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1.
Chin Med J (Engl) ; 132(14): 1706-1712, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31261200

RESUMO

BACKGROUND: Pulsed radiofrequency (PRF) is a minimally invasive interventional technique that provides a novel and effective treatment strategy for neuropathic pain (NP). PRF is advantageous because it does not damage nerves and avoids sensory loss after treatment. At present, animal studies have demonstrated that PRF is safe and effective for relieving the NP associated with sciatic nerve damage in rats with chronic constriction injury (CCI). However, the mechanism through which this effect occurs is unknown. An increasing body of evidence shows that the expression of the P2X ligand-gated ion channel 3 (P2X3) receptor is closely related to NP; this study was to investigate whether the expression of this receptor is involved in NP relief due to PRF. METHODS: A total of 36 healthy adult male Sprague-Dawley (SD) rats were randomly divided into three groups: Sham group, CCI group, and PRF group. The right sciatic nerve was ligated in CCI group and PRF group to establish a CCI model; the right sciatic nerve was separated but not ligated in Sham group. On day 14 after the operation, PRF was administered to the ligated sciatic nerve in PRF group (42°C, 45 V, 2 min). A non-live electrode was placed at the exposed sciatic nerve for the rats in Sham and CCI groups. The hindpaw withdrawal threshold (HWT) and thermal withdrawal latency (TWL) were measured at the right hindpaw at different time points before and after PRF or sham therapy. On day 28 after treatment, the dorsal root ganglion (DRG) and spinal dorsal horn of the right L4-6 were harvested from each group to determine the mRNA and protein levels of the P2X3 receptor. RESULTS: On day 28 after PRF treatment, the HWT (8.33 ±â€Š0.67 g vs. 3.62 ±â€Š0.48 g) and TWL (25.42 ±â€Š1.90 s vs. 15.10 ±â€Š1.71 s) were significantly higher in PRF group as compared to CCI group (P < 0.05). The mRNA expression of the P2X3 receptor in the DRG in PRF group was 23.7% lower than that in CCI group (P < 0.05), in the spinal dorsal horns in PRF group was 22.7% lower than that in CCI group (P < 0.05). The protein expression of the P2X3 receptor in the DRG in PRF group was 27.8% lower than that in CCI group (P < 0.05), in the spinal dorsal horns in PRF group was 35.6% lower than that in CCI group (P < 0.05). CONCLUSION: PRF possibly reduces NP in CCI rats by inhibiting the expression of the P2X3 receptor in the L4-6 DRG and spinal dorsal horns.


Assuntos
Constrição , Neuralgia/metabolismo , Neuralgia/terapia , Traumatismos dos Nervos Periféricos/metabolismo , Traumatismos dos Nervos Periféricos/terapia , Tratamento por Radiofrequência Pulsada/métodos , Receptores Purinérgicos P2X3/metabolismo , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Neuropatia Ciática/metabolismo , Neuropatia Ciática/terapia
2.
J Bone Joint Surg Am ; 101(6): 523-530, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30893233

RESUMO

BACKGROUND: Peripheral nerve compression and entrapment can be debilitating. Using a validated animal model of peripheral nerve compression, we examined the utility of 2 drugs approved for other uses in humans, 4-aminopyridine (4-AP) and erythropoietin (EPO), as treatments for surgically induced ischemia and as adjuvants to surgical decompression. METHODS: Peripheral nerve compression was induced in wild-type mice by placing an inert silicone sleeve around the sciatic nerve. Decompression surgery was performed at 6 weeks with mice receiving 4-AP, EPO, or saline solution either during and after compression or only after decompression. A nerve conduction study and morphometric analyses were performed to compare the extent of the injury and the efficacy of the therapies, and the findings were subjected to statistical analysis. RESULTS: During peripheral nerve compression, there was a progressive decline in nerve conduction velocity compared with that in sham-treatment animals, in which nerve conduction velocity remained normal (∼55 m/s). Mice treated with 4-AP or EPO during the compression phase had significantly smaller declines in nerve conduction velocity and increased plateau nerve conduction velocities compared with untreated controls (animals that received saline solution). Histomorphometric analyses of newly decompressed nerves (i.e., nerves that underwent decompression on the day that the mouse was sacrificed) revealed that both treated groups had significantly greater proportions of large (>5-µm) axons than the untreated controls. Following surgical decompression, all animals recovered to a normal baseline nerve conduction velocity by day 15; however, treatment significantly accelerated improvement (in both the 4-AP and the EPO group), even when it was only started after decompression. Histomorphometric analyses at 7 and 15 days following surgical decompression revealed significantly increased myelin thickness and significantly greater proportions of large axons among the treated animals. CONCLUSIONS: Both the 4-AP and the EPO-treated group demonstrated improvements in tissue architectural and electrodiagnostic measurements, both during and after peripheral nerve compression, compared with untreated mice. CLINICAL RELEVANCE: Peripheral nerve decompression is one of the most commonly performed procedures in orthopaedic surgery. We believe that there is reason for some optimism about the translation of our findings to the clinical setting. Our findings in this murine model suggest that 4-AP and EPO may lessen the effects of nerve entrapment and that the use of these agents after decompression may speed and perhaps otherwise optimize recovery after surgery.


