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Neuroscience Bulletin ; (6): 720-740, 2022.
Article in English | WPRIM | ID: wpr-939842


Enhancing remyelination after injury is of utmost importance for optimizing the recovery of nerve function. While the formation of myelin by Schwann cells (SCs) is critical for the function of the peripheral nervous system, the temporal dynamics and regulatory mechanisms that control the progress of the SC lineage through myelination require further elucidation. Here, using in vitro co-culture models, gene expression profiling of laser capture-microdissected SCs at various stages of myelination, and multilevel bioinformatic analysis, we demonstrated that SCs exhibit three distinct transcriptional characteristics during myelination: the immature, promyelinating, and myelinating states. We showed that suppressor interacting 3a (Sin3A) and 16 other transcription factors and chromatin regulators play important roles in the progress of myelination. Sin3A knockdown in the sciatic nerve or specifically in SCs reduced or delayed the myelination of regenerating axons in a rat crushed sciatic nerve model, while overexpression of Sin3A greatly promoted the remyelination of axons. Further, in vitro experiments revealed that Sin3A silencing inhibited SC migration and differentiation at the promyelination stage and promoted SC proliferation at the immature stage. In addition, SC differentiation and maturation may be regulated by the Sin3A/histone deacetylase2 (HDAC2) complex functionally cooperating with Sox10, as demonstrated by rescue assays. Together, these results complement the recent genome and proteome analyses of SCs during peripheral nerve myelin formation. The results also reveal a key role of Sin3A-dependent chromatin organization in promoting myelinogenic programs and SC differentiation to control peripheral myelination and repair. These findings may inform new treatments for enhancing remyelination and nerve regeneration.

Animals , Axons , Chromatin/metabolism , Gene Expression Profiling , Myelin Sheath/metabolism , Nerve Regeneration/physiology , Rats , Schwann Cells/metabolism , Sciatic Nerve/injuries
Article in Chinese | WPRIM | ID: wpr-928293


Spinal cord injury is a severe central nervous system disease, which will cause a series of complex pathophysiological changes and activate a variety of signaling pathways including Notch signaling. Studies have evidenced that activation of the Notch signaling pathway is not conducive to nerve repair and symptom improvement after spinal cord injury. Its mechanisms include inhibiting neuronal differentiation and axon regeneration, promoting reactive astrocyte proliferation, promoting M1 macrophage polarization and the release of proinflammatory factors, and inhibiting angiogenesis. Therefore, it has become a promising therapeutic strategy to inhibit Notch signal as a target in the treatment of spinal cord injury. In recent years, some researchers have used drugs, cell transplantation or genetic modification to regulate Notch signaling, which can promote the recovery of nerve function after spinal cord injury, thereby providing new treatment strategies for the treatment of spinal cord injury. This article will summarize the mechanism of Notch signaling pathway in spinal cord injury, and at the same time review the research progress in the treatment of spinal cord injury by modulating Notch signaling pathway in recent years, so as to provide new research ideas for further exploring new strategies for spinal cord injury.

Axons/metabolism , Cell Transplantation , Humans , Nerve Regeneration , Signal Transduction/genetics , Spinal Cord/metabolism , Spinal Cord Injuries/metabolism
Article in English | WPRIM | ID: wpr-929039


Carbon nanotube (CNT) composite materials are very attractive for use in neural tissue engineering and biosensor coatings. CNT scaffolds are excellent mimics of extracellular matrix due to their hydrophilicity, viscosity, and biocompatibility. CNTs can also impart conductivity to other insulating materials, improve mechanical stability, guide neuronal cell behavior, and trigger axon regeneration. The performance of chitosan (CS)/polyethylene glycol (PEG) composite scaffolds could be optimized by introducing multi-walled CNTs (MWCNTs). CS/PEG/CNT composite scaffolds with CNT content of 1%, 3%, and 5% (1%=0.01 g/mL) were prepared by freeze-drying. Their physical and chemical properties and biocompatibility were evaluated. Scanning electron microscopy (SEM) showed that the composite scaffolds had a highly connected porous structure. Transmission electron microscope (TEM) and Raman spectroscopy proved that the CNTs were well dispersed in the CS/PEG matrix and combined with the CS/PEG nanofiber bundles. MWCNTs enhanced the elastic modulus of the scaffold. The porosity of the scaffolds ranged from 83% to 96%. They reached a stable water swelling state within 24 h, and swelling decreased with increasing MWCNT concentration. The electrical conductivity and cell adhesion rate of the scaffolds increased with increasing MWCNT content. Immunofluorescence showed that rat pheochromocytoma (PC12) cells grown in the scaffolds had characteristics similar to nerve cells. We measured changes in the expression of nerve cell markers by quantitative real-time polymerase chain reaction (qRT-PCR), and found that PC12 cells cultured in the scaffolds expressed growth-associated protein 43 (GAP43), nerve growth factor receptor (NGFR), and class III β‍-tubulin (TUBB3) proteins. Preliminary research showed that the prepared CS/PEG/CNT scaffold has good biocompatibility and can be further applied to neural tissue engineering research.

