cell injury and cells were then treated with curcumin. Caspase-3, NGF level and Akt phosphorylation were determined using flow cytometry and western blotting. Then, cells were treated with NGF specific siRNA followed by measurement of apoptosis, NGF and Akt phosphorylation levels. In animal model, rats were subjected to SNI and then randomly designated into four different groups: curcumin, curcumin + LY294002, curcumin + NGF shRNA, and negative controls and 12 rats in each group (n = 12). After four weeks of continuous treatment, tissue samples were obtained and subjected to TUNEL, NeuN double staining and western blotting. RESULTS: Curcumin significantly reduced the number of apoptotic cells induced by H2O2 and this effect was associated with upregulation of TrkA, Akt and downregulation of p17. ProNGF level was significantly decreased while mature NGF level was increased with curcumin treatment. When NGF was suppressed, anti-apoptotic effect of curcumin was attenuated. In addition, inhibition of PI3K/Akt results in increased apoptotic rate compared to vehicles following curcumin treatment which was reflected by decreased p17, Ki67, and cyclin D1. Suppression of NGF and inhibition of PI3K led to increased neuron cell death through increasing proNGF and decreasing mNGF, Akt, TrkA, p75NTR, and p17. CONCLUSION: Our findings revealed that curcumin exerts its protective effect against injured neurons through stimulating NGF release which further activates TrkA and PI3K/Akt cell survival signaling.


Assuntos
Curcumina/farmacologia , Neurônios Motores/efeitos dos fármacos , Fator de Crescimento Neural/metabolismo , Fármacos Neuroprotetores/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neuropatia Ciática/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Curcumina/uso terapêutico , Modelos Animais de Doenças , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Fator de Crescimento Neural/genética , Neuroproteção/efeitos dos fármacos , Neuroproteção/genética , Fármacos Neuroprotetores/uso terapêutico , Células PC12 , Ratos , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/lesões , Nervo Isquiático/metabolismo , Neuropatia Ciática/metabolismo , Neuropatia Ciática/patologia , Transdução de Sinais
10.
Anat Rec (Hoboken) ; 301(10): 1638-1645, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29710422

RESUMO

Minocycline has been reported to be both beneficial and detrimental for nerve regeneration after peripheral nerve injury. By reducing the inflammatory response, minocycline administration reduces pain and has neuroprotective effects, but it also inhibits Wallerian degeneration in the distal stump, and reduces microglia and macrophages activity on motor and sensory neurons, which could reduce their intrinsic regenerative capacity. The aim of this study was to determine if the administration of minocycline after nerve injury inhibits the regenerative capacity of motoneurons and sensory neurons after a conditioning lesion. We used two groups of mice: a control group and a group treated with minocycline (30 mg kg-1 ip twice daily). We labeled motor and sensory neurons that had regenerated to a distance of 3 mm in a predegenerated graft, after a conditioning lesion. Our results indicate that minocycline administration is not detrimental for nerve regeneration. Indeed, it even promoted a slight, no significant increase 7 days after the nerve graft. These results indicate that minocycline, given at a dose able to reduce pain after peripheral nerve injury, does not interfere with the intrinsic growth capacity of injured peripheral neurons. Anat Rec, 301:1638-1645, 2018. © 2018 Wiley Periodicals, Inc.


Assuntos
Minociclina/uso terapêutico , Neurônios Motores/efeitos dos fármacos , Regeneração Nervosa/efeitos dos fármacos , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Células Receptoras Sensoriais/efeitos dos fármacos , Animais , Avaliação Pré-Clínica de Medicamentos , Feminino , Camundongos , Microglia/efeitos dos fármacos , Minociclina/farmacologia , Neuropatia Ciática/tratamento farmacológico
11.
Int J Mol Sci ; 19(5)2018 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-29735961

