Investigation of the Neuro-Regenerative Effects of Bioresonance and Magnetotherapy in Sciatic Nerve Damage-Induced Rats / Investigación de los Efectos Neurorregenerativos de Biorresonancia y Magnetoterapia en Ratas Inducidas por Daño del Nervio Ciático

SUMMARY: Peripheral nerve damage is a significant clinical problem that can lead to severe complications in patients. Regarding the regeneration of peripheral nerves, it is crucial to use experimental animals' nerves and use different evaluation methods. Epineural or perineural suturing is the gold standard in treating sciatic nerve injury, but nerve repair is often unsuccessful. This study aimed to investigate the neuroregenerative effects of magnetotherapy and bioresonance in experimental animals with sciatic nerve damage. In this study, 24 female Wistar rats were divided into 7 groups (n=6) as follows: Group 1 (Control), Group 2 (Axonotmesis control), Group 3 (Anastomosis control), Group 4 (Axonotmesis + magnetotherapy), Group 5 (Anastomosis + magnetotherapy), Group 6 (Axonotmesis + bioresonance), Group 7 (Anastomosis + bioresonance). Magnetotherapy and bioresonance treatments were applied for 12 weeks. Behavioural tests and EMG tests were performed at the end of the 12th week. Then the rats were sacrificed, and a histopathological evaluation was made. The statistical significance level was taken as 5 % in the calculations, and the SPSS (IBM SPSS for Windows, ver.21) statistical package program was used for the calculations. Statistically significant results were obtained in animal behaviour tests, EMG, and pathology groups treated with magnetotherapy. There was no statistically significant difference in the groups treated with bioresonance treatment compared to the control groups. Muscle activity and nerve repair occurred in experimental animals with acute peripheral nerve damage due to 12 weeks of magnetotherapy, and further studies should support these results.

El daño a los nervios periféricos es un problema clínico importante que puede conducir a complicaciones graves en los pacientes. En cuanto a la regeneración de los nervios periféricos, es crucial utilizar los nervios de los animales de experimentación y diferentes métodos de evaluación. La sutura epineural o perineural es el gold estándar en el tratamiento de lesiones del nervio ciático, pero la reparación del nervio a menudo no tiene éxito. Este estudio tuvo como objetivo investigar los efectos neuroregenerativos de la magnetoterapia y la biorresonancia en animales de experimentación con daño del nervio ciático. En el estudio, 24 ratas hembras Wistar se dividieron en 7 grupos (n=6) de la siguiente manera: Grupo 1 (Control), Grupo 2 (Control de axonotmesis), Grupo 3 (Control de anastomosis), Grupo 4 (Axonotmesis + magnetoterapia), Grupo 5 (Anastomosis + magnetoterapia), Grupo 6 (Axonotmesis + biorresonancia), Grupo 7 (Anastomosis + biorresonancia). Se aplicaron durante 12 semanas tratamientos de magnetoterapia y biorresonancia. Las pruebas de comportamiento y las pruebas de EMG se realizaron al final de la semana 12. Luego se sacrificaron las ratas y se realizó una evaluación histopatológica. El nivel de significación estadística se tomó como 5 % en los cálculos, y se utilizó el programa de paquete estadístico SPSS (IBM SPSS para Windows, ver.21). Se obtuvieron resultados estadísticamente significativos en pruebas de comportamiento animal, EMG y grupos de patología tratados con magnetoterapia. No hubo diferencia estadísticamente significativa en los grupos con tratamiento de biorresonancia en comparación con los grupos controles. La actividad muscular y la reparación nerviosa, se produjeron en animales de experimentación con daño nervioso periférico agudo, debido a 12 semanas de magnetoterapia.Estudios adicionales deberían respaldar estos resultados.

The effects of fat graft and platelet-rich fibrin combination after epineurectomy in rats

SUMMARY OBJECTIVE: One of the most important factors that adversely affects the outcome of peripheral nerve surgery is the formation of epineural and extraneural scar tissue after surgery. Many surgical methods and pharmacological and chemical agents have been used to prevent the formation of epineural scar tissue, but satisfactory results have not been achieved in clinical applications. The purpose of this study was to investigate the combined effect of fat graft and platelet-rich fibrin on the formation of epineural scar tissue and on nerve healing in the mature rat model. METHODS: A total of 24 female Sprague-Dawley rats were used. A circumferential segment of epineurium was excised from both bilateral sciatic nerves. The epineurectomized right nerve segment was wrapped with a combination of fat graft and platelet-rich fibrin (experimental group), while the left nerve segment did not receive any surgical procedure other than the epineurectomy (sham group). Notably, 12 randomly selected rats were sacrificed in the fourth week for histopathological examination of early results. The other 12 rats were sacrificed in the eighth week for late results. RESULTS: The formation of fibrosis, inflammation, and myelin degeneration were less common in the experimental group, while nerve regeneration was found to be higher at both 4 and 8 weeks. CONCLUSION: The intraoperative application of a combination of fat graft and platelet-rich fibrin appears to be effective on nerve healing after surgery at both the early and late periods.

