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1.
Life Sci ; 241: 117102, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31790691

RESUMO

Peripheral nerve injuries are common conditions that often lead to dysfunctions. Although much knowledge exists on the several factors that mediate the complex biological process involved in peripheral nerve regeneration, there is a lack of effective treatments that ensure full functional recovery. Naringenin (NA) is the most abundant flavanone found in citrus fruits and it has promising neuroprotective, anti-inflammatory and antioxidant effects. This study aimed to enhance peripheral nerve regeneration using an inclusion complex containing NA and hydroxypropyl-ß-cyclodextrin (HPßCD), named NA/HPßCD. A mouse sciatic nerve crush model was used to evaluate the effects of NA/HPßCD on nerve regeneration. Sensory and motor parameters, hyperalgesic behavior and the sciatic functional index (SFI), respectively, improved with NA treatment. Western blot analysis revealed that the levels of p75NTR ICD and p75NTR full length as well phospho-JNK/total JNK ratios were preserved by NA treatment. In addition, NA treatment was able to decrease levels of caspase 3. The concentrations of TNF-α and IL-1ß were decreased in the lumbar spine, on the other hand there was an increase in IL-10. NA/HPßCD presented a better overall morphological profile but it was not able to increase the number of myelinated fibers. Thus, NA was able to enhance nerve regeneration, and NA/HPßCD decreased effective drug doses while maintaining the effect of the pure drug, demonstrating the advantage of using the complex over the pure compound.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/farmacologia , Flavanonas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Regeneração Nervosa/efeitos dos fármacos , Nervo Isquiático/fisiologia , Animais , Hiperalgesia/tratamento farmacológico , Interleucina-10/metabolismo , Masculino , Camundongos , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/metabolismo , Regeneração Nervosa/fisiologia , Medição da Dor , Receptores de Fator de Crescimento Neural/antagonistas & inibidores , Receptores de Fator de Crescimento Neural/metabolismo , Recuperação de Função Fisiológica , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/lesões , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
2.
Toxicol Lett ; 320: 95-102, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760062

RESUMO

Exposure to organic solvent in industry, including n-hexane is correlated with central-peripheral axonopathy, which is mediated by its active metabolite, 2,5-hexanedione (HD). However, the underlying mechanism is still largely unknown. Recently identified microRNAs (miRNAs) may play important roles in toxicant exposure and in the process of toxicant-induced neuropathys. To examine the role of miRNAs in HD-induced toxicity, neuropathic animal model was successfully built. miRNA microarray analysis revealed 105 differentially expressed miRNAs after HD exposure. Bioinformatics analysis showed that "Axon" and "Neurotrophin Signaling Pathway" was the top significant GO term and pathway, respectively. 7 miRNAs both related to "Axon" and "Neurotrophin Signaling Pathway" were screened out and further confirmed by Real-Time PCR. Correspondingly, the deregulation expression levels of proteins of four target genes (GSK3ß, Map3k1, BDNF and MAP1B) were further confirmed via western blot, verifying the results of gene target analysis. Taken together, our results showed that the axon-related miRNAs to be associated with MAP1B or neurotrophin signal pathways changed in nerve tissues following HD exposure. These miRNAs may play important roles in HD-induced neurotoxicity.


Assuntos
Axônios/efeitos dos fármacos , Hexanonas/toxicidade , MicroRNAs/metabolismo , Síndromes Neurotóxicas/etiologia , Nervo Isquiático/efeitos dos fármacos , Solventes/toxicidade , Medula Espinal/efeitos dos fármacos , Animais , Axônios/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Bases de Dados Genéticas , Regulação da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , MAP Quinase Quinase Quinase 1/genética , MAP Quinase Quinase Quinase 1/metabolismo , Masculino , MicroRNAs/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , Ratos Sprague-Dawley , Nervo Isquiático/metabolismo , Transdução de Sinais , Medula Espinal/metabolismo , Transcriptoma
3.
Braz J Med Biol Res ; 53(1): e8669, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31859913

RESUMO

This study aimed to investigate the therapeutic effect of fasudil on treating experimental autoimmune neuritis (EAN). Twenty-four EAN mice were randomly assigned to fasudil treatment (Fasudil group) or saline treatment (EAN model group) for 28 days. Clinical symptom score was evaluated every other day; inflammatory cell infiltration, demyelination, anti-myelin basic protein (MBP), inflammatory cytokines, inducible nitric oxide synthase (iNOS), and arginase-1 were detected in sciatic nerves at day 28. Th1, Th2, Th17, and Tregs proportions in splenocytes were detected at day 28. Clinical symptom score was found to be attenuated in the Fasudil group compared to the EAN model group from day 12 to day 28. Sciatic nerve inflammatory cell counts by HE staining and demyelination by luxol fast blue staining were both reduced, while MBP was increased in the Fasudil group compared to the EAN model group at day 28. Interferon γ (IFN-γ) and interleukin (IL)-17 were reduced, while IL-4 and IL-10 were elevated in the Fasudil group at day 28. Sciatic nerve M1 macrophages marker iNOS was decreased while M2 macrophages marker arginase-1 was increased in the Fasudil group at day 28. CD4+IFN-γ+ (Th1) and CD4+IL-17+ (Th17) cell proportions were both decreased, CD4+IL-4+ (Th2) cell proportion was similar, while CD25+FOXP3+ (Treg) cell proportion in splenocytes was increased in the Fasudil group. In summary, fasudil presented a good therapeutic effect for treating EAN by attenuating Th1/Th17 cells and promoting Tregs activation as well as M2 macrophages polarization.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Interferon gama/sangue , Interleucinas/sangue , Neurite Autoimune Experimental/tratamento farmacológico , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/administração & dosagem , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Neurite Autoimune Experimental/sangue , RNA Mitocondrial , Reação em Cadeia da Polimerase em Tempo Real , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/metabolismo , Fatores de Tempo
4.
Int. j. morphol ; 37(4): 1527-1533, Dec. 2019. tab, graf
Artigo em Espanhol | LILACS | ID: biblio-1040165