RESUMO

Ultra-fine bubbles (<200 nm in diameter) have several unique properties and have been tested in various medical fields. The purpose of this study was to investigate the effects of oxygen ultra-fine bubbles (OUBs) on a sciatic nerve crush injury (SNC) model rats. Rats were intraperitoneally injected with 1.5 mL saline, OUBs diluted in saline, or nitrogen ultra-fine bubbles (NUBs) diluted in saline three times per week for 4 weeks in four groups: (1) control, (sham operation + saline); (2) SNC, (crush + saline); (3) SNC+OUB, (crush + OUB-saline); (4) SNC+NUB, (crush + NUB-saline). The effects of the OUBs on dorsal root ganglion (DRG) neurons and Schwann cells (SCs) were examined by serial dilution of OUB medium in vitro. Sciatic functional index, paw withdrawal thresholds, nerve conduction velocity, and myelinated axons were significantly decreased in the SNC group compared to the control group; these parameters were significantly improved in the SNC+OUB group, although NUB treatment did not affect these parameters. In vitro, OUBs significantly promoted neurite outgrowth in DRG neurons by activating AKT signaling and SC proliferation by activating ERK1/2 and JNK/c-JUN signaling. OUBs may improve nerve dysfunction in SNC rats by promoting neurite outgrowth in DRG neurons and SC proliferation.


Assuntos
Microbolhas/uso terapêutico , Oxigênio/uso terapêutico , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/lesões , Neuropatia Ciática/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/fisiopatologia , Masculino , Compressão Nervosa , Regeneração Nervosa/efeitos dos fármacos , Oxigênio/administração & dosagem , Ratos Wistar , Células de Schwann/efeitos dos fármacos , Células de Schwann/patologia , Nervo Isquiático/fisiopatologia , Neuropatia Ciática/fisiopatologia
12.
Lasers Med Sci ; 33(6): 1341-1349, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29611064

RESUMO

To analyze the effect of photobiomodulation and dexamethasone on nerve regeneration after a sciatic nerve crushing model. Twenty-six Swiss mice were divided into the following groups: naive; sham; injured, low-level laser therapy (LLLT) (660 nm, 10 J/cm2, 0.6 J, 16.8 J total energy emitted during the 28 days of radiation, 20 s, for 28 days); dexamethasone (Dex) (local injection of 2 mg/kg for 10 consecutive days); and LLLT group associated with Dex (LLLT/Dex), with the same parameters of the other groups. For nerve injury, a portable adjustable pinch was used. The animals were evaluated using the Sciatic Functional Index (SFI) and Sciatic Static Index (SSI). The results obtained were evaluated with Image J™ and Kinovea™. Data and images were obtained at baseline and after 7, 14, 21, and 28 days after surgery. The evaluation of hyperalgesia, using Hargreaves, and behavior through the open field was also performed. In functional and static analysis, all groups presented significant differences when compared to the injured group. In the analysis of the SSI results, the group treated with both LLLT and dexamethasone was more effective in improving the values of this parameter, and in the SFI, the laser-treated group obtained better results. In the evaluation through the open field and the Hargreaves, there was no difference. The application of LLLT and dexamethasone was effective in nerve regeneration according to the results and was more effective when LLLT was associated with dexamethasone than in LLLT alone for the SSI.


Assuntos
Dexametasona/uso terapêutico , Terapia com Luz de Baixa Intensidade/métodos , Nervo Isquiático/lesões , Neuropatia Ciática/tratamento farmacológico , Neuropatia Ciática/radioterapia , Animais , Dexametasona/farmacologia , Modelos Animais de Doenças , Masculino , Camundongos , Regeneração Nervosa/fisiologia , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia , Nervo Isquiático/efeitos da radiação , Neuropatia Ciática/fisiopatologia
13.
J Neurosci Res ; 96(7): 1223-1242, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29659058

RESUMO

Complete severance of major peripheral mixed sensory-motor nerve proximally in a mammalian limb produces immediate loss of action potential conduction and voluntary behaviors mediated by the severed distal axonal segments. These severed distal segments undergo Wallerian degeneration within days. Denervated muscles atrophy within weeks. Slowly regenerating (∼1 mm/day) outgrowths from surviving proximal stumps that often nonspecifically reinnervate denervated targets produce poor, if any, restoration of lost voluntary behaviors. In contrast, in this study using completely transected female rat sciatic axons as a model system, we provide extensive morphometric, immunohistochemical, electrophysiological, and behavioral data to show that these adverse outcomes are avoided by microsuturing closely apposed axonal cut ends (neurorrhaphy) and applying a sequence of well-specified solutions, one of which contains polyethylene glycol (PEG). This "PEG-fusion" procedure within minutes reestablishes axoplasmic and axolemmal continuity and signaling by nonspecifically fusing (connecting) closely apposed open ends of severed motor and/or sensory axons at the lesion site. These PEG-fused axons continue to conduct action potentials and generate muscle action potentials and muscle twitches for months and do not undergo Wallerian degeneration. Continuously innervated muscle fibers undergo much less atrophy compared with denervated muscle fibers. Dramatic behavioral recovery to near-unoperated levels occurs within days to weeks, almost certainly by activating many central nervous system and peripheral nervous system synaptic and other plasticities, some perhaps to a greater extent than most neuroscientists would expect. Negative control transections in which neurorrhaphy and all solutions except the PEG-containing solution are applied produce none of these remarkably fortuitous outcomes observed for PEG-fusion.