Animals , Axons , Biocompatible Materials/chemistry , Chitosan/chemistry , Nanotubes, Carbon/chemistry , Nerve Regeneration , Polyethylene Glycols , Porosity , Rats , Tissue Engineering/methods , Tissue Scaffolds/chemistry
Arq. bras. neurocir ; 40(2): 152-158, 15/06/2021.
Article in English | LILACS | ID: biblio-1362205


There are four types of anastomoses between themedian and ulnar nerves in the upper limbs. It consists of crossings of axons that produce changes in the innervation of the upper limbs, mainly in the intrinsic muscles of the hand. The forearm has two anatomical changes ­ Martin-Gruber: branch originating close to the median nerve joining distally to the ulnar nerve; and Marinacci: branch originating close to the ulnar nerve and distally joining the median nerve. The hand also has two types of anastomoses, which are more common, and sometimes considered a normal anatomical pattern ­ Berrettini: Connection between the common digital nerves of the ulnar and median nerves; and Riche-Cannieu: anastomosis between the recurrent branch of the median nerve and the deep branch of the ulnar nerve. Due to these connection patterns, musculoskeletal disorders and neuropathies can be misinterpreted, and nerve injuries during surgery may occur, without the knowledge of these anastomoses. Therefore, knowledge of them is essential for the clinical practice. The purpose of the present review is to provide important information about each type of anastomosis of the median and ulnar nerves in the forearm and hand.

Arteriovenous Anastomosis/anatomy & histology , Ulnar Nerve/anatomy & histology , Median Nerve/anatomy & histology , Axons , Hand Joints/innervation , Forearm/innervation
Int. j. morphol ; 39(1): 179-185, feb. 2021. ilus
Article in English | LILACS-Express | LILACS | ID: biblio-1385323


SUMMARY: Despite the existence of a large amount of actin in the axons, the concentration F-actin was quite low in the myelinated axons and almost all the F-actin were located in the peripheries of the myelinated axons. Until now, the ultrastructural localization of F-actin has still not been reported in the myelinated axons, probably due to the lack of an appropriate detection method. In the present study, a phalloidin-based FITC-anti-FITC technique was adopted to investigate the subcellular localization of F-actin in the myelinated axons. By using this technique, F-actin is located in the outer and inner collars of myelinated cytoplasm surrounding the intermodal axon, the Schmidt-Lanterman incisures, the paranodal terminal loops and the nodal microvilli. In addition, the satellite cell envelope, which encapsulates the axonal initial segment of the peripheral sensory neuron, was also demonstrated as an F-actin-enriched structure. This study provided a hitherto unreported ultrastructural view of the F-actin in the myelinated axons, which may assist in understanding the unique organization of axonal actin cytoskeleton.

RESUMEN: A pesar de la existencia de una gran cantidad de actina en los axones, la concentración de F-actina era bastante baja en los axones mielinizados y casi la totalidad de F-actina se localizaba en las periferias de los axones mielinizados. A la fecha aún no se ha reportado la localización ultraestructural de F-actina en los axones mielinizados, probablemente debido a la falta de un método de detección apropiado. En el presente estudio, se adoptó una técnica FITC-anti-FITC basada en faloidina para investigar la localización subcelular de F-actina en los axones mielinizados. Mediante el uso de esta técnica, la F-actina se localiza en los collares externo e interno del citoplasma mielinizado que rodea el axón intermodal, a las incisiones de Schmidt-Lanterman,a las asas terminales paranodales y a las microvellosidades nodales. Además, la envoltura de la célula satélite, que encapsula el segmento axonal inicial de la neurona sensorial periférica, también se demostró como una estructura enriquecida con F-actina. Este estudio proporcionó una vista ultraestructural de la F-actina en los axones mielinizados, que puede ayudar a comprender la organización única del citoesqueleto de actina axonal.