RESUMO

En órganos dañados, el ácido láctico (AL) modifica la respuesta inmune innata e inflamatoria, induciendo una menor expresión de citoquinas pro-inflamatorias, que provocan, la modulación del reclutamiento de células inmunes. El daño por compresión del nervio isquiático (NI) desencadena una respuesta inflamatoria y un aumento exponencial del infiltrado inflamatorio de células inmunes, produciendo la destrucción de axones y pérdida funcional del nervio. El objetivo de este estudio es evaluar el efecto agudo de la inyección de AL, sobre la proporción de células inmunes en la fase inflamatoria temprana, en el sitio de lesión del NI post compresión. Para ello, se utilizaron 15 ratas machos Sprague Dawley adultas, en tres grupos de compresión nerviosa. Un grupo control, un grupo control negativo con placebo (100 µL PBS) y un grupo experimental con inyección de 100 µL de AL [20mM]. Al tercer día los NI se analizaron histológicamente y se estableció la proporción de células inmunes en el sitio de lesión. Los resultados muestran que la inyección intraneural de AL provoca una disminución en el porcentaje de linfocitos y un aumento en el porcentaje de macrófagos. Este es el primer trabajo de inyección intraneural de AL y demuestra el efecto modulador del AL sobre las células inmunes en el sistema nervioso periférico.


In damaged organs, lactic acid (LA) modifies the innate and inflammatory immune response, inducing a lower expression of pro-inflammatory cytokines, which provoke the modulation of immune cell recruitment. Damage by compression of the sciatic nerve (SN) triggers an inflammatory response and an exponential increase in the inflammatory infiltrate of immune cells, producing the destruction of axons and functional loss of the nerve. The objective of this study is to evaluate the acute effect of the injection of LA, on the proportion of immune cells in the early inflammatory phase, in the site of SN post-compression injury. For this, 15 adult Sprague Dawley rats were used in three groups of nervous compression. A control group, a negative control group with placebo (100 mL PBS) and an experimental group with injection of 100 mL of LA [20mM]. On the third day, the SNs were histologically analyzed and the proportion of immune cells at the injury site was established. The results show that the intraneural injection of LA causes a decrease in the percentage of lymphocytes and an increase in the percentage of macrophages. This is the first work of intraneural injection of LA and demonstrates the modulating effect of LA on immune cells in the peripheral nervous system.


Assuntos
Animais , Masculino , Ratos , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/imunologia , Ácido Láctico/farmacologia , Síndromes de Compressão Nervosa/patologia , Nervo Isquiático/patologia , Linfócitos/efeitos dos fármacos , Citocinas/imunologia , Citocinas/metabolismo , Ratos Sprague-Dawley , Ácido Láctico/administração & dosagem , Inflamação/imunologia , Macrófagos/efeitos dos fármacos
5.
Turk Neurosurg ; 29(6): 901-908, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31573061

RESUMO

AIM: To evaluate the effects of agomelatine on the biochemical and pathological features of cisplatin-induced peripheral neuropathy. MATERIAL AND METHODS: This study included a total of 30 male Wistar albino rats that weighed 285â€"300 grams and were divided into three groups: healthy controls (HC, n=10); cisplatin group (CIS, n=10) and agomelatine plus cisplatin group (AC, n=10). The CIS group received only cisplatin (EbeweLiba, Turkey) at a dose of 2.5 mg/kg, whereas the AC group received both agomelatine (25 mg/kg, Les Laboratoires Servier, France) and cisplatin (2.5 mg/kg). The animals were sacrificed by thiopental anaesthesia (50 mg/ kg, IE Ulagay, Turkey) and sciatic nerves were dissected. The sciatic nerve tissue was analysed for the levels of malondialdehyde (MDA), myeloperoxidase (MPO), total glutathione (tGSH) and superoxide dismutase (SOD) and was examined histopathologically. RESULTS: The mean levels of MDA, MPO, tGSH and SOD were 34.90 ± 13.83, 41.30 ± 18.03, 15.40 ± 6.06 and 48.60 ± 18.19, respectively. MDA and MPO were significantly lower in the AC group than in the CIS group (p < 0.001 for both). However, the antioxidative parameters tGSH and SOD were significantly higher in the AC group than in the CIS group (p < 0.001 for both). Pathological examinations revealed swollen myelinated nerve fibres and evident myelin sheath degeneration in the CIS group; in the AC group, the myelin sheath degeneration was less and the blood vessels were normal. CONCLUSION: Agomelatine decreased the oxidative status in an experimental rat model of cisplatin-induced peripheral neuropathy. Myelin sheath degeneration was less in the AC group than in the CIS group. To our knowledge, this was the first study that showed the positive effects of agomelatine on cisplatin-induced neuropathy in rats.