Assuntos
Axônios/efeitos dos fármacos , Axônios/fisiologia , Regeneração Nervosa/efeitos dos fármacos , Junção Neuromuscular/efeitos dos fármacos , Junção Neuromuscular/fisiologia , Polietilenoglicóis/farmacologia , Nervo Isquiático/efeitos dos fármacos , Animais , Axotomia , Modelos Animais de Doenças , Feminino , Regeneração Nervosa/fisiologia , Condução Nervosa/efeitos dos fármacos , Ratos , Recuperação de Função Fisiológica , Nervo Isquiático/fisiologia , Nervo Isquiático/cirurgia , Neuropatia Ciática/induzido quimicamente , Neuropatia Ciática/tratamento farmacológico , Neuropatia Ciática/patologia , Degeneração Walleriana/tratamento farmacológico , Degeneração Walleriana/patologia
14.
Braz J Med Biol Res ; 51(4): e7097, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29513797

RESUMO

Vitamin E (vit. E) and vitamin C (vit. C) are antioxidants that inhibit nociception. The effect of these vitamins on oxidative-stress markers in the spinal cord of rats with chronic constriction injury (CCI) of the sciatic nerve is unknown. This study investigated the effect of intraperitoneal administration of vit. E (15 mg·kg-1·day-1) and vit. C (30 mg·kg-1·day-1), given alone or in combination, on spinal cord oxidative-stress markers in CCI rats. Adult male Wistar rats weighing 200-250 g were divided equally into the following groups: Naive (rats did not undergo surgical manipulation); Sham (rats in which all surgical procedures involved in CCI were used except the ligature), and CCI (rats in which four ligatures were tied loosely around the right common sciatic nerve), which received injections of vitamins or vehicle (saline containing 1% Tween 80) for 3 or 10 days (n=6/each group). The vitamins prevented the reduction in total thiol content and the increase in superoxide-anion generation that were found in vehicle-treated CCI rats. While nitric-oxide metabolites increased in vehicle-treated CCI rats 3 days after surgery, these metabolites did not show significant changes in vitamin-treated CCI rats. In all rats, total antioxidant capacity and hydrogen-peroxide levels did not change significantly. Lipid hydroperoxides increased 25% only in vehicle-treated CCI rats. These changes may contribute to vit. C- and vit. E-induced antinociception, because scavenging reactive oxygen species seems to help normalize the spinal cord oxidative status altered by pain.


Assuntos
Antioxidantes/uso terapêutico , Ácido Ascórbico/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Neuropatia Ciática/tratamento farmacológico , Medula Espinal/efeitos dos fármacos , alfa-Tocoferol/uso terapêutico , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Masculino , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Wistar , Neuropatia Ciática/metabolismo , Medula Espinal/metabolismo
15.
Prog Neuropsychopharmacol Biol Psychiatry ; 84(Pt A): 257-266, 2018 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-29524514

RESUMO

The persistent activation of N-methyl-d-aspartate acid receptors (NMDARs) seems to be responsible for a series of changes in neurons associated with neuropathic pain, including the failure of opioids that act through mu-opioid receptors (MORs) to provide efficacious pain relief. As the noradrenergic locus coeruleus (LC) forms part of the endogenous analgesic system, we explored how intra-LC administration of morphine, a MORs agonist, alone or in combination with MK-801, a NMDARs antagonist, affects the sensorial and affective dimension of pain in a rat model of neuropathic pain; chronic constriction injury (CCI). Intra-LC microinjection of morphine induced analgesia in CCI rats, as evident in the von Frey and cold plate test 7 and 30 days after surgery, although it was not able to reverse pain-related aversion when evaluated using the place escape/avoidance test. However, the thermal anti-nociception produced by morphine was enhanced when it was administered to the LC of CCI animals in combination with MK-801, without altering its effects on the mechanical thresholds. Furthermore, pain-related aversion was reduced by co-administration of these agents, yet only in the short-term CCI (7 day) rats. Overall the data indicate that administration of morphine to the LC produces analgesia in nerve injured animals and that this effect is potentiated in specific pain modalities by the co-administration of MK-801. While a combination of morphine and MK-801 could reduce pain-related aversion in short-term neuropathic animals, it was ineffective in the long-term, suggesting that its sensorial effects and its influence on the affective component of pain are regulated by different mechanisms.