Assuntos
4-Aminopiridina/uso terapêutico , Epoetina alfa/uso terapêutico , Hematínicos/uso terapêutico , Síndromes de Compressão Nervosa/terapia , Bloqueadores dos Canais de Potássio/uso terapêutico , Neuropatia Ciática/terapia , Animais , Descompressão Cirúrgica , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Síndromes de Compressão Nervosa/fisiopatologia , Condução Nervosa/fisiologia , Neuropatia Ciática/fisiopatologia
3.
Behav Brain Res ; 360: 303-311, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30543902

RESUMO

Peripheral neuropathy is a common adverse effect observed during the use of paclitaxel (PTX) as chemotherapy. The present investigation was directed to estimate the modulatory effect of bone marrow derived mesenchymal stem cells (BM-MSCs) on pregabalin (PGB) treatment in PTX-induced peripheral neuropathy. Neuropathic pain was induced in rats by injecting PTX (2 mg/kg, i.p) 4 times every other day. Rats were then treated with PGB (30 mg/kg/day, p.o.) for 21 days with or without a single intravenous administration of BM-MSCs. At the end of experiment, behavioral and motor abnormalities were assessed. Animals were then sacrificed for measurement of total antioxidant capacity (TAC), nerve growth factor (NGF), nuclear factor kappa B p65 (NF-κB p65), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and active caspase-3 in the sciatic nerve. Moreover, protein expressions of Notch1 receptor, phosphorylated Janus kinase 2 (p-JAK2), phosphorylated signal transducer and activator of transcription 3 (p-STAT3), and phosphorylated p38 mitogen-activated protein kinase (p-p38-MAPK) were estimated. Finally, histological examinations were performed to assess severity of sciatic nerve damage and for estimation of BM-MSCs homing. Combined PGB/BM-MSCs therapy provided an additional improvement toward reducing PTX-induced oxidative stress, neuro-inflammation, and apoptotic markers. Interestingly, BM-MSCs therapy effectively prevented motor impairment observed by PGB treatment. Combined therapy also induced a significant increase in cell homing and prevented PTX-induced sciatic nerve damage in histological examination. The present study highlights a significant role for BM-MSCs in enhancing treatment potential of PGB and reducing its motor side effects when used as therapy in the management of peripheral neuropathy.


Assuntos
Antineoplásicos Fitogênicos/toxicidade , Terapia Baseada em Transplante de Células e Tecidos/métodos , Células-Tronco Mesenquimais/fisiologia , Transtornos Motores/etiologia , Transtornos Motores/terapia , Paclitaxel/toxicidade , Pregabalina/uso terapêutico , Receptor Notch1/metabolismo , Neuropatia Ciática , Acetona/toxicidade , Análise de Variância , Animais , Antioxidantes/metabolismo , Caspase 3/metabolismo , Modelos Animais de Doenças , Hiperalgesia/fisiopatologia , Hiperalgesia/terapia , Interleucina-6/metabolismo , Janus Quinases/metabolismo , Masculino , Fator de Crescimento Neural/metabolismo , Ratos , Ratos Wistar , Teste de Desempenho do Rota-Rod , Fatores de Transcrição STAT/metabolismo , Neuropatia Ciática/induzido quimicamente , Neuropatia Ciática/complicações , Neuropatia Ciática/terapia , Fatores de Tempo , Fator de Necrose Tumoral alfa/metabolismo
4.
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
5.
J Oral Sci ; 60(4): 526-535, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30587687

RESUMO

The effects of transplanted human dental pulp-derived cells (DPCs) on peripheral nerve regeneration were studied in a rat model of sciatic nerve crush injury. In one group, DPCs were transplanted into the compression site (cell transplantation group); the control group underwent no transplantation (crushed group). Sciatic nerve regeneration was determined based on the recovery of motor function and histological and immunohistochemical analyses. The cell transplantation group showed improved motor function compared with the crushed group using the CatWalk XT system, which corresponded to a higher ratio of tibialis to anterior muscle weight 14 days after surgery. Histological analysis revealed a smaller interspace area and few vacuoles in the sciatic nerve after cell transplantation compared with the crushed group. The myelin sheath was visualized with Luxol Fast Blue (LFB) staining and anti-myelin basic protein (anti-MBP) antibody labeling; the percentages of LFB- and MBP-positive areas were higher in the cell transplantation group than in the crushed group. Human mitochondria-positive cells were also identified in the sciatic nerve at the transplantation site 14 days after surgery. Taken together, the observed correlation between morphological findings and functional outcomes following DPC transplantation indicates that DPCs promote peripheral nerve regeneration in rats.