The efficacy of corticosteroid after facial nerve neurorrhaphy: a systematic review and meta-analysis of randomized controlled trial

Abstract Objectives: The benefit of corticosteroids following facial nerve neurorrhaphy in the setting of complete transection is questionable. This systematic review and meta-analysis aimed to evaluate corticosteroid efficacy on facial nerve regeneration and functional recovery after complete disruption and neurorrhaphy. Methods: Randomized controlled trials on both human and animal models from Ovid MEDLINE and Ovid EMBASE studying corticosteroid efficacy in complete facial nerve disruption followed by neurorrhaphy were included. Data were extracted and pooled for meta-analysis. The outcomes were evaluated from electrophysiology, histology, and functional recovery. However, no randomized controlled trial in human was performed. Possibly, performing human trials with histopathology may not be feasible in clinical setting. Results: Six animal studies (248 participants) met inclusion criteria. Electrophysiologic outcomes revealed no differences in latency (Standardized Mean Difference (SMD) = −1.97, 95% CI −7.38 to 3.44, p = 0.47) and amplitude (SMD = 0.37, 95% CI −0.44 to 1.18, p = 0.37) between systemic corticosteroids and controls. When analysis compared topical corticosteroid and control, the results provided no differences in latency (Mean Difference (MD)=0.10, 95% CI −0.04 to 0.24, p = 0.16) and amplitude (SMD = 0.01, 95% CI −0.08 to 0.10, p = 0.81). In histologic outcomes, the results showed no differences in axon diameter (MD = 0.13, 95% CI −0.15 to 0.41, p = 0.37) between systemic corticosteroid and control; however, the result in myelin thickness (MD = 0.06, 95% CI 0.04 to 0.08, p < 0.05) favored control group. When comparing systemic corticosteroid with control in eye blinking, the results favored control (MD= 1.33, 95% CI 0.60 to 2.06, p = 0.0004). Conclusions: This evidence did not show potential benefits of systemic or topical corticosteroid deliveries after facial nerve neurorrhaphy in complete transection when evaluating electrophysiologic, histologic, and functional recovery outcomes in animal models.

Human Platelet-Rich Plasma-Derived Exosomes Promote the Proliferation of Schwann Cells Cultured in Vitro / 中国医学科学院学报

Objective To investigate the effect of human platelet-rich plasma-derived exosomes(PRP-exos)on the proliferation of Schwann cell(SC)cultured in vitro. Methods PRP-exos were extracted by polymerization-precipitation combined with ultracentrifugation.The morphology of PRP-exos was observed by transmission electron microscopy,and the concentration and particle size distribution of PRP-exos were determined by nanoparticle tracking analysis.Western blotting was employed to determine the expression of the marker proteins CD63,CD81,and CD9 on exosome surface and the platelet membrane glycoprotein CD41.The SCs of rats were isolated and cultured,and the expression of the SC marker S100β was detected by immunofluorescence staining.The fluorescently labeled PRP-exos were co-cultured with SCs in vitro for observation of their interaction.EdU assay was employed to detect the effect of PRP-exos on SC proliferation,and CCK-8 assay to detect the effects of PRP-exos at different concentrations(0,10,20,40,80,and 160 μg/ml)on SC proliferation. Results The extracted PRP-exos appeared as uniform saucer-shaped vesicles with the average particle size of(122.8±38.7)nm and the concentration of 3.5×1012 particles/ml.CD63,CD81,CD9,and CD41 were highly expressed on PRP-exos surface(P<0.001,P=0.025,P=0.004,and P=0.032).The isolated SCs expressed S100β,and PRP-exos could be taken up by SCs.PRP-exos of 40,80,and 160 μg/ml promoted the proliferation of SCs,and that of 40 μg/ml showed the best performance(all P<0.01). Conclusions High concentrations of PRP-exos can be extracted from PRP.PRP-exos can be taken up by SCs and promote the proliferation of SCs cultured in vitro.

Sciatic nerve derived exosomes in promotion of axon regeneration and functional recovery following peripheral nerve injury in rat / 中华显微外科杂志

Objective:To explore the effect of sciatic nerve derived exosomes(SN-EXO) on axon regeneration and functional recovery after peripheral nerve injury(PNI).Methods:From March 2021 to October 2022, the Department of Orthopedics of the First Affiliated Hospital of Zhengzhou University studied the effect of SN-EXO on the proliferation of Schwann cells(SCs) through EdU cell proliferation experiment. Twenty-one healthy male SD rats were randomly divided into 3 groups of sham operation, peripheral nerve injury(PNI) and SN-EXO treatment, with 7 rats in each group. The right sciatic nerves of rat models in sham group were exposed without injury. In the rat in PNI group and SN-EXO treatment group, PBS and SN-EXO were injected under the epineurium of right sciatic nerves following sciatic nerve crush. Sciatic nerve function index(SFI) was performed at 28 days after operation, and then sacrificed. Right sciatic nerves were removed for further exploration of nerve regeneration. The histopathological changes and axon arrangement of sciatic nerves were evaluated by HE staining. Regeneration efficiency of neurofilaments and SCs were obserred by NF200 and S100β double staining of sciatic nerve. The data obtained were statistically analyzed, and P<0.05 was statistically significant. Results:It was found that SN-EXO can significantly enhance the proliferation ability of SCs, with statistically significant difference( P<0.05). SFI in SN-EXO treatment group and PNI group were(-27.65±4.36) and(-57.33±7.49), respectively, and the difference was statistically significant( P<0.05). Axons in SN-EXO treatment group were arranged more closely and orderly than those in the PNI group at 28 days after operation, and there were less injury induced axon disintegration and vacuolation. Immunofluorescence assay indicated that NF200 and S100β fluorescence intensity in SN-EXO treatment group was significantly higher than that in the PNI group, and the difference was statistically significant( P<0.05). Conclusion:SN-EXO could enhance the proliferation of SCs to promote axon regeneration following peripheral nerve injury.