Assuntos
Analgésicos Opioides/farmacologia , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Locus Cerúleo/efeitos dos fármacos , Morfina/farmacologia , Neuralgia/tratamento farmacológico , Animais , Ansiedade/tratamento farmacológico , Ansiedade/fisiopatologia , Constrição Patológica , Modelos Animais de Doenças , Quimioterapia Combinada , Locus Cerúleo/fisiopatologia , Masculino , Neuralgia/fisiopatologia , Neuralgia/psicologia , Dor Nociceptiva/tratamento farmacológico , Dor Nociceptiva/fisiopatologia , Dor Nociceptiva/psicologia , Ratos Sprague-Dawley , Neuropatia Ciática/tratamento farmacológico , Neuropatia Ciática/fisiopatologia , Neuropatia Ciática/psicologia
16.
Pain ; 159(6): 1155-1165, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29528965

RESUMO

A great need exists for the identification of new effective analgesics to treat sustained pain. However, most preclinical nociceptive assays measure behavioral responses evoked by noxious stimuli (ie, pain-stimulated behavior), which presents a challenge to distinguish between motor impairing and antinociceptive effects of drugs. Here, we demonstrate that chronic constriction injury (CCI) of the sciatic nerve elicits common pain-stimulated responses (ie, mechanical allodynia and thermal hyperalgesia) as well as reduces marble burying/digging behaviors that occur during the early stages of the neuropathy and resolve within 1 week. Although drugs representing distinct classes of analgesics (ie, morphine, valdecoxib, and gabapentin) reversed both CCI-induced and CCI-depressed nociceptive measures, diazepam lacked antinociceptive effects in all assays and the kappa-opioid receptor agonist U69593 reversed pain-stimulated, but not pain-depressed behaviors. In addition, we tested drugs targeting distinct components of the endocannabinoid system, including agonists at cannabinoid receptors type 1 (CB1) and type 2 (CB2), as well as inhibitors of the endocannabinoid-regulating enzymes fatty acid amide hydrolase and monoacylglycerol lipase. Each of these drugs reversed all CCI-induced nociceptive measures, with the exception of the fatty acid amide hydrolase inhibitor that reversed pain-stimulated behaviors, only. These findings support the use of the mouse marble-burying assay as a model of pain-depressed behavior within the first week of sciatic nerve injury to examine candidate analgesics. These data also support existing preclinical research that cannabinoid receptor agonists and inhibitors of endocannabinoid-regulating enzymes merit consideration for the treatment of pain.


Assuntos
Analgésicos/classificação , Analgésicos/uso terapêutico , Depressão/etiologia , Neuropatia Ciática/complicações , Neuropatia Ciática/tratamento farmacológico , Animais , Antidepressivos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Diazepam/uso terapêutico , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Medição da Dor , Estimulação Física/efeitos adversos
17.
Mol Pain ; 14: 1744806918767549, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29592782

RESUMO

Resveratrol has been showed to relieve neuropathic pain through its anti-inflammatory effects on the peripheral nerve system. However, it is not clear whether resveratrol, especially when administered systemically, is effective in alleviating the peripheral neuropathy-induced imbalance between pro- and anti-inflammatory responses in the central nervous system. To test this, we used a rat neuropathic pain model resulting from chronic constriction injury of the sciatic nerve. Resveratrol (200 mg/kg) or vehicle (dimethylsulfoxide) were administered intraperitoneally once daily for 14 consecutive days after chronic constriction injury. We found that resveratrol attenuated mechanical allodynia and thermal hyperalgesia in rats with chronic constriction injury. After 14 days of resveratrol treatment, expression of several anti-inflammatory cytokine receptors, including IL-1RA and IL-1R2, was increased in the dorsal spinal cord of rats with chronic constriction injury, and IL-4Rα was increased in dorsal spinal cord neurons. Knockdown of IL-4Rα in a neuronal cell line reversed the resveratrol-induced upregulation of IL-1RA and IL-1R2. These results indicate that resveratrol enhances IL-4 receptor-mediated anti-inflammatory responses in the spinal cord and thus might contribute to the alleviation of central sensitization following peripheral nerve injury.