Assuntos
Acetamidas/uso terapêutico , Antineoplásicos/toxicidade , Antioxidantes/uso terapêutico , Cisplatino/toxicidade , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Acetamidas/farmacologia , Animais , Antioxidantes/farmacologia , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/uso terapêutico , Masculino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Doenças do Sistema Nervoso Periférico/metabolismo , Ratos , Ratos Wistar , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/metabolismo
6.
BMC Musculoskelet Disord ; 20(1): 441, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601208

RESUMO

BACKGROUND: Continuous popliteal sciatic nerve block (CPSNB) has been performed in outpatient foot and ankle surgery as a regional anesthesia method to relieve postoperative pain. Its efficacy as well as safety is yet to be established. There are two purposes of this study: (1) to validate the efficacy of CPSNB with regards to better pain relief and reduced analgesics consumption; (2) to assess the safety of CPSNB. METHODS: We performed a comprehensive literature review on Web of Science, the Cochrane Library, PubMed and Embase and only included randomized controlled trials (RCTs). Five RCTs that compared the efficacy and safety of CPSNB with the single-injection popliteal sciatic nerve block group were included. The primary outcome parameters were visual analog scale (VAS) scores at postoperative 24, 48 and 72 h. The secondary outcome parameters were amount of oral analgesics consumed, overall patient satisfaction and need of admission after surgery. A sensitivity analysis was performed to explore the consistency of the results. RESULTS: In comparison with the single-injection group, CPSNB was associated with a lower VAS score at postoperative 24 and 48 h (p < 0.05). There were no neuropathic symptoms or infection events after the nerve block. However, there were several minor complications associated with the pump and catheter system, with drug leakage being the most common complication (N = 26 of 187, 13.9%). CONCLUSION: CPSNB is an effective method in pain management for outpatient foot and ankle surgery. Both methods appear to be safe as none of the patients experienced neuropathic symptoms or infection. Further studies with larger sample size are needed to compare the risk of major complications between the two methods. LEVEL OF EVIDENCE: I; meta-analysis.


Assuntos
Procedimentos Cirúrgicos Ambulatórios/efeitos adversos , Anestésicos Locais/administração & dosagem , Bloqueio Nervoso/métodos , Procedimentos Ortopédicos/efeitos adversos , Dor Pós-Operatória/prevenção & controle , Nervo Isquiático/efeitos dos fármacos , Anestésicos Locais/efeitos adversos , Tornozelo/cirurgia , Esquema de Medicação , Pé/cirurgia , Humanos , Bloqueio Nervoso/efeitos adversos , Medição da Dor , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/etiologia , Resultado do Tratamento
7.
J Mater Sci Mater Med ; 30(9): 107, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31512084

RESUMO

In the present study, collagen hydrogel containing naringin was fabricated, characterized and used as the scaffold for peripheral nerve damage treatment. The collagen was dissolved in acetic acid, naringin added to the collagen solution, and cross-linked with 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide powder (EDC; 0.10 mM) to form the hydrogel. The microstructure, swelling behavior, biodegradation, and cyto/hemocompatibility of the fabricated hydrogels were assessed. Finally, the healing efficacy of the prepared collagen hydrogel loaded with naringin on the sciatic nerve crush injury was assessed in the animal model. The characterization results showed that the fabricated hydrogels have a porous structure containing interconnected pores with the average pore size of 90 µm. The degradation results demonstrated that about 70% of the primary weight of the naringin loaded hydrogel had been lost after 4 weeks of storage in PBS. The in vitro study showed that the proliferation of Schwann cells on the collagen/naringin hydrogel was higher than the control group (tissue culture plate) at both 48 and 72 h after cell seeding and even significantly higher than pure collagen 72 h after cell seeding (*p < 0.005, **p < 0.001). The animal study implied that the sciatic functional index reached to -22.13 ± 3.00 at the end of 60th days post-implantation which was statistically significant (p < 0.05) compared with the negative control (injury without the treatment) (-82.60 ± 1.06), and the pure collagen hydrogel (-59.80 ± 3.20) groups. The hot plate latency test, the compound muscle action potential, and wet weight-loss of the gastrocnemius muscle evaluation confirmed the positive effect of the prepared hydrogels on the healing process of the induced nerve injury. In the final, the histopathologic examinations depicted that the collagen/naringin hydrogel group reduced all the histological changes induced from the nerve injury and showed more resemblance to the normal sciatic nerve, with well-arranged fibers and intact myelin sheath. The overall results implied that the prepared collagen/naringin hydrogel can be utilized as a sophisticated alternative to healing peripheral nerve damages.