Assuntos
Polpa Dentária/citologia , Compressão Nervosa , Regeneração Nervosa/fisiologia , Neuropatia Ciática/terapia , Animais , Modelos Animais de Doenças , Humanos , Técnicas Imunoenzimáticas , Masculino , Ratos , Ratos Endogâmicos F344
6.
Einstein (Sao Paulo) ; 16(3): eAO4206, 2018 Sep 17.
Artigo em Inglês, Português | MEDLINE | ID: mdl-30231143

RESUMO

OBJECTIVE: To evaluate the effects of right sciatic nerve compression and cryotherapy on muscle tissue. METHODS: We used 42 male Wistar rats, subdivided in the following Groups Control, Injury 3, Injury 8 and Injury 15 submitted to nerve compression and euthanized in the 3rd, 8th and 15th day after surgery. The Cryotherapy Injury 3 was entailed treatment with cryotherapy by immersion of the animal in recipient for 20 minutes during 1 day, then animals were euthanized at the 3rd day after surgery, and the Cryotherapy Injury 8 and the Cryotherapy Injury 15 was treated for 6 days, and euthanized at the 8th and 15th day after surgery. Functional evaluation was performed by the grasping strength of the right pelvic limb. The right tibialis anterior muscles were evaluated for mass, smaller diameter and cross-sectional area. In the Cryotherapy Injury 8 and the Cryotherapy Injury 15 groups, the hydroxyproline was dosed in the right soles. RESULTS: In the compression there was a significant difference in the Injury Groups compared with the Control Group (p<0.05). In the smaller diameter, the compression in Control Group was higher than Injury 8 (p=0.0094), Injury 15 (p=0.002) and Cryotherapy Injury 15 (p<0.001) groups. The comparison between groups with euthanasia in the same post-operative period, a significant difference (p=0.0363) was seen in day 8th after surgery, and this result in Cryotherapy Injury Group was greater than Injury Group. In the fiber area, Control Group was also higher than the Injury 8 (p=0.0018), the Injury 15 (p<0.001) and the Cryotherapy Injury 15 (p<0.001). In hydroxyproline, no significant difference was seen between groups. CONCLUSION: Nerve damage resulted in decreased muscle strength and trophism, the cryotherapy delayed hypotrophy, but this effect did not persist after cessation of treatment.


Assuntos
Crioterapia/métodos , Síndromes de Compressão Nervosa/patologia , Síndromes de Compressão Nervosa/terapia , Nervo Isquiático/patologia , Neuropatia Ciática/patologia , Neuropatia Ciática/terapia , Animais , Modelos Animais de Doenças , Hipertrofia/fisiopatologia , Masculino , Debilidade Muscular/fisiopatologia , Síndromes de Compressão Nervosa/fisiopatologia , Distribuição Aleatória , Ratos Wistar , Valores de Referência , Reprodutibilidade dos Testes , Nervo Isquiático/fisiopatologia , Nervo Isquiático/cirurgia , Neuropatia Ciática/fisiopatologia , Fatores de Tempo , Resultado do Tratamento
7.
Neurol Res ; 40(12): 1060-1070, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30246623

RESUMO

OBJECTIVE: Peripheral nerve injuries comprise significant portion of the nervous system injuries. Although peripheral nerves show some capacity of regeneration after injury, the extent of regeneration is not remarkable. The present study aimes to evaluate the regeneration of transected sciatic nerve by a therapeutic value of dexamethasone (DEX) associated with cell therapy (Cell) and biodegradable membrane (Mem) in rat. METHODS: Male Wistar rats (n = 42, 180-200g) were randomly divided into control (Ctrl), Membrane+ Cell, Mem, DEX, DEX+ Cell, DEX+ Mem and DEX+ Cell+ Mem groups. Functional recovery was evaluated at 2, 4, 6, 8 and 12 weeks after surgery using sciatic functional index (SFI), withdrawal reflex latency (WRL) test, electrophysiological and histological analyses. RESULTS: The rats in the DEX+ Cell+ Mem-treated group showed a significant improvement in SFI, WRL and electrophysiological findings during the 2nd to 12th weeks after surgery. In addition, histomorphological findings showed a significant improvement in the DEX+ Cell+ Memtreated group, at 12 weeks after surgery. DISCUSSION: Taken together, use of DEX associated with cell and biodegradable membrane could improve functional and histomorphological properties of the sciatic nerve after injury.


Assuntos
Anti-Inflamatórios/uso terapêutico , Dexametasona/farmacologia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/fisiologia , Recuperação de Função Fisiológica/fisiologia , Neuropatia Ciática/terapia , Potenciais de Ação/fisiologia , Análise de Variância , Animais , Antígenos CD/metabolismo , Modelos Animais de Doenças , Eletromiografia , Masculino , Regeneração Nervosa/efeitos dos fármacos , Ratos , Ratos Wistar , Tempo de Reação/fisiologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Fatores de Tempo
8.
Medicine (Baltimore) ; 97(36): e12254, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30200159

RESUMO

RATIONALE: Sciatic neuropathy has various causes; however, cases in which a pressure ulcer led to sciatic neuropathy have not been reported to date. PATIENT CONCERNS: A 33-year-old woman with no pre-existing mobility problems visited our department with the chief complaint of an extensive pressure ulcer and necrosis in her right buttock. She had a medical history of being bedridden for 2 days while in a coma due to a drug overdose 2 months previously. Physical examination revealed loss of sensation and foot drop in the right foot. DIAGNOSIS: Physical examination, magnetic resonance imaging, and nerve conduction studies were conducted; the patient was diagnosed with a common peroneal branch injury of the right sciatic nerve. INTERVENTIONS: The necrotic tissue was debrided and sciatic nerve decompression was performed, followed by frequent dressing changes. In addition, psychiatric treatment and physical therapy were performed simultaneously. OUTCOMES: The pressure ulcer decreased in size and healed to some extent with granulation tissue. However, gait disorders, accompanied by symptoms of sciatic neuropathy, continued. The patient was transferred to the department of gastroenterology for the treatment of toxic hepatitis, which occurred during her inpatient treatment. LESSONS: Physicians should be aware that sciatic neuropathy may occur during the treatment of patients with a pressure ulcer who exhibit no symptoms of paraplegia or quadriplegia. To prevent neuropathy, aggressive treatment of the pressure ulcer is necessary.