Assuntos
Anti-Inflamatórios/uso terapêutico , Neuralgia/tratamento farmacológico , Neuralgia/etiologia , Receptores de Interleucina-4/metabolismo , Neuropatia Ciática/complicações , Neuropatia Ciática/tratamento farmacológico , Medula Espinal/patologia , Estilbenos/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Constrição , Técnicas de Silenciamento de Genes , Masculino , Modelos Biológicos , Neuralgia/patologia , Células PC12 , Ratos , Ratos Sprague-Dawley , Resveratrol , Neuropatia Ciática/patologia , Transdução de Sinais/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Estilbenos/farmacologia , Transcrição Genética/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
18.
J Neuroinflammation ; 15(1): 96, 2018 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-29587798

RESUMO

BACKGROUND: Neuro-immune interaction underlies chronic neuroinflammation and aberrant sensory processing resulting in neuropathic pain. Despite the pathological significance of both neuroinflammation-driven peripheral sensitization and spinal sensitization, the functional relationship between these two distinct events has not been understood. METHODS: In this study, we determined whether inhibition of inflammatory macrophages by administration of α4ß2 nicotinic acetylcholine receptor (nAChR) agonists improves neuropathic pain and affects microglial activation in the spinal dorsal horn (SDH) in mice following partial sciatic nerve ligation (PSL). Expression levels of neuroinflammatory molecules were evaluated by RT-qPCR and immunohistochemistry, and PSL-induced mechanical allodynia was defined by the von Frey test. RESULTS: Flow cytometry revealed that CD11b+ F4/80+ macrophages were accumulated in the injured sciatic nerve (SCN) after PSL. TC-2559, a full agonist for α4ß2 nAChR, suppressed the upregulation of interleukin-1ß (IL-1ß) in the injured SCN after PSL and attenuated lipopolysaccharide-induced upregulation of IL-1ß in cultured macrophages. Systemic (subcutaneous, s.c.) administration of TC-2559 during either the early (days 0-3) or middle/late (days 7-10) phase of PSL improved mechanical allodynia. Moreover, local (perineural, p.n.) administration of TC-2559 and sazetidine A, a partial agonist for α4ß2 nAChR, during either the early or middle phase of PSL improved mechanical allodynia. However, p.n. administration of sazetidine A during the late (days 21-24) phase did not show the attenuating effect, whereas p.n. administration of TC-2559 during this phase relieved mechanical allodynia. Most importantly, p.n. administration of TC-2559 significantly suppressed morphological activation of Iba1+ microglia and decreased the upregulation of inflammatory microglia-dominant molecules, such as CD68, interferon regulatory factor 5, and IL-1ß in the SDH after PSL. CONCLUSION: These findings support the notion that pharmacological inhibition of inflammatory macrophages using an α4ß2 nAChR agonist exhibit a wide therapeutic window on neuropathic pain after nerve injury, and it could be nominated as a novel pharmacotherapy to relieve intractable pain.


Assuntos
Macrófagos/efeitos dos fármacos , Microglia/efeitos dos fármacos , Agonistas Nicotínicos/uso terapêutico , Neuropatia Ciática/tratamento farmacológico , Neuropatia Ciática/patologia , Medula Espinal/patologia , Animais , Citocinas/genética , Citocinas/metabolismo , Di-Hidro-beta-Eritroidina/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Lateralidade Funcional/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperalgesia/tratamento farmacológico , Ativação de Macrófagos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Agonistas Nicotínicos/farmacologia , Limiar da Dor/efeitos dos fármacos , Piridinas/farmacologia , Piridinas/uso terapêutico , RNA Mensageiro/metabolismo , Fatores de Tempo
19.
Pharm Biol ; 56(1): 124-131, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29385888