An enriched environment can promote nerve regeneration in a mouse model of sciatic nerve compression / 中华物理医学与康复杂志

Objective:To document any effect of environmental enrichment on nerve regeneration in a mouse model of sciatic nerve compression and explore its mechanism.Methods:A crushed sciatic nerve model was successfully established in 22 C57BL/6 mice, and they were then randomly divided into an intervention group and a control group. The mice of the intervention group were raised in a cage with an enriched environment, while those of the control group were kept in a standard cage. Two weeks later, both groups′ gait was analyzed and the compound muscle action potential (CMAP) of the sciatic nerve was measured. The proportion of myelinated sciatic nerve fibers was examined using toluidine blue staining, and the expression of myelin basic protein (MBP), growth associated protein-43 (GAP43) and p75 neurotrophin receptor (p75 NTR) was measured using immunofluorescence intensity. Results:①The latency of the CMAP [(1.05±0.04)ms] was significantly shortened in the intervention group compared with the control group and the amplitude was significantly higher. ②Gait analysis showed a significant increase in the average contact intensity, stride length and stride rate of the intervention group compared with the control group. However, the step axis angle of the intervention group was significantly smaller than in the control group on average. ③The stained nerve fibers in the intervention group were orderly and dense, and the average number of myelinated fibers was significantly greater than in the control group. ④Quantitative analysis of the immunofluorescence showed that the levels of MBP, GAP43 and p75 NTR in the sciatic nerves of the intervention group were, on average, significantly higher than in the control group. Conclusion:An enriched environmental can promote the regeneration and functional recovery of crushed sciatic nerves by promoting the proliferation and myelination of Schwann cells.

Effects of activating mTORC2/Akt signaling pathway on dopaminergic neurons and behaviors in 6-hydroxydopamin model mice / 解剖学报

Objective To explore the effect of activation of mammalian target of rapmycin complex 2(mTORC2)/Akt signaling pathway on dopaminergic neurons and behavior in 6-hydroxydopamine (6-OHDA) model mice and its possible mechanism. Methods Selecting 36 mice which The Nestin-CreERTM and ROSA26-LacZ reporter genes were detected at the same time in 3-month-old male C57BL/6J mice weighing 20-25 g divideng them into 4 gruops, NS+ corn oil group, 6-OHDA+corn oil group, 6-OHDA+PP242 group and 6-OHDA+A-443654 group, and 6-OHDA was injected into the right striatum of the brain to replicate the Parkinson’s disease (PD) model of mice, and then daily intraperitoneal injection of mTORC2/Akt signaling pathway agonist A-443654 or inhibitor PP242. Serum interleukin-1β (IL-1β) and tumor necrosis factor-α(TNF-α)levels were measured by enzyme-linked immunosorbent assay. Immunohistochemistry and immunofluorescence staining were performed to investigate the change of microglia, dopaminergic neurons as well as neural progenitor cells (NPCs). Western blotting was used to detect the expression of related protein of mTORC2/Akt signaling pathway including rictor, p-Akt and regulated in development and DNA dgmage responses 1(REDD1) and the interaction between them were verified by immunoprecipitation. Finally, the behavioral performance of each group of mice was observed. Results With the activation of microglia and the increase of inflammatory factors in PD model mice, the number of dopaminergic neurons in the substantia nigra(SN) decreased significantly, and the motor function of the mice was impaired, but the number of NPCs increased significantly compared with the control mice, mTORC2/Akt signaling pathway related protein expression was also significantly up-regulated. A-443654 treatment further up-regulated the expression of these proteins, meanwhile the indicators mentioned above were ameliorated. However, the inhibitor PP242 treatment group showed completely opposite result with the agonist group. Conclusion A-443654 can promote the proliferation of NPCs and the number of new-born dopaminergic neurons by up-regulating related proteins of mTORC2/Akt signaling pathway, and reducing the activation of microglia and the level of inflammation factors, which ultimately lead to the amelioration of SN-striatal dopaminergic neurons and behavioral performance in PD model mice.

Nerve repair effect of olanzapine-mediated cyclic AMP response element binding protein/brain-derived neurotrophic factor/receptor tyrosine kinase receptors B pathway on schizophrenic rats / 解剖学报

Objective To stud)' the nerve repair effect of olanzapine on schizophrenia model rats through its effect on cyclic AMP response element binding protein (CREB)/brain-derived neurotrophic factor (BDNF)/receptor tyrosine kinase receptors B (TrkB) pathway. Methods Total 60 rats were divided into control group, model group, olanzapine low, middle and high dose group. The rats in the model group, olanzapine low, middle and high dose groups were injected intraperitoneally with MK-801[0. 2 mg/(kg-d) ], while the control injected with the same amount of normal saline. The low, middle and high dose olanzapine groups were perfused with olanzapine solution of 0. 5 mg/(kg-d),1. 0 mg/(kg-d) and 1. 5 mg/(kg-d) respectively. The behavior of rats was scored according to ataxia and stereotyped behavior standards, cognitive function and learning ability were evaluated by Moms water maze test, serum tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6) levels were detected by ELISA method, hippocampal histopathology was observed under microscope, and apoptosis and expression of CREB/BDNF/TrkB pathway related proteins in hippocampus were detected. Results Compared with the control group, the ataxia, the score of stereotyped behavior, the expression of TNF-a, IL-6 and the rate of apoptosis in the model group increased significantly (P < 0 . 01). Compared with the control group, the number of crossing the platform, the time of staying in the target quadrant and the relative expression of CREB, p-CREB, p-TrkB, TrkB and BDNF protein in the model group decreased significantly (P<0. 01), and those in the low and middle dose olanzapine groups decreased significantly (P < 0 . 05). Compared with the model group, the times of crossing the platform and the stay time in the target quadrant increased significantly in the low and middle dose olanzapine groups (P< 0. 05). In the model group and the low dose olanzapine group, the hippocampal cells were swollen obviously, the nucleus was broken and divided, pyknosis, and the tissue aiTangement was disorderly, while the phenomenon of fragmentation and nuclear pyknosis was rarely seen in the middle and high dose olanzapine groups. Conclusion The nerve repair mechanism of olanzapine on schizophrenic model rats is related to improving cognitive impainnent, protecting hippocampal neurons and activating the expression of CREB/BDNF/TrkB signal pathway in rats.