Animals , Female , Rats , Axons/ultrastructure , Actins/ultrastructure , Myelin Sheath/ultrastructure , Microscopy, Electron
Article in Chinese | WPRIM | ID: wpr-921772


When ischemia or hemorrhagic stroke occurs, astrocytes are activated by a variety of endogenous regulatory factors to become reactive astrocytes. Subsequently, reactive astrocytes proliferate, differentiate, and migrate around the lesion to form glial scar with the participation of microglia, neuron-glial antigen 2(NG2) glial cells, and extracellular matrix. The role of glial scars at different stages of stroke injury is different. At the middle and late stages of the injury, the secreted chondroitin sulfate proteoglycan and chondroitin sulfate are the main blockers of axon regeneration and nerve function recovery. Targeted regulation of glial scars is an important pathway for neurological rehabilitation after stroke. Chinese medicine has been verified to be effective in stroke rehabilitation in clinical practice, possibly because it has the functions of promoting blood resupply, anti-inflammation, anti-oxidative stress, inhibiting cell proliferation and differentiation, and benign intervention in glial scars. This study reviewed the pathological process and signaling mechanisms of glial scarring after stroke, as well as the intervention of traditional Chinese medicine upon glial scar, aiming to provide theoretical reference and research evidence for developing Chinese medicine against stroke in view of targeting glial scarring.

Astrocytes , Axons/pathology , Cicatrix/pathology , Gliosis/pathology , Humans , Medicine, Chinese Traditional , Nerve Regeneration , Stroke/drug therapy
Article in Chinese | WPRIM | ID: wpr-879412


Perineuronal nets (PNNs) is a complex network composed of highly condensed extracellular matrix molecules surrounding neurons. It plays an important role in maintaining the performance of neurons and protecting them from harmful substances. However, after spinal cord injury, PNNs forms a physical barrier that surrounds the neuron and limits neuroplasticity, impedes axonal regeneration and myelin formation, and promotes local neuroinflammatory uptake. This paper mainly describes the composition and function of PNNs of neurons and its regulatory effects on axonal regeneration, myelin formation and neuroinflammation after spinal cord injury.

Axons , Extracellular Matrix , Humans , Nerve Regeneration , Neuronal Plasticity , Neurons , Spinal Cord , Spinal Cord Injuries
Chinese Medical Journal ; (24): 2710-2720, 2021.
Article in English | WPRIM | ID: wpr-921234


BACKGROUND@#Histological and functional recovery after peripheral nerve injury (PNI) is of significant clinical value as delayed surgical repair and longer distances to innervate terminal organs may account for poor outcomes. Low-intensity extracorporeal shock wave therapy (LiESWT) has already been proven to be beneficial for injured tissue recovery on various pathological conditions. The objective of this study was to explore the potential effect and mechanism of LiESWT on PNI recovery.@*METHODS@#In this project, we explored LiESWT's role using an animal model of sciatic nerve injury (SNI). Shockwave was delivered to the region of the SNI site with a special probe at 3 Hz, 500 shocks each time, and 3 times a week for 3 weeks. Rat Schwann cells (SCs) and rat perineurial fibroblasts (PNFs) cells, the two main compositional cell types in peripheral nerve tissue, were cultured in vitro, and LiESWT was applied through the cultured dish to the adherent cells. Tissues and cell cultures were harvested at corresponding time points for a reverse transcription-polymerase chain reaction, Western blotting, and immunofluorescence staining. Multiple groups were compared by using one-way analysis of variance followed by the Tukey-Kramer test for post hoc comparisons.@*RESULTS@#LiESWT treatment promoted the functional recovery of lower extremities with SNI. More nerve fibers and myelin sheath were found after LiESWT treatment associated with local upregulation of mechanical sensitive yes-associated protein (YAP)/transcriptional co-activator with a PDZ-binding domain (TAZ) signaling pathway. In vitro results showed that SCs were more sensitive to LiESWT than PNFs. LiESWT promoted SCs activation with more expression of p75 (a SCs dedifferentiation marker) and Ki67 (a SCs proliferation marker). The SCs activation process was dependent on the intact YAP/TAZ signaling pathway as knockdown of TAZ by TAZ small interfering RNA significantly attenuated this process.@*CONCLUSION@#The LiESWT mechanical signal perception and YAP/TAZ upregulation in SCs might be one of the underlying mechanisms for SCs activation and injured nerve axon regeneration.