RESUMO

CONTEXT: Andrographolide (Andro), found in large quantities in Andrographis paniculata Nees (Acanthaceae), is anti-inflammatory, especially in the central nervous system (CNS) glia. OBJECTIVE: The objective of this study is to test Andro's ability to reduce allodynia in a spared nerve injury model. MATERIAL AND METHODS: Male 30 g BalbC mice were divided into four groups: (1) Sham-operated control (Sham-group); (2) nerve injured and treated with saline (Saline-group); (3) nerve injured and treated with Andro (Andro-group); (4) nerve injured and treated with non-steroidal anti-inflammatory drugs (NSAIDS) (NSAIDS-group). Andro or NSAIDS (diclofenac salt) were injected intraperitoneally at 5 mg/kg body weight daily. Mechanical allodynia was assessed by von Frey tests at 3, 7, and 14 d. For immunohistochemical analysis, samples were collected at 7 d. RESULTS: The threshold for inducing allodynia increased and the response percentage reduced in the Andro-group when compared with the Saline-group, as well as when compared with NSAIDS groups throughout 3-14 d. The ratio of threshold for OP-Andro/OP-saline and for OP-Andro/OP-NSAIDS groups was 20.42 and 11.67 at 14 d, respectively. The ratio of response percentage for OP-Andro/OP-saline and for OP-Andro/OP-NSAIDS was 0.32 and 0.39 at 14 d, respectively. Interleukin-1 (IL-1) immunostaining in the spinal cord was reduced in the Andro-group. Astrocytic activities were not significantly reduced in the Andro-group compared with the Saline-group at 7 d post-operation (PO) Conclusions: Andro reduced mechanical allodynia more than NSAIDS at the same concentration, and the observed behaviour was associated with a reduction in inflammatory cytokine produced in the spinal cord.


Assuntos
Anti-Inflamatórios/uso terapêutico , Modelos Animais de Doenças , Diterpenos/uso terapêutico , Hiperalgesia/tratamento farmacológico , Dor/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Hiperalgesia/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Dor/patologia , Neuropatia Ciática/tratamento farmacológico , Neuropatia Ciática/patologia
20.
Anesth Analg ; 127(3): 775-783, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29324503

RESUMO

BACKGROUND: Neuropathic pain is an intractable and complex disease. Recent studies have shown a close relationship between endoplasmic reticulum (ER) stress and neuropathic pain. Here, we investigated the effect of α-asarone, an ER stress inhibitor, on chronic constriction injury (CCI)-induced neuropathic pain. METHODS: Two parts were included in this study. In part 1, rats were assigned to 7 groups: the sham group, the sham + α-asarone 20 mg/kg group, the CCI group, the CCI + vehicle group, the CCI + α-asarone 5 mg/kg group, the CCI + α-asarone 10 mg/kg group, and the CCI + α-asarone 20 mg/kg group. After surgery, the rats were treated with α-asarone or normal saline daily. Pain thresholds were measured, and samples of the L3-6 spinal cord were taken for western blotting and immunofluorescence on day 7. In part 2, rats were intrathecally implanted with PE-10 tubes and divided into 4 groups: the CCI + α-asarone 20 mg/kg group, the CCI + α-asarone 20 mg/kg + vehicle group, the CCI + α-asarone 20 mg/kg + SR9243 group, and the CCI group. Five rats in each group were separated for behavioral tests 1 hour after intrathecal injection. The rest of them were killed for western blotting on day 7. RESULTS: In this study, CCI surgery significantly induced mechanical allodynia and thermal hyperalgesia. CCI surgery significantly induced activation of ER stress (PERK-eIF2α, IRE1α, CHOP, and XBP-1s) in rats. However, treatment with 20 mg/kg of α-asarone significantly alleviated CCI-induced activation of ER stress. Behavioral results showed that daily treatment with 20 mg/kg of α-asarone significantly alleviated CCI-induced nociceptive behaviors, on day 7 (mechanical allodynia, P = .016, 95% confidence interval, 0.645-5.811; thermal hyperalgesia, P = .012, 95% confidence interval, 0.860-6.507). Furthermore, α-asarone induced upregulated expression of liver X receptor ß (LXRß) and downstream proteins in the spinal cord. The LXR antagonist SR9243 completely inhibited the anti-ER stress and antinociceptive effects of α-asarone in rats. CONCLUSIONS: α-Asarone relieved CCI-induced neuropathic pain in an LXR-dependent manner. α-Asarone may be a potential agent for treatment of neuropathic pain.


Assuntos
Anisóis/administração & dosagem , Estresse do Retículo Endoplasmático/fisiologia , Receptores X do Fígado/fisiologia , Neuralgia/tratamento farmacológico , Neuropatia Ciática/tratamento farmacológico , Animais , Constrição , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fibrinolíticos/administração & dosagem , Injeções Espinhais , Receptores X do Fígado/agonistas , Receptores X do Fígado/antagonistas & inibidores , Masculino , Neuralgia/patologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Neuropatia Ciática/patologia , Sulfonamidas/administração & dosagem
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