Assuntos
Lesão por Pressão/complicações , Neuropatia Ciática/etiologia , Adulto , Diagnóstico Diferencial , Feminino , Humanos , Lesão por Pressão/diagnóstico por imagem , Lesão por Pressão/patologia , Lesão por Pressão/terapia , Neuropatia Ciática/diagnóstico por imagem , Neuropatia Ciática/patologia , Neuropatia Ciática/terapia
9.
Neurol Res ; 40(11): 955-962, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30091393

RESUMO

OBJECTIVE: This study aims to investigate morphological alterations caused by partial sciatic nerve ligation (PNL) and the efficacy of a moderate-intensity swimming training as therapeutic strategy for nerve regeneration. METHODS: A number of 30 male adult mice were equally divided in control, 14 days after PNL (PNL 14 days), 42 days after PNL (PNL 42 days), 70 days after PNL (PNL 70 days) and 5-week exercise training after 7 days post-lesion (PNL trained 35 days) groups. PNL trained 35 days group began with a 10-min session for 3 days and this time was gradually increased by 10 min every three sessions until the animals had swum for 50 min per session. Morphoquantitative analysis was carried out to assess nerve regeneration in each group. RESULTS: PNL 14 days group exhibited less degenerating signs than PNL 42 days group, where most post-lesion alterations were visualized. Nerve area and minimum diameter were significantly lower (p < 0.05) than control group. PNL 70 days group showed a greater degree of regenerating fibers and similar morphometric parameters to control group. PNL trained 35 days demonstrated signs of regeneration, reaching control group values in the morphometric analysis. DISCUSSION: PNL promotes great histopathological changes, which became more visible at 42 post-injury days. A natural nerve-regeneration tendency was observed throughout time, as observed in PNL 70 days group; nevertheless, moderate swimming training was found to be a therapeutic resource for nerve regeneration, accelerating such process from a morphoquantitative perspective. ABBREVIATIONS: ANOVA: One-way analysis of variance; BDNF: Brain-derived neurotrophic factor; FGF-2: Fibroblast growth factor 2; GDNF: Glial cell line derived neurotrophic factor; IGF: Insulin-link growth factor; IL-1ß: Interleukin-1ß; NGF: Neural growth factor; PBS: Phosphate-buffered saline; PNL: Partial sciatic nerve ligation.


Assuntos
Terapia por Exercício , Regeneração Nervosa , Neuropatia Ciática/patologia , Neuropatia Ciática/terapia , Natação , Animais , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos BALB C , Síndromes de Compressão Nervosa/patologia , Síndromes de Compressão Nervosa/terapia , Degeneração Neural/patologia , Degeneração Neural/terapia , Neuralgia/patologia , Neuralgia/terapia , Distribuição Aleatória , Nervo Isquiático/patologia
10.
Brain Behav ; 8(7): e01027, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29920989

RESUMO

BACKGROUND: The aim was to evaluate the regenerative effect of epineural injection of rat ASCs (rASCs) in three different settings of acute and chronic compression in a rat sciatic nerve model. METHODS: Acute compression (60 s) with a vessel clamp over a distance of 1 mm (group 1) or 10 mm (group 2), as well as chronic compression with a permanent remaining, nonabsorbable polymeric clip over a distance of 1 mm (group 3) was performed. Depending on the group, either 5 × 106 rASCs or the same volume (25 µl) of culture medium (CM) was injected with a 30G needle in the epineurium at the time of compression. Outcome measures were functional gait evaluations, imaging analysis, histomorphometric analyses, and muscle weight. RESULTS: The rats in group 2 had a better function than those with group 1 at one and especially at 2 weeks. After 4 weeks however, almost all rats were close to a normal function. There was a similar Muscle Weight Ratio (MWR) after 2 weeks in all groups, whereas after 4 weeks, the MWR in group 3 was lower compared with group 1 and 2. Histomorphometric analysis showed a better myelination in group 1 & 2 compared to group 3 after 4 weeks. ASCs have a beneficial effect on myelin thickness (G-Ratio). CONCLUSIONS: We successfully evaluated the regenerative effect of epineural injection of rASCs in three different settings of acute and chronic compression. However, there were no significant differences in outcomes between the ASC-treated groups and control groups.