Animals , Axons , Extracorporeal Shockwave Therapy , Nerve Regeneration , Peripheral Nerve Injuries/therapy , Rats , Schwann Cells , Sciatic Nerve , Signal Transduction
Neuroscience Bulletin ; (6): 1529-1541, 2021.
Article in English | WPRIM | ID: wpr-922669


The cerebellum is conceptualized as a processor of complex movements and is also endowed with roles in cognitive and emotional behaviors. Although the axons of deep cerebellar nuclei are known to project to primary thalamic nuclei, macroscopic investigation of the characteristics of these projections, such as the spatial distribution of recipient zones, is lacking. Here, we studied the output of the cerebellar interposed nucleus (IpN) to the ventrolateral (VL) and centrolateral (CL) thalamic nuclei using electrophysiological recording in vivo and trans-synaptic viral tracing. We found that IpN stimulation induced mono-synaptic evoked potentials (EPs) in the VL but not the CL region. Furthermore, both the EPs induced by the IpN and the innervation of IpN projections displayed substantial heterogeneity across the VL region in three-dimensional space. These findings indicate that the recipient zones of IpN inputs vary between and within thalamic nuclei and may differentially control thalamo-cortical networks.

Axons , Cerebellar Nuclei , Cerebellum , Thalamic Nuclei
Int. j. morphol ; 38(2): 505-512, abr. 2020. graf
Article in English | LILACS | ID: biblio-1056469


Sexual dimorphism exists at all levels of the nervous system. These sex differences could underlie genderrelated differences in behavior and neuropsychological function, as well as the gender differences in the prevalence of various mental disorders such as autism, attention deficit disorders, and schizophrenia. Myelination, on the other hand, is a unique cellular process that can have a dramatic impact on the structure and physiology of an axon and its surrounding tissue. The corpus callosum (CC) is the largest of the brain commissures, which connects the cerebral cortices of the two hemispheres, and provides interhemispheric connectivity for information transfer and processing between cortical regions. Variation in the axonal properties of CC will alter the interhemispheric connectivity. The CC consists of myelinated and unmyelinated axons, glial cells and blood vessels. Several functional studies have reported that the function of CC is associated with its axons density and myelination properties. The sexual dimorphism in the axonal content of the CC has always been controversial; hence, the aim of this study was to analyze the differences in axons' diameter and myelin sheath thickness of the CC between male and female rats. For this purpose, five pairs of adult male and female rats were perfused and the CC were removed and sectioned. Four sections from different subregions of the corpus callosum that represent the genu, anterior body, posterior body, and splenium of the CC were stained and electron microscopic images were captured using stereological guidelines. Later, the axons diameter and myelin sheath thickness for each subregion were calculated and compared between males and females. Our preliminary findings of the present study indicated region specific differences in the myelinated axon thickness and diameter in the CC between male and female rats.

El dimorfismo sexual existe en todos los niveles del sistema nervioso. Estas diferencias de sexo podrían ser la base de las diferencias de comportamiento y función neuropsicológica relacionadas con el sexo, así como las diferencias en la prevalencia de diversos trastornos mentales, como el autismo, los trastornos por déficit de atención y la esquizofrenia. La mielinización, por otro lado, es un proceso celular único que puede tener un impacto dramático en la estructura y fisiología de un axón y su tejido circundante. El cuerpo calloso (CC) es la mayor comisura cerebral, que conecta las cortezas cerebrales de ambos hemisferios, y proporciona la conectividad interhemisférica para la transferencia y el procesamiento de información entre regiones corticales. La variación en las propiedades axonales de CC alterará la conectividad interhemisférica. El CC consiste en axones mielinizados y no mielinizados, células gliales y vasos sanguíneos. Varios estudios funcionales han informado que la función de CC está asociada con la densidad de axones y las propiedades de mielinización. El dimorfismo sexual en el contenido axonal del CC siempre ha sido controvertido; por lo tanto, el objetivo de este estudio fue analizar las diferencias en el diámetro de los axones y el grosor de la vaina de mielina del CC entre ratas macho y hembra. Para este propósito, se perfundieron cinco pares de ratas macho y hembra adultas y se extrajeron y seccionaron las CC. Se tiñeron cuatro secciones de diferentes subregiones del cuerpo calloso que representan el genu, el cuerpo anterior, el cuerpo posterior y el esplenio y se capturaron imágenes de microscopía electrónicas utilizando referencias estereológicas. Posteriormente se calculó el diámetro de los axones y el grosor de la vaina de mielina para cada subregión y se compararon entre machos y hembras. Nuestros hallazgos preliminares del presente estudio indicaron diferencias específicas en el grosor y diámetro del axón mielinizado en el CC entre ratas macho y hembra.