Expression pattern of MMP-12 in long-term optic nerve regeneration induced by lens injury / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To investigate the expression changes of MMP-12 during the long-term axon regeneration induced by the lens injury after the optic nerve clamp trauma in sprague-dawley(SD)rats.METHODS: The optic nerve injury model and lens injury model of SD rats were established, and the 24 experimental animals were divided into control group; lens injury group; optic nerve injury group; lens injury combined with optic nerve injury group, with 6 rats in each group. Reference transcriptome sequencing was used to analyze the expression changes of differentially expressed genes in the injured optic nerve region, and relevant differentially expressed genes with high expression were screened. Quantitative real-time polymerase chain reaction(qRT-PCR)and enzyme-linked immunosorbent assay(ELISA)were used to quantify the expression changes of matrix metalloproteinase-12(MMP-12)in the injured optic nerve region.RESULTS: The Principal Component Analysis of transcriptome sequencing indicated that lens injury combined with optic nerve injury was the principal component of gene expression change. Analysis of gene expression differences showed that the expression of MMP-12 gene was up-regulated in the lens injury combined with optic nerve injury group. The mRNA expression level of MMP-12 in the lens injury combined optic nerve injury group was up-regulated compared with the control group, the optic nerve injury group and the lens injury group at 14d and 21d after successful modeling(P<0.05). At 7, 28d, there was no difference in expression among all groups. The protein expression level of MMP-12 in the lens injury combined with optic nerve injury group was up-regulated compared with the control group and optic nerve injury group at 7, 14 and 21d after successful modeling(P<0.05), and it was up-regulated in the lens injury group combined with optic nerve injury group compared with optic nerve injury group at 21d(P<0.05). At 28d, there was no difference in expression among all groups.CONCLUSION: The up-regulated expression of MMP-12 may be involved in the long-term regeneration of the optic nerve after lens injury.

Advances in the raw material selection and functional design of artificial nerve guidance conduits / 生物工程学报

Artificial nerve guidance conduits (NGCs) are synthetic nerve grafts that are capable of providing the structural and nutritional support for nerve regeneration. The ideal NGCs have plenty of requirements on biocompatibility, mechanical strength, topological structure, and conductivity. Therefore, it is necessary to continuously improve the design of NGCs and establish a better therapeutic strategy for peripheral nerve injury in order to meet clinical needs. Although current NGCs have made certain process in the treatment of peripheral nerve injury, their nerve regeneration and functional outcomes on repairing long-distance nerve injury remain unsatisfactory. Herein, we review the nerve conduit design from four aspects, namely raw material selection, structural design, therapeutic factor loading and self-powered component integration. Moreover, we summarize the research progress of NGCs in the treatment of peripheral nerve injury, in order to facilitate the iterative updating and clinical transformation of NGCs.

Two birds, one stone: a surgical approach for third nerve palsy with aberrant regeneration / Tratamento cirúrgico de paralisia de terceiro nervo craniano com regeneração aberrante

ABSTRACT Aberrant regeneration in third nerve palsies, linking medial rectus contraction to the levator palpebrae muscle, is a great opportunity for surgical planning to address both the ptosis and horizontal deviation in a single procedure. We report a case of severe ptosis associated with exotropia that was successfully corrected with a single horizontal strabismus surgery owing to aberrant regeneration and discuss the basis underlying the surgical planning.

RESUMO A regeneração aberrante nas paralisias do terceiro nervo, ligando a contração do reto medial ao músculo levantador da pálpebra, é uma grande oportunidade para fazer um planejamento cirúrgico para tratar tanto a ptose quanto o desvio horizontal em um procedimento único. Relatamos uma ptose grave associada à exotropia corrigida com sucesso com uma única cirurgia de estrabismo horizontal devido à regeneração aberrante e discutimos as bases do planejamento cirúrgico.

Fotobiomodulação com LED induz melhora na funcionalidade da marcha em ratos após lesão nervosa periférica / Photobiomodulation with LED increased the gait functionality in rats submitted to peripheral nerve injury

Introdução: As lesões nervosas periféricas (LNP) podem resultar em distúrbios motores e sensoriais alterando a funcionalidade do membro afetado, porém pouco se conhece a respeito dos efeitos da fotobiomodulação (FBM) com diodo emissor de luz (LED). Objetivo: Analisar os efeitos do LED sobre a funcionalidade da marcha de ratos Wistar pós LNP. Metodologia: Ratos Wistar foram submetidos a LNP por esmagamento de ciático e analisados nos seguintes grupos experimentais: (1) Controle; (2) LNP; (3) LNP+ LED (780 nm, potência média 40 mW, exposição radiante, energia por ponto, 3,2 J sobre o nervo ciático (LEDn); (4) LNP+ LED em nervo e região do músculo envolvido (LEDnm) e (5) LNP+ LED apenas em região do músculo (LEDm). Após 7, 14, 21 e 28 dias foram realizadas as análises de marcha utilizando o Índice Funcional Ciático (IFC). Resultado: Após 7 dias, os grupos tratados com LED apresentaram uma melhora da marcha em relação ao grupo Lesão, sendo essa melhora mais pronunciada no grupo LEDn. Após 14 dias, os grupos LEDn e LEDnm apresentaram valores semelhantes ao grupo controle e após 21 e 28 dias o IFC não apresentou diferenças entre os grupos experimentais. Conclusão: O LED aumentou a funcionalidade da marcha avaliada pelo IFC após 1 e 2 semanas pós LNP, especialmente quando foi usado na região nervosa associada ou não à região muscular.