Assuntos
Adipócitos/transplante , Células-Tronco Adultas/transplante , Regeneração Nervosa/fisiologia , Nervo Isquiático/fisiologia , Animais , Constrição , Modelos Animais de Doenças , Feminino , Marcha/fisiologia , Injeções , Músculo Esquelético/fisiologia , Síndromes de Compressão Nervosa/terapia , Tamanho do Órgão/fisiologia , Nervos Periféricos , Ratos Sprague-Dawley , Neuropatia Ciática/terapia
11.
J Neurosci Res ; 96(7): 1243-1264, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29659046

RESUMO

Many publications report that ablations of segments of peripheral nerves produce the following unfortunate results: (1) Immediate loss of sensory signaling and motor control; (2) rapid Wallerian degeneration of severed distal axons within days; (3) muscle atrophy within weeks; (4) poor behavioral (functional) recovery after many months, if ever, by slowly-regenerating (∼1mm/d) axon outgrowths from surviving proximal nerve stumps; and (5) Nerve allografts to repair gap injuries are rejected, often even if tissue matched and immunosuppressed. In contrast, using a female rat sciatic nerve model system, we report that neurorrhaphy of allografts plus a well-specified-sequence of solutions (one containing polyethylene glycol: PEG) successfully addresses each of these problems by: (a) Reestablishing axonal continuity/signaling within minutes by nonspecific ally PEG-fusing (connecting) severed motor and sensory axons across each anastomosis; (b) preventing Wallerian degeneration by maintaining many distal segments of inappropriately-reconnected, PEG-fused axons that continuously activate nerve-muscle junctions; (c) maintaining innervation of muscle fibers that undergo much less atrophy than otherwise-denervated muscle fibers; (d) inducing remarkable behavioral recovery to near-unoperated levels within days to weeks, almost certainly by CNS and PNS plasticities well-beyond what most neuroscientists currently imagine; and (e) preventing rejection of PEG-fused donor nerve allografts with no tissue matching or immunosuppression. Similar behavioral results are produced by PEG-fused autografts. All results for Negative Control allografts agree with current neuroscience data 1-5 given above. Hence, PEG-fusion of allografts for repair of ablated peripheral nerve segments expand on previous observations in single-cut injuries, provoke reconsideration of some current neuroscience dogma, and further extend the potential of PEG-fusion in clinical practice.


Assuntos
Regeneração Nervosa/efeitos dos fármacos , Nervo Fibular/efeitos dos fármacos , Nervo Fibular/transplante , Polietilenoglicóis/farmacologia , Nervo Isquiático/efeitos dos fármacos , Neuropatia Ciática/terapia , Aloenxertos/efeitos dos fármacos , Animais , Axônios/efeitos dos fármacos , Axônios/fisiologia , Axotomia , Modelos Animais de Doenças , Feminino , Músculo Esquelético , Fibras Nervosas/efeitos dos fármacos , Condução Nervosa/efeitos dos fármacos , Junção Neuromuscular/efeitos dos fármacos , Traumatismos dos Nervos Periféricos/patologia , Traumatismos dos Nervos Periféricos/terapia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/efeitos dos fármacos , Nervo Isquiático/patologia , Nervo Isquiático/fisiologia , Nervo Isquiático/cirurgia , Neuropatia Ciática/induzido quimicamente , Transplante Homólogo , Degeneração Walleriana/prevenção & controle
12.
World Neurosurg ; 114: e267-e282, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29524702

RESUMO

OBJECTIVE: We used functional magnetic resonance imaging to provide a longitudinal description of cortical plasticity caused by electroacupuncture (EA) of sciatic nerve transection and direct anastomosis in rats. METHODS: Sixteen rats in a sciatic nerve transection and direct anastomosis model were randomly divided into intervention and control groups. EA intervention in the position of ST-36, GB-30 was conducted continuously for 4 months in the intervention group. Functional magnetic resonance imaging and gait assessment were performed every month after intervention. RESULTS: The somatosensory area was more activated in the first 2 months and then deactivated in the rest 2 months when EA was applied. The pain-related areas had the same activation pattern as the somatosensory area. The limbic/paralimbic areas fluctuated more during the EA intervention, which was not constantly activated or deactivated as previous studies reported. We attributed such changes in somatosensory and pain-related areas to the gradual reduction of sensory afferentation. The alterations in limbic/paralimbic system might be associated with the confrontation between the upregulating effect of paresthesia or pain and the downregulating effect of EA intervention through the autonomic nerve system. The gait analysis showed significantly higher maximum contact mean intensity in the intervention group. CONCLUSIONS: The alterations in the brain brought about by the long-term therapeutic effect of EA could be described as a synchronized activation pattern in the somatosensory and pain-related areas and a fluctuating pattern in the limbic/paralimbic system.


Assuntos
Anastomose Cirúrgica/métodos , Mapeamento Encefálico , Córtex Cerebral/fisiopatologia , Eletroacupuntura/métodos , Neuropatia Ciática/terapia , Animais , Córtex Cerebral/diagnóstico por imagem , Modelos Animais de Doenças , Lateralidade Funcional , Transtornos Neurológicos da Marcha/etiologia , Processamento de Imagem Assistida por Computador , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Oxigênio/sangue , Ratos , Ratos Sprague-Dawley , Neuropatia Ciática/complicações , Neuropatia Ciática/patologia
13.
Sci Rep ; 8(1): 5219, 2018 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-29581478