Animals , Male , Female , Rats , Axons/ultrastructure , Sex Characteristics , Corpus Callosum/ultrastructure , Myelin Sheath/ultrastructure , Microscopy, Electron , Corpus Callosum/cytology
Rev. chil. neuro-psiquiatr ; 58(1): 50-60, mar. 2020.
Article in Spanish | LILACS | ID: biblio-1115470


Resumen Introducción: Este artículo presenta avances de la medicina regenerativa y la ingeniería de tejidos orientados a la regeneración de neuronas, de axones y nervios. Revisamos las técnicas que existen actualmente, las más utilizas o prometedoras, en la búsqueda de avances para regenerar este tipo de tejidos. Objetivo: Con esta revisión queremos describir el conocimiento actual sobre la medicina regenerativa y la ingeniería de tejidos orientados a la reparación de tejidos nerviosos. Metodología: Para desarrollar esta revisión se realizó una búsqueda de artículos entre los años 2007 y el 2018, la búsqueda se restringió a los artículos que incluyeran dentro de sus palabras clave; Ingeniería tisular, Enfermedades Neurodegenerativas, Medicina regenerativa, Regeneración axonal, Regeneración neuronal, Regeneración tisular. Con el fin de seleccionar los artículos más adecuados, se realizó una búsqueda exhaustiva en bases de datos como Springer, Medline Ebsco y Science direct. Conclusiones: Se mencionan técnicas como implantación de injertos, terapia celular y terapia molecular e implantación de andamios 3D para regeneración de neuronas, axones y nervios; a partir de esta revisión pudimos observar que estas técnicas en su mayoría funcionan mejor cuando se combinan, aprovechando las ventajas de cada una para promover la regeneración de los diferentes tejidos nerviosos.

Introduction: This article presents advances in regenerative medicine aimed at the regeneration of nervous and neuronal tissue, focusing on regeneration of neurons, axons and nerve regeneration. We will review the techniques that currently exist, the most used or promising, in the search of advances to regenerate this type of tissues. Objective: With this review we want to describe the current knowledge about regenerative medicine and tissue engineering oriented to nerve tissue repair. Methodology: To carry out this review, a search of articles was carried out between 2007 and 2018, the search was restricted to the articles that they included within their keywords; Tissue Engineering, Neurodegenerative Diseases, Regenerative Medicine, Axonal Regeneration, Neuronal Regeneration, Tissue Regeneration. We will mention about techniques such as implantation. Conclusions: with this review we could observe that most of the mentioned techniques work better when combined, taking advantage of each one to promote a greater regeneration of the different tissues.

Axons , Neurodegenerative Diseases , Tissue Engineering , Cell- and Tissue-Based Therapy , Nerve Tissue , Neurons
Article in Chinese | WPRIM | ID: wpr-828540


The intrinsic regrowth ability of injured neurons is essential for axon regeneration and functional recovery. Recently, numerous intrinsic pathways that regulate axon regeneration have been discovered, among which the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway are arguably the best characterized examples. MAPK signaling pathway is involved in multiple processes including sensing injury signals, initiating and promoting axonal regrowth through regulating cytoskeleton dynamics and protein synthesis. The PI3K/Akt signaling pathway regulates axon regeneration mainly through gene transcription and translation. Combinatory manipulation of multiple regeneration-promoting signals can further improve the extend of axonal regrowth. This paper summarizes current progresses on axon regeneration studies in various organisms and discuss their potentials in promoting functional recovery .

Axons , Physiology , Nerve Regeneration , Neurons , Phosphatidylinositol 3-Kinases , Regeneration , Signal Transduction
Rev. chil. neuro-psiquiatr ; 57(1): 64-69, mar. 2019. ilus
Article in Spanish | LILACS | ID: biblio-1003679