Introduction: Peripheral nerve injuries (PNI) can result in motor and sensory disturbances altering the functionality of the affected limb, however not much is known about the effects of photobiomodulation (PBM) with light emitting diode (LED). Objective: We aimed to analyze the effects of LED on the gait function of Wistar rats after PNI. Methodology: Wistar rats were submitted to PNI by sciatic crush and analyzed in the following experimental groups: (1) Control; (2) PNI; (3) PNI+ LED (780 nm, mean power 40 mW, radiant exposure, energy per spot, 3.2 J on the sciatic nerve) (LEDn); (4) LNP+ LED on nerve and involved muscle region (LEDnm) and (5) LNP+ LED only on muscle region (LEDm). After 7-, 14-, 21- and 28-days gait analyses were performed using the Sciatic Functional Index (SFI). Results: After 7 days, the groups treated with LED showed an improvement in gait compared to the PNI group, with this improvement being more pronounced in the LEDn group. After 14 days, the LEDn and LEDnm groups showed similar values to the control group and after 21 and 28 days the SFI did not show differences between the experimental groups. Conclusion: LED increased the gait functionality evaluated by SFI after 1 and 2 weeks post-PNI, especially when it was used in the nerve region associated or not with the muscle region.

Effect of Tacrolimus and Cyclosporine Immunosuppressants on Peripheral Nerve Regeneration: Systematic Review and Meta-analysis / Efeito dos imunossupressores tacrolimus e ciclosporina na regeneração de nervos periféricos: Revisão sistemática e metanálises

Abstract Peripheral nerve damage is an important cause of seeking medical attention. It occurs when the continuity of structures is interrupted and the propagation of nervous impulses is blocked, affecting the functional capacity of individuals. To assess the effects of the immunosuppressants tacrolimus and cyclosporine on the regeneration of peripheral nerves, a systematic review of the literature was carried out. The articles included were published until September 2018 and proposed to evaluate the effects of the immunosuppressants tacrolimus and cyclosporine on nerve regeneration and neuroprotection, available in the MEDLINE, EMBASE, Cochrane Library, Web of Science, Oxford Pain Relief Database, and LILACS databases. The research analysed a total of 56 articles, of which 22 were included in the meta-analysis. Statistical analysis suggests the protective effect of tacrolimus in the regeneration of the number of myelinated axons (95% confidence interval [CI]: 0.93-2.39; p< 0.01); however, such effect was not observed in relation to cyclosporine (95%CI: - 0.38-1.18; p» 0.08) It also suggests that there is a significant relationship between the use of tacrolimus and myelin thickness (95%CI» 2.00-5.71; p< 0. 01). The use of immunosuppressants in the regeneration of peripheral nerve damage promotes an increase in the number of myelinated axons in general, regardless of the administered dose. In addition, it ensures greater myelin thickness, muscle weight and recovery of the sciatic functional index. However, heterogeneity was high in most analyses performed.

Resumo As lesões nervosas periféricas são uma causa importante de busca por atendimento médico. Elas ocorrem quando há a interrupção da continuidade das estruturas e do bloqueio da propagação dos impulsos nervosos, afetando a capacidade funcional dos indivíduos. Para avaliar os efeitos dos imunossupressores tacrolimus e ciclosporina na regeneração de nervos periféricos, foi realizada uma revisão sistemática da literatura. Foram incluídos artigos publicados até setembro de 2018, que se propunham avaliar os efeitos dos imunossupressores tacrolimus e ciclosporina na regeneração nervosa e neuroproteção, disponíveis nas bases de dados MEDLINE, EMBASE, Cochrane Library, Web of Science, Oxford Pain Relief Database e LILACS. A pesquisa analisou um total de 56 artigos, dos quais 22 foram para metanálise. A análise estatística sugere o efeito protetor do tacrolimus na regeneração do número de axônios mielinizados (intervalo de confiança [IC] 95%: 0,93-2,39; p< 0,01); todavia tal efeito não foi observado em relação à ciclosporina (IC95%: - 0,38-1,18; p» 0,08). Ela também sugere haver uma relação significativa entre o uso do tacrolimus e a espessura da mielina (IC95%: 2,00-5,71; p< 0,01). O uso de imunossupressores na regeneração de lesão nervosa periférica promove um aumento no número de axônios mielinizados de forma geral, independentemente da dose administrada. Além disso, garante uma maior espessura da mielina, um maior peso muscular e restabelecimento do índice da função do nervo ciático. Todavia, a heterogeneidade foi alta na maioria das análises realizadas.

Effect of hyperbaric oxygen therapy on nerve regeneration in rats / Efeito da terapia hiperbárica de oxigênio na regeneração nervosa em ratos

ABSTRACT Objective: To evaluate histological changes in peripheral nerves of rats after sciatic nerve neurorrhaphy, according to the time of exposure to hyperbaric oxygen chamber treatment. Methods: Twenty-five Wistar rats were divided into 5 groups according to the amount of exposure to hyperbaric oxygen chamber treatment. Group 1 was the control and there was no use of hyperbaric oxygen chamber; group 2 received one week of therapy; group 3, two weeks; group 4, three weeks; and group 5, four weeks. After the fourth postoperative week, the animals were submitted to euthanasia and a sciatic nerve sample sent for histological analysis. Axons proximal and distal to the neurorrhaphy were counted with axonal regeneration index measurement. Results: We observed that the number of axons distal to neurorrhaphy increases with the amount of hyperbaric oxygen chamber exposure, the results were more expressive from the third week of treatment. However, the statistical analysis found no significant difference between the groups. Conclusion: The descriptive analysis suggests benefit of using hyperbaric oxygen chamber directly proportional to the time of therapy. The study, however, did not present statistically relevant results, probably due to the reduced sample size. Subsequent studies with more significant sampling would be of great value. Level of Evidence II, Prospective Comparative Study.