RESUMO

Axon degeneration underlies many nervous system diseases; therefore understanding the regulatory signalling pathways is fundamental to identifying potential therapeutics. Previously, we demonstrated heparan sulphates (HS) as a potentially new target for promoting CNS repair. HS modulate cell signalling by both acting as cofactors in the formation of ligand-receptor complexes and in sequestering ligands in the extracellular matrix. The enzyme heparanase (Hpse) negatively regulates these processes by cleaving HS and releasing the attached proteins, thereby attenuating their ligand-receptor interaction. To explore a comparative role for HS in PNS axon injury/repair we data mined published microarrays from distal sciatic nerve injury. We identified Hpse as a previously unexplored candidate, being up-regulated following injury. We confirmed these results and demonstrated inhibition of Hpse led to an acceleration of axonal degeneration, accompanied by an increase in ß-catenin. Inhibition of ß-catenin and the addition of Heparinase I both attenuated axonal degeneration. Furthermore the inhibition of Hpse positively regulates transcription of genes associated with peripheral neuropathies and Schwann cell de-differentiation. Thus, we propose Hpse participates in the regulation of the Schwann cell injury response and axo-glia support, in part via the regulation of Schwann cell de-differentiation and is a potential therapeutic that warrants further investigation.


Assuntos
Glucuronidase/genética , Traumatismos dos Nervos Periféricos/genética , Nervo Isquiático/metabolismo , Neuropatia Ciática/genética , beta Catenina/genética , Animais , Axônios/metabolismo , Axônios/patologia , Membrana Celular/genética , Membrana Celular/patologia , Matriz Extracelular/genética , Matriz Extracelular/patologia , Regulação da Expressão Gênica/genética , Glucuronidase/metabolismo , Heparitina Sulfato/genética , Heparitina Sulfato/metabolismo , Humanos , Regeneração Nervosa , Neuroglia/metabolismo , Neuroglia/patologia , Traumatismos dos Nervos Periféricos/fisiopatologia , Traumatismos dos Nervos Periféricos/terapia , Ratos , Células de Schwann/metabolismo , Células de Schwann/patologia , Nervo Isquiático/crescimento & desenvolvimento , Nervo Isquiático/lesões , Nervo Isquiático/patologia , Neuropatia Ciática/fisiopatologia , Neuropatia Ciática/terapia , Transdução de Sinais/genética
14.
Pain ; 159(3): 526-539, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29447134

RESUMO

A strong link between histone deacetylases (HDACs) and nociceptive hypersensitivity has been indicated in different pain models. However, the underlying molecular and cellular mechanisms remain elusive. Here, we discovered that partial sciatic nerve ligation-induced mechanical allodynia and thermal hyperalgesia in mice were associated with increased mRNA and protein expressions of HDAC5 (a member of class IIa HDACs) and SRY-related HMG-box 10 (SOX10) in the ipsilateral lumbar dorsal horn. Gene knockdown of spinal HDAC5 or SOX10 attenuated partial sciatic nerve ligation-induced nociceptive hypersensitivity, companied with decrease of spinal neuronal sensitization markers, namely phosphorylated-Erk, phosphorylated-GluN1 (ser896), and c-Fos. Conversely, overexpression of spinal HDAC5 or SOX10 by lentiviruses in naive mice not only induced pain-like behaviors but also increased the expression of these spinal neuronal sensitization markers. Of note, in contrast to its conventional deacetylation effect to silence gene expression, overexpression of HDAC5 not only enhanced SOX10 expression but also induced nociceptive hypersensitivity in naive mice, which were reversed by SOX10 gene knockdown. Chromatin-immunoprecipitation assay further confirmed a novel nonhistone modulation function of HDACs on SOX10 expression, that is, HDAC5 regulates SOX10 by binding to the promoter region of Sox10 gene. In conclusion, this study for the first time demonstrates that HDAC5 regulates spinal neuronal sensitization in neuropathic pain by upregulating modulating SOX10 expression. Thus, interventions that reduce HDAC5/SOX10 expression may represent promising avenues in the treatment of neuropathic pain.


Assuntos
Regulação da Expressão Gênica/genética , Histona Desacetilases/metabolismo , Fatores de Transcrição SOXE/metabolismo , Neuropatia Ciática/metabolismo , Animais , Imunoprecipitação da Cromatina , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Histona Desacetilases/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/metabolismo , Medição da Dor/métodos , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/administração & dosagem , Fatores de Transcrição SOXE/genética , Neuropatia Ciática/patologia , Neuropatia Ciática/fisiopatologia , Neuropatia Ciática/terapia , Corno Dorsal da Medula Espinal/metabolismo , Transdução Genética
15.
Biomed Mater ; 13(4): 044104, 2018 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-29411711

RESUMO

In a previous study, we demonstrated a novel manufacturing approach to fabricate multi-channel scaffolds (MCS) for use in spinal cord injuries (SCI). In the present study, we extended similar materials processing technology to fabricate significantly longer (5X) porous poly caprolactone (PCL) MCS and evaluated their efficacy in 1 cm sciatic peripheral nerve injury (PNI) model. Due to the increase in MCS dimensions and the challenges that may arise in a longer nerve gap model, microstructural characterization involved MCS wall permeability to assess nutrient flow, topography, and microstructural uniformity to evaluate the potential for homogeneous linear axon guidance. It was determined that the wall permeability dramatically varied from 0.02 ± 0.01 × 10-13 to 21.7 ± 11.4 × 10-13 m2 for 50% and 70% porous PCL, respectively. Using interferometry, the porous PCL surface roughness was determined to be 10.7 ± 1.2 µm, which is believed to be sufficient to promote cell integration. Using micro computed tomography, the 3D MCS microstructure was determined to be uniform over 1 cm with an open lumen volume of 44.6% ± 3.6%. In vivo implantation, in the rat sciatic nerve model, over 4 weeks, demonstrated that MCS scaffolds maintained structural integrity, were biocompatible, and supported linear axon guidance and distal end egress over 1 cm. Taken together, this study demonstrated that MCS technology previously developed for the SCI is also relevant to longer nerve gap PNI.