Resumen Antecedentes: El virus linfotrópico T tipo I (HTLV-I) origina la paraparesia espástica tropical (PET) en el 3% de los infectados, afectando predominante mujeres. Excepcionalmente la PET puede asociar un síndrome vestibular central y atrofia cerebelosa. Propósito: Presentar un nuevo y excepcional caso de paraparesia espástica y atrofia cerebelosa. Sugerir una interpretación patogénica del predominio femenino en esta patología Paciente: Mujer de 20 años de talla baja y menuda, infectada con HTLV-I durante la lactancia. Aproximadamente a los 15 años inició un síndrome ataxo-espástico progresivo, con grave alteración de la marcha, posteriormente agregó daño cognitivo y atrofia cerebelosa en la RM. Se constató a su ingreso una elevada carga viral y altos niveles de proteína Tax. Fue tratada con 4 mg betametasona diarios durante 10 días, que mejoraron la marcha. Conclusión: La PET es una axonopatía de la vía motora central, originada por la crónica perturbación del transporte axoplásmico, atribuible a la presencia de elevados niveles de la proteína Tax del virus. Circunstancialmente este aumento de Tax logra dañar axones del centro oval (deterioro cognitivo) o del vermis cerebeloso (síndrome vestibular central). La PET afecta mayoritariamente a mujeres 3:1, prevalencia que hace aparecer a las mujeres con una mayor vulnerabilidad en su SNC. Sin embargo, esta aparente minusvalía, sería debida a un aumento en la concentración de Tax en el SNC de ellas, causado por la adversa relación entre peso corporal y cantidad absoluta de Tax, que fue evidente en nuestra paciente, quien dio la clave para esta hipótesis.

Background: Lymphotropic Virus Type I (HTLV-I) causes Tropical Spastic Paraparesis (PET) in 3% of infected patients; in whom have been described exceptionally associated a central vestibular syndrome and cerebellar atrophy. Those alterations of CNS are predominating in women. Purpose: To present a new case of the exceptional form of spastic paraparesis and cerebellar atrophy. To suggest a pathogenic interpretation of female predominance in this pathology Patient: A 20-year-old woman of small size, infected with HTLV-I during lactation. Approximately at 15 years of age he started a progressive ataxo-spastic syndrome, later cognitive damage and cerebellar atrophy were added. Upon admission, high viral load and high levels of Tax protein, leukemoid lymphocytes and Sicca syndrome were observed. Conclusion: PET is an axonopathy of the central motor pathway, originated by a chronic disturbance of axoplasmic transport, attributable to the action of elevated levels of Tax protein in the CNS. In addition axons of the oval center (cognitive impairment) or the cerebellar vermis (central vestibular syndrome) are occasionally damaged. Although PET mainly affects 3: 1 women, this prevalence increases in accordance with the increase of neurological damage. The apparent greater vulnerability of the CNS in women would be due to the higher concentration of Tax in the CNS of them, originated in the adverse relationship between body weight and absolute amount of Tax, which was evident in our patient, who gave the key to this hypothesis.

Humans , Female , Adult , Atrophy , Axons , Syndrome , Human T-lymphotropic virus 1 , Paraparesis, Tropical Spastic
Int. j. morphol ; 37(1): 349-357, 2019. graf
Article in English | LILACS | ID: biblio-990050


SUMMARY: The aim of this study was to determine the possible regenerative effect of neuroectodermal stem cells on the ultrastructural, and locomotor function resulting from compressed injury to the spinal cord in a rat model. Forty male rats were divided into control and sham groups (20 rats each). Compressed spinal cord injured (CSCI) were forty rats which subdivided equally into: untreated, treated by neuroectodermal stem cells (NESCs). After four weeks, all rats in different groups were scarified, samples were taken from central, cranial, and caudal to the site of spinal cord injury. Specimens were prepared for light and electron microscopic examination. The number of remyelinated axons in central, cranial and caudal regions to the injured spinal cord after transplantation of NESCs was counted. The open field test assessed the locomotor function. Results revealed that compressed spinal cord injury resulted in loss and degeneration of numerous nerve fibers, myelin splitting and degeneration of mitochondria. Four weeks after transplantation of NESCs regenerated axons were noticed in cranial and central sites, while degenerate axons were noticed caudal to the lesion. Number of remyelinated axons was significantly increased in both central and cranial to the site of spinal cord injury in comparison with caudal region which had the least number of remyelinated axons. Transplantation of NESCs improved significantly the locomotor functional activity In conclusion, neuroectodermal stem cells transplantation ameliorated the histopathological and ultrastructural changes, and improved the functional locomotor activity in CSCI rat.