Assuntos
Colágeno Tipo I/química , Flavanonas/farmacologia , Regeneração Tecidual Guiada/métodos , Hidrogéis/farmacologia , Regeneração Nervosa/efeitos dos fármacos , Nervo Isquiático/lesões , Nervo Isquiático/fisiologia , Animais , Células Cultivadas , Colágeno Tipo I/farmacologia , Flavanonas/química , Humanos , Hidrogéis/química , Masculino , Teste de Materiais , Traumatismos dos Nervos Periféricos/patologia , Traumatismos dos Nervos Periféricos/terapia , Ratos , Ratos Wistar , Células de Schwann/citologia , Células de Schwann/efeitos dos fármacos , Células de Schwann/fisiologia , Nervo Isquiático/efeitos dos fármacos , Tecidos Suporte/química , Cicatrização/efeitos dos fármacos
8.
Eur Cytokine Netw ; 30(2): 59-66, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31486397

RESUMO

Recent studies have demonstrated that nicotine exhibited anti-inflammatory and neuroprotective properties by interacting with the alpha 7 nicotinic acetylcholine receptor (α7nAChR). However, the role of nicotine in regeneration during peripheral nerve injury has not been elucidated. The aim of this study was to investigate whether nicotine down-regulated production of proinflammatory cytokines and promoted peripheral nerve regeneration in rats. Rats challenged with sciatic nerve crush injury were treated with nicotine (1.5 mg/kg), three times per day. The expression of the proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin (IL-1ß), pinch test results, growth-associated protein 43 (GAP-43) expression, morphometric analyses, and the sciatic functional indexes were determined in sciatic nerves. Treatment with nicotine decreased local levels of TNF-α and IL-1ß, and increased the expression of GAP-43. Nicotine also improved nerve regeneration and functional recovery. The overall protective effects of nicotine were reversed by concomitant treatment with α7nACHR antagonist methyllycaconitine, indicating that nicotine exerted its specific anti-inflammatory and neuroprotective effects through the α7nAChR. These findings show that nicotine administration can provide a potential therapeutic pathway for the treatment of peripheral nerve injury, by a direct protective effect through the α7nAChR-mediated cholinergic anti-inflammatory pathway.


Assuntos
Lesões por Esmagamento/metabolismo , Lesões por Esmagamento/patologia , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Fármacos Neuroprotetores/farmacologia , Nicotina/farmacologia , Nervo Isquiático/metabolismo , Nervo Isquiático/patologia , Animais , Modelos Animais de Doenças , Proteína GAP-43/metabolismo , Interleucina-1beta/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Regeneração Nervosa/efeitos dos fármacos , Ratos Wistar , Nervo Isquiático/efeitos dos fármacos , Células Receptoras Sensoriais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
9.
Muscle Nerve ; 60(5): 613-620, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31397908

RESUMO

INTRODUCTION: The objective of this study is to assess the efficacy of local tacrolimus (FK506) delivery to improve outcomes in the setting of nerve transection injury. METHODS: FK506 embedded poly(lactide-co-caprolactone) films capable of extended, localized release of FK506 were developed. FK506 rate of release testing and bioactivity assay was performed. Mouse sciatic nerve transection and direct repair model was used to evaluate the effect extended, local delivery of FK506 had on nerve regeneration outcomes. RESULTS: Linear release of FK506 was observed for 30 days and released FK506 matched control levels of neurite extension in the dorsal root ganglion assay. Groups treated with local FK506 had greater gastrocnemius muscle weight, foot electromyogram, and number of axons distal of the repair site than non-FK506 groups. DISCUSSION: Results of this study indicate that extended, localized delivery of FK506 to nerve injuries can improve nerve regeneration outcomes in a mouse sciatic nerve transection and repair.


Assuntos
Imunossupressores/farmacologia , Denervação Muscular , Músculo Esquelético/efeitos dos fármacos , Regeneração Nervosa/efeitos dos fármacos , Nervo Isquiático/lesões , Tacrolimo/farmacologia , Animais , Axônios/efeitos dos fármacos , Axônios/patologia , Preparações de Ação Retardada , Eletromiografia , Gânglios Espinais/efeitos dos fármacos , Imunossupressores/administração & dosagem , Camundongos , Músculo Esquelético/patologia , Neuritos/efeitos dos fármacos , Neuritos/patologia , Procedimentos Neurocirúrgicos , Tamanho do Órgão , Traumatismos dos Nervos Periféricos , Poliésteres , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia , Nervo Isquiático/cirurgia , Tacrolimo/administração & dosagem
10.
J Pharmacol Sci ; 140(3): 291-294, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31377017

RESUMO

Oxaliplatin induces severe peripheral neuropathy. The effect of donepezil, a drug used for treatment of Alzheimer's disease, on oxaliplatin-induced peripheral neuropathy was investigated using both in vivo and in vitro models. Donepezil effectively attenuated oxaliplatin- and cisplatin-induced inhibition of neurite outgrowth in cultured PC12 cells. In a rat model, repeated oral administration of donepezil (5 times/week for 4 weeks) ameliorated oxaliplatin-induced mechanical allodynia (von Frey test) and sciatic nerve axonal degeneration. Moreover, donepezil did not inhibit the anti-tumor activity of oxaliplatin in any cultured cancer cell line. Therefore, donepezil may be useful for managing oxaliplatin-induced peripheral neuropathy.