RESUMO Objetivo: Avaliar as alterações histológicas nos nervos periféricos após neurorrafia do nervo ciático de ratos, de acordo com o tempo de exposição ao tratamento com câmara hiperbárica de oxigênio. Métodos: Vinte e cinco ratos da raça Wistar foram divididos em cinco grupos conforme o tempo de exposição ao tratamento com câmara hiperbárica de oxigênio. O grupo 1 não recebeu o tratamento; o grupo 2 recebeu uma semana de terapia; o grupo 3, duas semanas; o grupo 4, três semanas; e o grupo 5, quatro semanas. Após quatro semanas de pós-operatório, os animais foram submetidos à eutanásia e uma amostra do nervo ciático foi enviada para análise histológica. Foram feitas contagens do número de axônios proximalmente e distalmente à neurorrafia, com medição do índice de regeneração axonal. Resultados: Observamos que o aumento do número de axônios distais à neurorrafia foi diretamente proporcional ao tempo de exposição à câmara hiperbárica de oxigênio, sendo mais expressivo a partir da terceira semana de tratamento. Entretanto, a análise estatística não encontrou diferença significativa entre os grupos. Conclusão: A análise descritiva sugere benefício do uso da câmara hiperbárica de oxigênio. Porém, devido à amostra reduzida, o estudo não apresentou resultados estatisticamente relevantes, sendo necessária a realização de estudos subsequentes com amostragem mais significativa. Nível de Evidência II, Estudo Prospectivo Comparativo.

Effect of Ginsenoside Rg1 on Biological Activity of Cryopreserved Schwann Cells and Nerve Regeneration After Allograft in Rat Sciatic Nerve / 中国实验方剂学杂志

ObjectiveTo observe the effect of ginsenoside Rg1 （G-Rg1） on the biological activity of cryopreserved Schwann cells （SCs） of the rat sciatic nerve and explore the feasibility of G-Rg1 in reducing the cryopreservation-induced injury in SCs. MethodBilateral sciatic nerves of SD rats were randomly divided into a fresh group， a blank group， and five G-Rg1 groups of different doses （1×10-7， 1×10-6， 1×10-5， 1×10-4， and 1×10-3 mol·L-1）. The nerves in the blank group and the G-Rg1 groups were preserved in liquid nitrogen solutions containing 0， 1×10-7， 1×10-6， 1×10-5， 1×10-4， and 1×10-3 mol·L-1 G-Rg1 for four weeks. The apoptosis of SCs was detected by TdT-mediated dUTP-biotin nick end labeling （TUNEL）/S100 immunofluorescence staining. The expression of cysteinyl aspartate-specific protease （Caspase）-9， Caspase-3， major histocompatibility complex （MHC）-Ⅰ， and MHC-Ⅱ was detected by Western blot. Subsequently， all nerves were cultured in the incubator at 37 ℃ with 5% CO2 for 7 days. The expression of glial cell line-derived neurotrophic factor （GDNF） and nerve growth factor （NGF） was detected by Western blot. In addition， the above cryopreserved nerves in the blank group and the 1×10-6， 1×10-5， and 1×10-4 mol·L-1 G-Rg1 groups were transplanted to the Wistar rats by allografting （blank transplantation group and the 1×10-6， 1×10-5， and 1×10-4 mol·L-1 G-Rg1 transplantation groups）， and fresh sciatic nerve allograft and isograft control group were set up. Sixteen weeks after transplantation， compound muscle action potential （CMAP） and nerve conduction velocity （NCV） were measured by electrophysiology. Nerve filament （NF）200 immunofluorescence staining， transmission electron microscopy， and toluidine blue staining were used to analyze the histology of the regenerated nerves. ResultCompared with the fresh group， the blank group and the G-Rg1 groups showed increased expression of Caspase-9， Caspase-3， and the apoptosis of SCs （P<0.05，P<0.01） and decreased expression of GDNF， NGF， MHC-Ⅰ， and MHC-Ⅱ （P<0.01）. Compared with the results in the blank group， the expression of Caspase-9 and Caspase-3 decreased in the 1×10-7， 1×10-6， 1×10-5，1×10-4 mol·L-1 G-Rg1 groups （P<0.01）， and the apoptosis of SCs was reduced in the 1×10-7-1×10-4 mol·L-1 G-Rg1 groups（P<0.05，P<0.01） and increased in the 1×10-3 mol·L-1 group （P<0.05）， while the expression of GDNF and NGF increased in the 1×10-7， 1×10-6， 1×10-5，1×10-4 mol·L-1 G-Rg1 groups and decreased in the 1×10-3 mol·L-1 group （P<0.05）. There was no statistical significance in the expression of MHC-Ⅰ and MHC-Ⅱ between the blank group and the G-Rg1 groups. Compared with the 1×10-7 mol·L-1 and 1×10-3 mol·L-1 G-Rg1 groups， the 1×10-6 1×10-5， 1×10-4 mol·L-1 G-Rg1 groups showed decreased expression of Caspase-3 and the apoptosis of SCs （P<0.05，P<0.01） and increased expression of GDNF and NGF （P<0.05，P<0.01）. There was no statistical significance in MHC-Ⅰ and MHC-Ⅱ expression among G-Rg1 groups. Sixteen weeks after transplantation， compared with the isograft group， the blank transplantation group and the G-Rg1 transplantation groups showed decreased CMAP， NCV， myelin sheath thickness， and number of myelinated nerve fibers （P<0.01）， and the 1×10-6 and 1×10-4 mol·L-1 G-Rg1 transplantation groups showed decreased NF200 （P<0.01）. Compared with the allograft group， the blank transplantation group and the G-Rg1 transplantation groups showed increased CMAP， NCV， NF200， myelin sheath thickness， and number of myelinated nerve fibers （P<0.05，P<0.01）. Compared with the blank transplantation group， the G-Rg1 transplantation groups showed increased CMAP， NCV， NF200， myelin sheath thickness， and number of myelinated nerve fibers （P<0.05，P<0.01）. Among all groups of G-Rg1 transplantation， each index of the 1×10-5 mol·L-1 G-Rg1 transplantation group was superior to that of the 1×10-4 and 1×10-6 mol·L-1 G-Rg1 transplantation group （P<0.05）. ConclusionG-Rg1 at a certain centration can maintain the biological activity of cryopreserved SCs of rat sciatic nerve， alleviate the cryopreservation-induced injury of rat sciatic nerve， and promote nerve regeneration after allograft.