RESUMEN: El objetivo de este estudio fue determinar el posible efecto regenerativo de las células madre neuroectodérmicas en la función ultraestructural y locomotora de una lesión comprimida en la médula espinal en un modelo de rata. Cuarenta ratas macho se dividieron en grupos control y sham (20 ratas en cada grupo). La médula espinal lesionada (CSCI) tenía cuarenta ratas que se subdividieron de igual forma en los siguientes grupos: no tratadas, tratadas con células madre neuroectodérmicas (NESCs). Al término de cuatro semanas, todas las ratas en los diferentes grupos fueron escarificadas, se tomaron muestras de las áreas central, craneal y caudal en relación al sitio de la lesión de la médula espinal. Las muestras fueron preparadas para examen microscópico de luz y electrónica. Se contó el número de axones remielinizados en las regiones central, craneal y caudal de la médula espinal lesionada después del trasplante de NESCs. La prueba de campo abierto evaluó la función locomotora. Los resultados revelaron que la lesión de la médula espinal comprimida provocó la pérdida y degeneración de numerosas fibras nerviosas, la división de la mielina y la degeneración de las mitocondrias. Cuatro semanas después del trasplante de NESCs, se notaron axones regenerados en los sitios craneales y centrales, mientras que los axones degenerados se notaron caudal a la lesión. El número de axones remielinizados aumentó significativamente tanto en el centro como en el cráneo hasta el sitio de la lesión de la médula espinal en comparación con la región caudal que tenía el menor número de axones remielinizados. El trasplante de NESCs mejoró significativamente la actividad funcional locomotora. En conclusión, el trasplante de células madre neuroectodérmicas mejoró los cambios histopatológicos y ultraestructurales, y mejoró la actividad locomotora funcional en la rata CSCI.

Animals , Female , Rats , Spinal Cord Injuries/therapy , Stem Cell Transplantation/methods , Nerve Regeneration/physiology , Spinal Cord/ultrastructure , Axons , Motor Activity
Experimental Neurobiology ; : 172-182, 2019.
Article in English | WPRIM | ID: wpr-739545


Rheb (Ras homolog enriched in the brain) is a small GTPase protein that plays an important role in cell signaling for development of the neocortex through modulation of mTORC1 (mammalian-target-of-rapamycin-complex-1) activity. mTORC1 is known to control various biological processes including axonal growth in forming complexes at the lysosomal membrane compartment. As such, anchoring of Rheb on the lysosomal membrane via the farnesylation of Rheb at its cysteine residue (C180) is required for its promotion of mTOR activity. To test the significance of Rheb farnesylation, we overexpressed a farnesylation mutant form of Rheb, Rheb C180S, in primary rat hippocampal neurons and also in mouse embryonic neurons using in utero electroporation. Interestingly, we found that Rheb C180S maintained promotional effect of axonal elongation similar to the wild-type Rheb in both test systems. On the other hand, Rheb C180S failed to exhibit the multiple axon-promoting effect which is found in wild-type Rheb. The levels of phospho-4EBP1, a downstream target of mTORC1, were surprisingly increased in Rheb C180S transfected neurons, despite the levels of phosphorylated mTOR being significantly decreased compared to control vector transfectants. A specific mTORC1 inhibitor, rapamycin, also could not completely abolish axon elongation characteristics of Rheb C180S in transfected cells. Our data suggests that Rheb in a non-membrane compartment can promote the axonal elongation via phosphorylation of 4EBP1 and through an mTORC1-independent pathway.

Animals , Axons , Biological Phenomena , Cysteine , Electroporation , GTP Phosphohydrolases , Hand , Membranes , Mice , Neocortex , Neurons , Phosphorylation , Prenylation , Protein Prenylation , Rats , Sirolimus , TOR Serine-Threonine Kinases
Experimental Neurobiology ; : 119-129, 2019.
Article in English | WPRIM | ID: wpr-739526


Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a progressive degenerative white matter disorder caused by mutations in the tyrosine kinase domain of the CSF1R gene. ALSP is often misdiagnosed as other diseases due to its rarity and various clinical presentations such as Parkinsonism, pyramidal signs, cognitive impairment and/or psychiatric symptoms. We describe an autopsy case of ALSP with a CSF1R mutation. A 61-year-old woman presented insidious-onset gait difficulty for 12 years since her age of 49, and premature ovarian failure since her age of 35. At initial hospital visit, brain magnetic resonance imaging revealed hydrocephalus. Initially, Parkinson's syndrome was diagnosed, and she was prescribed L-dopa/carbidopa because of spasticity and rigidity of extremities, which had worsened. Subsequently, severe neuropsychiatric symptoms and cognitive impairment developed and radiologically, features of leukoencephalopathy or leukodystrophy were detected. She showed a down-hill course and died, 12 years after initial diagnosis. At autopsy, the brain showed severe symmetric atrophy of bilateral white matter, paper-thin corpus callosum, thin internal capsule, and marked hydrocephalus. Microscopically, diffuse loss of white matter, relatively preserved subcortical U-fibers, and many eosinophilic bulbous neuroaxonal spheroids were noted, but there was no calcification. Pigmented glia with brown cytoplasmic pigmentation were readily found in the white matter, which were positive for Periodic acid-Schiff, p62, and CD163 stains, but almost negative for CD68. Whole-exome and Sanger sequencing revealed a CSF1R mutation (c.2539G>A, p.Glu847Lys) which was reported in prior one ALSP case. This example demonstrates that ALSP could be associated with premature ovarian failure.