Assuntos
Donepezila/farmacologia , Fármacos Neuroprotetores/farmacologia , Oxaliplatina/farmacologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Masculino , Camundongos , Células PC12 , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/efeitos dos fármacos
11.
Artif Cells Nanomed Biotechnol ; 47(1): 3423-3430, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31402711

RESUMO

A novel nerve conductor made out of polypyrrole (PPY), collagen (Coll) and nano-strontium substituted bioactive glass (n-Sr@BG) (PPY/Coll/n-Sr@BG) was fabricated by electrospinning. SEM demonstrated that the mean distances across of the pores in the nerve channels were under 15 mm and more prominent than 2 mm. These biocomposite films had biomimetic morphology, bigger porosity and moderately higher surface territory than customary nerve channels, consequently not just allowing the transportation of nerve development factor and glucose yet, in addition, hindering the section of lymphatic tissue and fibroblasts. The consistent filaments of the nerve can copy the characteristic ECM, which is valuable to cell bond, cell multiplication, and cell movement. PPY/Coll/n-Sr@BG demonstrated great cell fondness rate, which is useful for neurilemma cell cells bond, relocation and expansion. Its great viability empowers its wellbeing animal models. Sciatic nerve deformity was crossed over an animal model with PPY/Coll/n-Sr@BG in rodents. PPY/Coll and autotransplants were utilized as control gatherings. Contrasted with PPY/Coll and PPY/Coll/n-Sr@BG accomplished fundamentally increasingly viable recovery of sciatic nerve wounds following 24 weeks implantation and the mean distance across of muscle fibres occasions bigger than that in PPY/Coll/n-Sr@BG, and it was nearer to that in control. The rejuvenated nerve filaments in PPY/Coll/n-Sr@BG had an increasingly standard round shape, the thickness of neuro-filaments in c was more than those in PPY/Coll, and was near that in control.


Assuntos
Materiais Biocompatíveis/farmacologia , Colágeno/química , Vidro/química , Polímeros/química , Pirróis/química , Regeneração/efeitos dos fármacos , Nervo Isquiático/efeitos dos fármacos , Estrôncio/química , Animais , Materiais Biocompatíveis/química , Eletricidade , Humanos , Nanoestruturas/química , Nanotecnologia , Nervo Isquiático/fisiologia
12.
Anesth Analg ; 129(3): 709-717, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31425210

RESUMO

BACKGROUND: Capsaicin, the active component of chili peppers, can produce sensory-selective peripheral nerve blockade. Coadministration of capsaicin and tetrodotoxin, a site-1 sodium channel blocker, can achieve a synergistic effect on duration of nerve blocks. However, capsaicin can be neurotoxic, and tetrodotoxin can cause systemic toxicity. We evaluated whether codelivery of capsaicin and tetrodotoxin liposomes can achieve prolonged local anesthesia without local or systemic toxicity. METHODS: Capsaicin- and tetrodotoxin-loaded liposomes were developed. Male Sprague-Dawley rats were injected at the sciatic nerve with free capsaicin, capsaicin liposomes, free tetrodotoxin, tetrodotoxin liposomes, and blank liposomes, singly or in combination. Sensory and motor nerve blocks were assessed by a modified hotplate test and a weight-bearing test, respectively. Local toxicity was assessed by histologic scoring of tissues at the injection sites and transmission electron microscopic examination of the sciatic nerves. Systemic toxicity was assessed by rates of contralateral nerve deficits and/or mortality. RESULTS: The combination of capsaicin liposomes and tetrodotoxin liposomes achieved a mean duration of sensory block of 18.2 hours (3.8 hours) [mean (SD)], far longer than that from capsaicin liposomes [0.4 hours (0.5 hours)] (P < .001) or tetrodotoxin liposomes [0.4 hours (0.7 hours)] (P < .001) given separately with or without the second drug in free solution. This combination caused minimal myotoxicity and muscle inflammation, and there were no changes in the percentage or diameter of unmyelinated axons. There was no systemic toxicity. CONCLUSIONS: The combination of encapsulated tetrodotoxin and capsaicin achieved marked prolongation of nerve block. This combination did not cause detectable local or systemic toxicity. Capsaicin may be useful for its synergistic effects on other formulations even when used in very small, safe quantities.


Assuntos
Anestesia Local/métodos , Anestésicos Locais/administração & dosagem , Capsaicina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Bloqueio Nervoso/métodos , Tetrodotoxina/administração & dosagem , Anestésicos Locais/metabolismo , Animais , Capsaicina/metabolismo , Esquema de Medicação , Quimioterapia Combinada , Lipossomos , Masculino , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/química , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/metabolismo , Tetrodotoxina/metabolismo
13.
Adv Exp Med Biol ; 1155: 935-947, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468458