Assuntos
Orientação de Axônios , Materiais Biocompatíveis/química , Regeneração Tecidual Guiada/métodos , Regeneração Nervosa , Nervo Isquiático/lesões , Traumatismos da Medula Espinal/terapia , Tecidos Suporte/química , Animais , Axônios/fisiologia , Imagem Tridimensional , Interferometria , Traumatismos dos Nervos Periféricos/terapia , Permeabilidade , Poliésteres/química , Polímeros/química , Porosidade , Ratos , Neuropatia Ciática/terapia , Microtomografia por Raio-X
16.
Muscle Nerve ; 58(2): 251-260, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29406624

RESUMO

INTRODUCTION: Peripheral nerve damage is associated with high long-term morbidity. Because of beneficial secretome, immunomodulatory effects, and ease of clinical translation, transplantation with adipose-derived stem cells (ASC) represents a promising therapeutic modality. METHODS: Effect of ASC delivery in poloxamer hydrogel was assessed in a rat sciatic nerve model of critical-sized (1.5 cm) peripheral nerve injury. Nerve/muscle unit regeneration was assessed via immunostaining explanted nerve, quantitative polymerase chain reaction (qPCR), and histological analysis of reinnervating gastrocnemius muscle. RESULTS: On the basis of viability data, 10% poloxamer hydrogel was selected for in vivo study. Six weeks after transection and repair, the group treated with poloxamer delivered ASCs demonstrated longest axonal regrowth. The qPCR results indicated that the inclusion of ASCs appeared to result in expression of factors that aid in reinnervating muscle tissue. DISCUSSION: Delivery of ASCs in poloxamer addresses multiple facets of the complexity of nerve/muscle unit regeneration, representing a promising avenue for further study. Muscle Nerve 58: 251-260, 2018.


Assuntos
Adipócitos/transplante , Hidrogéis , Regeneração Nervosa/fisiologia , Nervos Periféricos/crescimento & desenvolvimento , Poloxâmero , Transplante de Células-Tronco/métodos , Adulto , Animais , Axônios/ultraestrutura , Feminino , Humanos , Imuno-Histoquímica , Neurônios Motores , Fibras Musculares Esqueléticas , Músculo Esquelético/crescimento & desenvolvimento , Músculo Esquelético/inervação , Ratos , Nervo Isquiático/lesões , Neuropatia Ciática/terapia
17.
Neurobiol Dis ; 113: 33-44, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29409912

RESUMO

Selective survival of small motor nerve fibers and their neuromuscular contacts in the SOD1G93A transgenic mouse model of amyotrophic lateral sclerosis (ALS) suggests that smaller regenerated nerve fibers are more able to sustain reformed nerve-muscle connections as functionally intact motor units (MUs). The sciatic nerve was crushed unilaterally in SOD1G93A transgenic mice at 40 days of age and contractile forces of reinnervated muscles and their MUs were recorded at 90 days in order to determine the capacities of the nerves to regenerate and to form and retain functional neuromuscular connections. Reduced MU numbers in fast-twitch tibialis anterior, extensor digitorum longus and medial gastrocnemius muscles and the lesser reductions in slow-twitch soleus muscle of SOD1G93A transgenic mice were reversed in reinnervated muscles: there were more reinnervated MUs and their contractile forces and the muscle forces and weights increased. In line with the contrasting ability of only small not large nerve fibers to sprout to form enlarged MUs in the SOD1G93A transgenic mouse, the smaller regenerating nerve fibers formed enlarged MUs that were better able to survive. Because nerve fibers with and without muscle contacts were severed by the sciatic nerve crush injury, the conditioning lesion is untenable as the explanation for improved maintenance of reinnervated neuromuscular junctions. Elevated neurotrophic factor expression in axotomized motoneurons and/or denervated Schwann cells and the synapse withdrawal from axotomized motoneurons are other factors that, in addition to reduced size of nerve fibers reinnervating muscles, may account for increased survival and size of reinnervated MUs in ALS.