Effect of monosialotetrahexosylganglioside sodium treatment on neurological function, inflammatory factor and blood coagulation function in patients with traumatic brain injury / 中国基层医药

Objective:To investigate the effect of monosialotetrahexosylganglioside sodium treatment on neurological function, inflammatory factor, and blood coagulation function in patients with traumatic brain injury.Methods:The clinical data of 90 patients with traumatic brain injury who received treatment in Taizhou Central Hospital from February 2018 to May 2020 were retrospectively analyzed. These patients were divided into a control group ( n = 46) and an observation group ( n = 44) according to different treatment methods. The control group was given routine symptomatic treatment and the observation group was given monosialotetrahexosylganglioside sodium treatment based on routine symptomatic treatment. Remission rate, inflammatory factor level, the National Institutes of Health Stroke Scale score, Glasgow Outcome Scale score, and coagulation function were compared between the two groups at each time point. Results:At 3 days and 2 weeks post-surgery, neuropeptide Y in the observation group was (121.13 ± 12.68) ng/L and (68.52 ± 10.21) ng/L, tumor necrosis factor α was (96.15 ± 8.16) ng/L and (46.68 ± 5.95) ng/L, interleukin-6 was (231.26 ± 9.41) ng/L and (126.74 ± 12.23) ng/L, C-reactive protein was (47.52 ± 4.32) μg/L and (18.65 ± 1.32) μg/L, the National Institutes of Health Stroke Scale score was (20.12 ± 2.22) points and (17.67 ± 1.31) points. They were significantly lower than those in the control group [neuropeptide Y: (135.69 ± 15.42) ng/L, (79.36 ± 11.15) ng/L; tumor necrosis factor-α: (108.56 ± 10.13) ng/L, (69.33 ± 6.42) ng/L; interleukin-6: (264.13 ± 10.24) ng/L and (157.89 ± 12.13) ng/L; C-reactive protein: (65.19 ± 5.17) μg/L and (24.39 ± 3.45) μg/L; the National Institutes of Health Stroke Scale score: (24.56 ± 2.54) points and (20.39 ± 2.55) points] ( t3 days post-surgery = 4.88, 6.38, 15.83, 17.55, 8.81; t2 weeks post-surgery= 4.80, 17.33, 12.12, 10.33, 6.32, all P < 0.001). At 3 days and 2 weeks post-surgery, the Glasgow Outcome Scale score in the observation group was (3.65 ± 0.35) points and (4.65 ± 0.26) points, respectively, which was significantly higher than (3.15 ± 0.10) points and (4.11 ± 0.11) points in the control group ( t = 9.30, 12.93, both P < 0.05). At 3 days and 2 weeks post-surgery, fibrinogen in the observation group was (4.52 ± 0.39) g/L and (3.12 ± 0.10) g/L, thrombin time was (18.46 ± 2.95) seconds and (21.79 ± 2.45) seconds, prothrombin time was (12.42 ± 1.33) seconds and (15.79 ± 2.36) seconds, activated partial thromboplastin time was (34.59 ± 2.64) seconds and (38.98 ± 2.78) seconds, which were significantly superior to those in the control group [fibrinogen: (5.02 ± 0.13) g/L and (4.29 ± 0.16) g/L; thrombin time: (17.36 ± 1.56) seconds and (19.63 ± 1.62) seconds; prothrombin time: (10.69 ± 1.21) seconds and (13.26 ± 1.78) seconds; activated partial thromboplastin time: (32.16 ± 2.59) seconds and (35.69 ± 2.91) seconds] ( t3 days post-surgery = 8.23, 2.22, 6.46, 4.40; t2 weeks post-surgery = 41.38, 4.95, 5.75, 5.48, all P < 0.001). At 1 and 2 weeks post-surgery, the remission rate in the observation group was significantly higher than that in the control group ( χ2 = 4.75, 4.44, both P < 0.05). Conclusion:Monosialotetrahexosylganglioside sodium treatment for a traumatic brain injury can inhibit inflammatory reactions, improve blood coagulation and protect brain tissue.