RESUMO

Taurine protect against diabetic neuropathy. However, the protective mechanism of taurine has been poorly understood. It has been demonstrated that microRNAs (miRNAs) are involved in regulating gene expression. Therefore, it is interested in whether taurine affects miRNAs expression profile in peripheral nerve tissue of diabetic neuropathy. In the present study, rats were treated as three group: (1) control (Con) group, (2) diabetic mellitus (DM) group and (3) taurine treatment (Tau) group. Sciatic nerve tissue was harvested and miRNA expression was determined using sequencing. The results showed that 80 miRNAs showed significant difference in DM group compared to Con group, of which 20 miRNAs showed up-regulating, as well as, 60 miRNAs showed down-regulating. On the other hand, 215 differential miRNAs were found between DM and Tau groups. Moreover, the numbers of up-regulated and down-regulated miRNAs were 1 and 214, respectively. Twelve specific miRNAs were screened out and the target genes were obtained by target analysis software. GO and KEGG enrichment analyses showed that these potential target genes for the miRNAs might be involved in axon guidance, generation of neurons, nervous system development and neurogenesis. Our results provided a miRNA profile for further exploring protective mechanisms of taurine against diabetic peripheral neuropathy.


Assuntos
Neuropatias Diabéticas/genética , MicroRNAs/genética , Nervo Isquiático/metabolismo , Taurina/farmacologia , Animais , Diabetes Mellitus Experimental , Ratos , Nervo Isquiático/efeitos dos fármacos
14.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 35(3): 232-238, 2019 May 28.
Artigo em Chinês | MEDLINE | ID: mdl-31257805

RESUMO

OBJECTIVE: To quantitatively investigate the effects of Ringer's solution with different concentrations of alcohol (1%~80%) on biphasic compound action potentials (AP) from frog sciatic nerve trunk, and their recoveries from alcohol effects. METHODS: Individual segments of frog sciatic nerve trunk with a length of 6 to 8 cm were prepared. Ringer's solution with different concentrations of alcohol (0%, 1%, 2%, 4%, 8%, 16%, 32%, 48%, 64% and 80%) was applied onto the segment of the trunk between the stimulus and ground electrodes via an agent reservoir which was newly armed in a nerve trunk shielded chamber for 5 minutes. The nerve trunk was respectively electro-stimulated to generate the biphasic compound AP which was recorded using the experimental system of BL-420F. This was followed by 5 times washout plus 5 min administration with Ringer's solution before recovery recording of AP. RESULTS: Compared to normal Ringer's solution, Ringer's solution with alcohol at ≤4% did not have dramatic impacts on the AP amplitude and conduction velocity, while Ringer's solution with alcohol at ≥8% there was significant decrease in these two parameters. Ringer's solution with alcohol at the conentrations of 16%, 32% and ≥48% could prevent a small proportion (30%), a large proportion (90%) and all (100%) of sciatic nerve trunks, respectively, from generating AP. Washout with normal Ringer's solution after alcohol application at the concentration of ≤32%, AP could totally recover to normal status. While alcohol at the concentration of 48%, 64% and 80%, the probabilities to regenerate APs were 90%, 40% and 0%, and the AP amplitudes were decreased to 60%, 36% and 0%, respectively. After washout, AP conduction velocity showed no difference with alcohol at the concentration of ≤8% when compared with that before washout, while it could not be recovered to normal under alcohol at ≥16%. CONCLUSION: Ringer's solution with different concentrations of alcohol exerts different effects on biphasic compound AP amplitude and conduction velocity. Hopefully, our findings could be helpful for the alcoholic usage and its recovery from alcoholic damage.


Assuntos
Potenciais de Ação , Anuros , Etanol/farmacologia , Solução de Ringer/farmacologia , Nervo Isquiático/efeitos dos fármacos , Animais
15.
Neurochem Res ; 44(8): 1964-1976, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31218567

RESUMO

Schwann cells are essential glial cells in the peripheral nervous system (PNS), and dysfunction of Schwann cells can induce various peripheral neurodegenerative diseases. Oxidative stress has been implicated as a causative factor in degenerative nerve diseases; however, there no effective molecules are available to inhibit nerve degeneration in peripheral neurodegenerative diseases. Ethyl pyruvate (EP) is a candidate regulator of oxidative stress, targeting Schwann cells during peripheral nerve degeneration. Here, we investigated the effects of EP on axonal degradation, demyelination, transcriptional regulation, and macrophage recruitment during Wallerian degeneration of the sciatic nerve, ex vivo and in vivo. EP prevented the expression of neuronal nitric oxide synthase (NOS1), but not that of inducible nitric oxide synthase (NOS2), during Wallerian degeneration. These results suggest that effect of EP on Schwann cells may protect against peripheral nerve degeneration through its NOS1-specific regulation.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Piruvatos/uso terapêutico , Células de Schwann/efeitos dos fármacos , Degeneração Walleriana/prevenção & controle , Animais , Axônios/efeitos dos fármacos , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/prevenção & controle , Macrófagos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Bainha de Mielina/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-jun/metabolismo , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia , Degeneração Walleriana/patologia
16.
Nat Commun ; 10(1): 2566, 2019 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-31189915

RESUMO

There is clinical and scientific interest in developing local anesthetics with prolonged durations of effect from single injections. The need for such is highlighted by the current opioid epidemic. Site 1 sodium channel blockers such as tetrodotoxin (TTX) are extremely potent, and can provide very long nerve blocks but the duration is limited by the associated systemic toxicity. Here we report a system where slow release of TTX conjugated to a biocompatible and biodegradable polymer, poly(triol dicarboxylic acid)-co-poly(ethylene glycol) (TDP), is achieved by hydrolysis of ester linkages. Nerve block by the released TTX is enhanced by administration in a carrier with chemical permeation enhancer (CPE) properties. TTX release can be adjusted by tuning the hydrophilicity of the TDP polymer backbone. In vivo, 1.0-80.0 µg of TTX released from these polymers produced a range of durations of nerve block, from several hours to 3 days, with minimal systemic or local toxicity.