Assuntos
Esclerose Amiotrófica Lateral/fisiopatologia , Esclerose Amiotrófica Lateral/terapia , Neurônios Motores/fisiologia , Compressão Nervosa/métodos , Junção Neuromuscular/fisiologia , Neuropatia Ciática/fisiopatologia , Neuropatia Ciática/terapia , Esclerose Amiotrófica Lateral/genética , Animais , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Contração Muscular/fisiologia , Neuropatia Ciática/genética , Superóxido Dismutase/genética
18.
Neurosci Bull ; 34(3): 419-437, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29356943

RESUMO

A previous study has indicated that Krüppel-like factor 7 (KLF7), a transcription factor that stimulates Schwann cell (SC) proliferation and axonal regeneration after peripheral nerve injury, is a promising therapeutic transcription factor in nerve injury. We aimed to identify whether inhibition of microRNA-146b (miR-146b) affected SC proliferation, migration, and myelinated axon regeneration following sciatic nerve injury by regulating its direct target KLF7. SCs were transfected with miRNA lentivirus, miRNA inhibitor lentivirus, or KLF7 siRNA lentivirus in vitro. The expression of miR146b and KLF7, as well as SC proliferation and migration, were subsequently evaluated. In vivo, an acellular nerve allograft (ANA) followed by injection of GFP control vector or a lentiviral vector encoding an miR-146b inhibitor was used to assess the repair potential in a model of sciatic nerve gap. miR-146b directly targeted KLF7 by binding to the 3'-UTR, suppressing KLF7. Up-regulation of miR-146b and KLF7 knockdown significantly reduced the proliferation and migration of SCs, whereas silencing miR-146b resulted in increased proliferation and migration. KLF7 protein was localized in SCs in which miR-146b was expressed in vivo. Similarly, 4 weeks after the ANA, anti-miR-146b increased KLF7 and its target gene nerve growth factor cascade, promoting axonal outgrowth. Closer analysis revealed improved nerve conduction and sciatic function index score, and enhanced expression of neurofilaments, P0 (anti-peripheral myelin), and myelinated axon regeneration. Our findings provide new insight into the regulation of KLF7 by miR-146b during peripheral nerve regeneration and suggest a potential therapeutic strategy for peripheral nerve injury.


Assuntos
Regulação da Expressão Gênica/fisiologia , Fatores de Transcrição Kruppel-Like/metabolismo , MicroRNAs/metabolismo , Regeneração Nervosa/fisiologia , Neuropatia Ciática/terapia , Animais , Movimento Celular/genética , Proliferação de Células/genética , Modelos Animais de Doenças , Feminino , Gânglios Espinais/citologia , Regulação da Expressão Gênica/genética , Células HEK293 , Humanos , Fatores de Transcrição Kruppel-Like/genética , Masculino , MicroRNAs/genética , Placa Motora/genética , Proteína P0 da Mielina/metabolismo , Regeneração Nervosa/genética , Proteínas do Tecido Nervoso/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Neuropatia Ciática/metabolismo , Neuropatia Ciática/cirurgia
19.
Turk Neurosurg ; 28(3): 474-478, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28585677

RESUMO

AIM: To analyze the cases discussed at the High Health Council (HHC) and to determine the solutions for problems related to gluteal intramuscular injection (IMI) applications. MATERIAL AND METHODS: In a 10-year period, the cases of IMI-related sciatic nerve injury (SNI) referred for an opinion from the HHC of Turkey were reviewed. The cases were analyzed based on demographic features, degree of nerve damage, side of gluteal injection, injected drugs, primary disease, appropriateness of parenteral therapy indications, and management. RESULTS: There were 107 SNIs from gluteal IMI during the 103 months. Eight of the 107 cases were male and 99 female. The mean age was 28 years. The left sciatic nerve was more commonly injured (41 right, 65 left side). SNI was partial in 48.5% of the cases. The most commonly injected drug was diclofenac sodium (29.9%), and 23.3% of cases were injected more than one drug together. Conservative management was performed in all cases, except one. CONCLUSION: Based on our findings, indications of parenteral therapies were exaggerated and nurses injected the drug while the patient"s position was inappropriate for IMI. However, an IMI into the gluteal region is potentially devastating. For those reasons, we conclude that physicians should be restricted in their indications for IMI, and continuous education courses should be organized for nurses. Injured patients should be managed according to their neurological damage.


Assuntos
Registros Eletrônicos de Saúde , Nervo Isquiático/lesões , Neuropatia Ciática/epidemiologia , Neuropatia Ciática/etiologia , Adolescente , Adulto , Idoso , Nádegas/patologia , Criança , Pré-Escolar , Feminino , Humanos , Injeções Intramusculares/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Nervo Isquiático/patologia , Neuropatia Ciática/terapia , Turquia/epidemiologia , Adulto Jovem
20.
Eur J Orthop Surg Traumatol ; 28(2): 305-308, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28840398

RESUMO

A 47-year-old man presented three months post-hamstring injury with posterior thigh and buttock pain, paraesthesia over the lateral part of the leg and dorsum of the foot and a foot drop. MRI identified a hamstring muscle injury with a lesion surrounding 20 cm of the proximal sciatic nerve consistent with an extensive haematoma. Surgical debridement and release was planned; however, his signs spontaneously resolved with rest, physiotherapy and splintage prior to surgery. There have been no other reports of a sciatic nerve lesion with neurological signs resolving without surgical exploration.


Assuntos
Músculos Isquiotibiais/lesões , Hematoma/complicações , Síndromes de Compressão Nervosa/etiologia , Neuropatia Ciática/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes de Compressão Nervosa/diagnóstico , Síndromes de Compressão Nervosa/terapia , Modalidades de Fisioterapia , Descanso , Neuropatia Ciática/diagnóstico , Neuropatia Ciática/terapia
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