Neuroprotection and neuroregeneration treatment strategy in non-arteritic anterior ischemic optic neuropathy / 中华实验眼科杂志

Non-arteritic anterior ischemic optic neuropathy (NAION) is a disease characterized by acute, painless visual acuity loss and visual field impairment, and there is still lack of unified and effective treatment.As new therapeutic strategies, neuroprotection and nerve regeneration have aroused wide public concern, which aim to prevent degeneration and death of neurons or establish a new neural circuit through inhibiting apoptosis pathway and inflammation, promoting axon growth and applying stem cells.Plenty of studies have applied the strategies to NAION patients or NAION animal models, which achieved certain success, but the limitations exist at the same time.For the sake of exploring practical therapies of NAION, researches on the neuroprotection and nerve regeneration strategies of NAION in recent years were reviewed in this article.

Recovery of motor function in rats with complete spinal cord injury following implantation of collagen/silk fibroin scaffold combined with human umbilical cord-mesenchymal stem cells

SUMMARY OBJECTIVE: This study aimed to assess the effect of the collagen/silk fibroin scaffolds seeded with human umbilical cord-mesenchymal stem cells on functional recovery after acute complete spinal cord injury. METHODS: The fibroin and collagen were mixed (mass ratio, 3:7), and the composite scaffolds were produced. Forty rats were randomly divided into the Sham group (without spinal cord injury), spinal cord injury group (spinal cord transection without any implantation), collagen/silk fibroin scaffolds group (spinal cord transection with implantation of the collagen/silk fibroin scaffolds), and collagen/silk fibroin scaffolds + human umbilical cord-mesenchymal stem cells group (spinal cord transection with the implantation of the collagen/silk fibroin scaffolds co-cultured with human umbilical cord-mesenchymal stem cells). Motor evoked potential, Basso-Beattie-Bresnahan scale, modified Bielschowsky's silver staining, and immunofluorescence staining were performed. RESULTS: The BBB scores in the collagen/silk fibroin scaffolds + human umbilical cord-mesenchymal stem cells group were significantly higher than those in the spinal cord injury and collagen/silk fibroin scaffolds groups (p<0.05 or p<0.01). The amplitude and latency were markedly improved in the collagen/silk fibroin scaffolds + human umbilical cord-mesenchymal stem cells group compared with the spinal cord injury and collagen/silk fibroin scaffolds groups (p<0.05 or p<0.01). Meanwhile, compared to the spinal cord injury and collagen/silk fibroin scaffolds groups, more neurofilament positive nerve fiber ensheathed by myelin basic protein positive structure at the injury site were observed in the collagen/silk fibroin scaffolds + human umbilical cord-mesenchymal stem cells group (p<0.01, p<0.05). The results of Bielschowsky's silver staining indicated more nerve fibers was observed at the lesion site in the collagen/silk fibroin scaffolds + human umbilical cord-mesenchymal stem cells group compared with the spinal cord injury and collagen/silk fibroin scaffolds groups (p<0.01, p< 0.05). CONCLUSION: The results demonstrated that the transplantation of human umbilical cord-mesenchymal stem cells on a collagen/silk fibroin scaffolds could promote nerve regeneration, and recovery of neurological function after acute spinal cord injury.

Claudin 14/15 play important roles in early wallerian degeneration after rat sciatic nerve injury / 中华创伤杂志(英文版)

PURPOSE@#Wallerian degeneration (WD) is an antegrade degenerative process distal to peripheral nerve injury. Numerous genes are differentially regulated in response to the process. However, the underlying mechanism is unclear, especially the early response. We aimed at investigating the effects of sciatic nerve injury on WD via CLDN 14/15 interactions in vivo and in vitro.@*METHODS@#Using the methods of molecular biology and bioinformatics analysis, we investigated the molecular mechanism by which claudin 14/15 participate in WD. Our previous study showed that claudins 14 and 15 trigger the early signal flow and pathway in damaged sciatic nerves. Here, we report the effects of the interaction between claudin 14 and claudin 15 on nerve degeneration and regeneration during early WD.@*RESULTS@#It was found that claudin 14/15 were upregulated in the sciatic nerve in WD. Claudin 14/15 promoted Schwann cell proliferation, migration and anti-apoptosis in vitro. PKCα, NT3, NF2, and bFGF were significantly upregulated in transfected Schwann cells. Moreover, the expression levels of the β-catenin, p-AKT/AKT, p-c-jun/c-jun, and p-ERK/ERK signaling pathways were also significantly altered.@*CONCLUSION@#Claudin 14/15 affect Schwann cell proliferation, migration, and anti-apoptosis via the β-catenin, p-AKT/AKT, p-c-jun/c-jun, and p-ERK/ERK pathways in vitro and in vivo. The results of this study may help elucidate the molecular mechanisms of the tight junction signaling pathway underlying peripheral nerve degeneration.

Neuroinflammation Mediates Faster Brachial Plexus Regeneration in Subjects with Cerebral Injury / 神经科学通报·英文版

Our previous investigation suggested that faster seventh cervical nerve (C7) regeneration occurs in patients with cerebral injury undergoing contralateral C7 transfer. This finding needed further verification, and the mechanism remained largely unknown. Here, Tinel's test revealed faster C7 regeneration in patients with cerebral injury, which was further confirmed in mice by electrophysiological recordings and histological analysis. Furthermore, we identified an altered systemic inflammatory response that led to the transformation of macrophage polarization as a mechanism underlying the increased nerve regeneration in patients with cerebral injury. In mice, we showed that, as a contributing factor, serum amyloid protein A1 (SAA1) promoted C7 regeneration and interfered with macrophage polarization in vivo. Our results indicate that altered inflammation promotes the regenerative capacity of the C7 nerve by altering macrophage behavior. SAA1 may be a therapeutic target to improve the recovery of injured peripheral nerves.