Assuntos
Anestésicos Locais/administração & dosagem , Portadores de Fármacos/química , Bloqueio Nervoso/métodos , Bloqueadores dos Canais de Sódio/administração & dosagem , Tetrodotoxina/administração & dosagem , Anestesia Local/métodos , Anestésicos Locais/farmacocinética , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/toxicidade , Plásticos Biodegradáveis/química , Plásticos Biodegradáveis/toxicidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/administração & dosagem , Portadores de Fármacos/toxicidade , Composição de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos , Liberação Controlada de Fármacos , Masculino , Camundongos , Permeabilidade , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/efeitos dos fármacos , Bloqueadores dos Canais de Sódio/farmacocinética , Tetrodotoxina/farmacocinética , Fatores de Tempo , Resultado do Tratamento
17.
Curr Med Sci ; 39(3): 419-425, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31209813

RESUMO

In order to investigate the role of the Notch signaling pathway in skeletal muscle fibrosis after nerve injury, 60 Sprague-Dawley rats were selected and divided randomly into a control and two experimental groups. Group A served as controls without any treatment. Rats in groups B were injected intraperitoneally with 0.2 mL PBS and those in group C were injected intraperitoneally with 0.2 mL PBS+100 µmol/L, 0.2 mL N-[N-(3,5-difluorophenacetyl)-l-alanyl]- S-phenylglycine t-butyl ester (DAPT, a gamma-secretase inhibitor that suppresses Notch signaling) respectively, on postoperative days 1, 3, 7, 10, and 14 in a model of denervation-induced skeletal muscle fibrosis by right sciatic nerve transection. Five rats from each group were euthanized on postoperative days 1, 7, 14, and 28 to collect the right gastrocnemii, and hematoxylin and eosin (HE) staining, immunohistochemistry test, real-time PCR, and Western blotting were performed to assess connective tissue hyperplasia and fibroblast density as well as expression of Notch 1, Jagged 1, and Notch downstream molecules Hes 1 and collagen I (COL I) on day 28. There was no significant difference in HE-stained fibroblast density between group B and C on postoperative day 1. However, fibroblast density was significantly higher in group B than in group C on postoperative days 7, 14, and 28. Notch 1, Jagged 1, Hes 1, and COL I proteins in the gastrocnemius were expressed at very low levels in group A but at high levels in group B. Expression levels of these proteins were significantly lower in group C than in group B (P<0.05), but they were higher in group C than in group A (P<0.05) on postoperative day 28. We are led to conclude that locking the Notch signaling pathway inhibits fibrosis progression of denervated skeletal muscle. Thus, it may be a new approach for treatment of fibrosis of denervated skeletal muscle.


Assuntos
Secretases da Proteína Precursora do Amiloide/genética , Dipeptídeos/farmacologia , Inibidores Enzimáticos/farmacologia , Fibroblastos/metabolismo , Receptor Notch1/genética , Nervo Isquiático/efeitos dos fármacos , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Fibrose/prevenção & controle , Regulação da Expressão Gênica , Músculos Isquiotibiais/efeitos dos fármacos , Músculos Isquiotibiais/inervação , Músculos Isquiotibiais/metabolismo , Injeções Intraperitoneais , Proteína Jagged-1/genética , Proteína Jagged-1/metabolismo , Masculino , Denervação Muscular/métodos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/inervação , Músculo Esquelético/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor Notch1/antagonistas & inibidores , Receptor Notch1/metabolismo , Nervo Isquiático/lesões , Nervo Isquiático/metabolismo , Transdução de Sinais , Fatores de Transcrição HES-1/genética , Fatores de Transcrição HES-1/metabolismo
18.
Int Immunopharmacol ; 74: 105672, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31195189

RESUMO

Metformin is the first line drug in the treatment of type 2 diabetes, however, little is known about its therapeutic potential to prevent or delay damage to the peripheral nerve. Thus, the aim of this study was to investigate whether metformin is able to attenuate the neuroinflammatory response in sciatic nerve of insulin-dependent diabetic mice. Swiss Webster mice were divided into four groups: Control, Diabetic (STZ), Diabetic +100 mg/kg/day of metformin (STZ + M100) and Diabetic +200 mg/kg/day of metformin. Diabetes was induced by streptozotocin (90 mg/kg, i.p.). Only animals with glycemia ≥270 mg/dl were considered diabetics. Metformin prevented atrophy of myelinated axons, and reduced expression of inflammatory mediators (interleukin-1ß, inducible nitric oxide synthase and nitric oxide). However, treatment with 200 mg of metformin was more effective in increasing neurotrophic (myelin basic protein and neural growth factor), angiogenic (vascular endothelial growth factor) and anti-inflammatory (inhibitor kappa B-alpha and interleukin 10) factors. Thus, metformin treatment, especially at the dose of 200 mg, protected the nerve from damages related to chronic hyperglycemia.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/prevenção & controle , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Hiperglicemia/complicações , Hiperglicemia/tratamento farmacológico , Camundongos , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/metabolismo
19.
PLoS Genet ; 15(6): e1008226, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31199789