Atrophy , Autopsy , Axons , Brain , Cognition Disorders , Coloring Agents , Corpus Callosum , Cytoplasm , Diagnosis , Eosinophils , Extremities , Female , Gait , Humans , Hydrocephalus , Internal Capsule , Leukoencephalopathies , Magnetic Resonance Imaging , Middle Aged , Muscle Spasticity , Neuroglia , Parkinsonian Disorders , Pigmentation , Primary Ovarian Insufficiency , Protein-Tyrosine Kinases , White Matter
Article in English | WPRIM | ID: wpr-739331


Recovery from central nervous system (CNS) injury, such as stroke or spinal cord injury (SCI), largely depends on axonal regeneration, and the neuronal and glial cells plasticity in the lesioned tissue. The lesioned tissue following CNS injury forms a scar that is composed of astrocytes and mixed with connective tissues. At the glial scar, the regenerating axon forms dystrophic endbulbs which do not regenerate and grow beyond the glial scar without a suitable environment. Along with the astrocytes, microglia are also suspected of being involved in necrotic and apoptotic neuronal cell death and the early response to axonal damage in CNS injury. The inflammatory response, a major component of secondary injury and controlled by the microglia, plays a pivotal role in nerve injury and control the regenerative response. As a result, it is very important to control the glial cell function in order to assure the recovery of the CNS injury. Studies have suggested that agmatine, a L-arginine derived primary amine, is a potential modulator of glial cell function after CNS injuries. Agmatine was found to possess anti-inflammatory and neuroprotective characteristics that benefited the rehabilitation process following CNS injury. In this review, we will discuss the effect of agmatine on glial cells in the process of recovery after CNS injury.

Agmatine , Arginine , Astrocytes , Axons , Cell Death , Central Nervous System , Cicatrix , Connective Tissue , Microglia , Neuroglia , Neurons , Plastics , Regeneration , Rehabilitation , Spinal Cord Injuries , Stroke
Article in English | WPRIM | ID: wpr-764369


BACKGROUND AND PURPOSE: Diagnosing small-fiber neuropathy (SFN) is challenging because there is no gold-standard test and few diagnostic tests. This study investigated the clinical symptom profile and its associations with the results of quantitative sensory testing (QST) and the quantitative sudomotor axon reflex test (QSART) as well as the quality of life (QOL) in patients with clinically suspected SFN. METHODS: This study involved 63 patients with clinically suspected length-dependent SFN. Assessments were performed using QST, QSART, SFN Symptoms Inventory Questionnaire, Neuropathic Pain Symptom Inventory, ‘Sirim’ frequency and ‘Sirim’ (cold) pain severity, and 36-item Short-Form Health Survey. Multiple logistic and linear regression analyses were performed to predict risk factors for QST or QSART abnormalities and QOL, respectively. RESULTS: ‘Sirim’ and ‘Sirim’ pain was the most-common (84%) and the most-severe complaint (mean score of 6.3 on a numerical rating scale ranging from 0 to 10) in patients with clinically suspected SFN. The findings of QST [cold detection threshold (CDT)] and QSART were abnormal in 71% (n=45/57) and 62% (n=39/56) of the patients, respectively. An abnormal CDT was correlated with more-severe stabbing pain (odds ratio=2.23, 95% CI=1.02–4.87, p=0.045). Restless-leg symptoms (β=−7.077) and pressure-evoked pain (β=−5.034) were independent predictors of the physical aspects of QOL. CONCLUSIONS: ‘Sirim’ pain, similar to cold pain, should be considered a major neuropathic pain in SFN. Among pain characteristics, stabbing pain of a spontaneous paroxysmal nature may be more pronounced in the setting of dysfunctional Aδ fibers with functional autonomic C fibers.

Axons , Diagnostic Tests, Routine , Erythromelalgia , Health Surveys , Humans , Linear Models , Nerve Fibers, Unmyelinated , Neuralgia , Quality of Life , Reflex , Risk Factors