RESUMO

Carbonic anhydrase-8 (CA8) is an intracellular protein that functions as an allosteric inhibitor of inositol trisphosphate receptor-1 (ITPR1) critical to intracellular Ca++ release, synaptic functions and neuronal excitability. We showed previously that murine nociception and analgesic responses are regulated by the expression of this gene in dorsal root ganglion (DRG) associated with a cis-eQTL. In this report, we identify an exon-level cis-eQTL (rs6471859) that regulates human DRG CA8 alternative splicing, producing a truncated 1,697bp transcript (e.g., CA8-204). Our functional genomic studies show the "G" allele at rs6471859 produces a cryptic 3'UTR splice site regulating expression of CA8-204. We developed constructs to study the expression and function of the naturally occurring CA8-204G transcript (G allele at rs6471859), CA8-204C (C allele at rs6471859 reversion mutation) and CA8-201 (full length transcript). CA8-204G transcript expression occurred predominantly in non-neuronal cells (HEK293), while CA8-204C expression was restricted to neuronal derived cells (NBL) in vitro. CA8-204G produced a stable truncated transcript in HEK293 cells that was barely detectable in NBL cells. We also show CA8-204 produces a stable peptide that inhibits pITPR1 and Ca++ release in HEK293 cells. These results imply homozygous G/G individuals at rs6471859, which are common in the general population, produce exclusively CA8-204G that is barely detectable in neuronal cells. CA8 null mutations that greatly impact neuronal functions are associated with severe forms of spinal cerebellar ataxia, and our data suggest G/G homozygotes should display a similar phenotype. To address this question, we show in vivo using AAV8-FLAG-CA8-204G and AAV8-V5-CA8-201 gene transfer delivered via intra-neural sciatic nerve injection (SN), that these viral constructs are able to transduce DRG cells and produce similar analgesic and anti-hyperalgesic responses to inflammatory pain. Immunohistochemistry (IHC) examinations of DRG tissues further show CA8-204G peptide is expressed in advillin expressing neuronal cells, but to a lesser extent compared to glial cells. These findings explain why G/G homozygotes that exclusively produce this truncated functional peptide in DRG evade a severe phenotype. These genomic studies significantly advance the literature regarding structure-function studies on CA8-ITPR1 critical to calcium signaling pathways, synaptic functioning, neuronal excitability and analgesic responses.


Assuntos
Biomarcadores Tumorais/genética , Sinalização do Cálcio/genética , Receptores de Inositol 1,4,5-Trifosfato/genética , Neurônios/metabolismo , Dor/genética , Processamento Alternativo/genética , Animais , Biomarcadores Tumorais/farmacologia , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Técnicas de Transferência de Genes , Células HEK293 , Humanos , Camundongos , Mutação/genética , Neurônios/patologia , Especificidade de Órgãos , Dor/patologia , Peptídeos/genética , Peptídeos/farmacologia , Locos de Características Quantitativas/genética , Sítios de Splice de RNA/genética , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/metabolismo
20.
J Trace Elem Med Biol ; 54: 126-133, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31109602

RESUMO

3-(4-Chlorophenylselanyl)-1-methyl-1H-indole (CMI) is an organoselenium compound that presents antioxidant activity, antinociceptive, anti-inflammatory and antidepressive-like effect in mice in previous studies conducted by our research group. In this study, we evaluate the anti-allodynic, anti-hyperalgesic and antidepressant-like effects of CMI on partial sciatic nerve ligation (PSNL) in male adult Swiss mice (25-35 g) as well as the involvement of oxidative stress in these effects. Mice underwent PSNL surgery and after 4 weeks they were treated with CMI (10 mg/kg, intragastric route [i.g.]) or vehicle. The treatment with CMI (10 mg/kg, i.g.) reversed the increased the percentage of response to Von-Frey Hair (VFH) stimulation, decreased the latency time to nociceptive response in the hot-plate test, increased immobility time in the forced swimming test (FST) and decreased groomings activity in the splash test, all induced by PSNL. Additionally, CMI also reversed increased the levels of reactive oxygen species (ROS) and lipid peroxidation in cortex and hippocampus and plasmatic levels of corticosterone in mice, induced by PSNL. Results demonstrate that CMI reversed behavioral and biochemical alterations in the dyad pain-depression induced by PSNL and possibly modulation of oxidative system.


Assuntos
Indóis/uso terapêutico , Neuralgia/sangue , Neuralgia/tratamento farmacológico , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/fisiopatologia , Compostos de Selênio/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Antidepressivos/uso terapêutico , Antioxidantes/uso terapêutico , Corticosterona , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Neuralgia/fisiopatologia , Espécies Reativas de Oxigênio/sangue , Selênio/sangue , Natação/fisiologia
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