RESUMEN

Amyotrophic lateral sclerosis (ALS) is a fatal illness characterized by progressive motor neuron degeneration. Conventional therapies for ALS are based on treatment of symptoms, and the disease remains incurable. Molecular mechanisms are unclear, but studies have been pointing to involvement of glia, neuroinflammation, oxidative stress, and glutamate excitotoxicity as a key factor. Nowadays, we have few treatments for this disease that only delays death, but also does not stop the neurodegenerative process. These treatments are based on glutamate blockage (riluzole), tyrosine kinase inhibition (masitinib), and antioxidant activity (edaravone). In the past few years, plant-derived compounds have been studied for neurodegenerative disorder therapies based on neuroprotection and glial cell response. In this review, we describe mechanisms of action of natural compounds associated with neuroprotective effects, and the possibilities for new therapeutic strategies in ALS.

Asunto(s)

Esclerosis Amiotrófica Lateral , Humanos , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/complicaciones , Riluzol , Edaravona/uso terapéutico , Ácido Glutámico , Fitoquímicos/uso terapéutico

RESUMEN

ABSTRACT Introduction: Paraplegia may develop as a result of spinal cord ischemia-reperfusion injury in patients who underwent thoracoabdominal aortic surgery. The objective of this research is to determine the neuroprotective effects of ginsenoside Rd pretreatment in a rat model of spinal cord ischemia-reperfusion injury. Methods: Sprague-Dawley rats (n=36) were randomly assigned to three groups. The sham (n=12) and control (n=12) groups received normal saline orally. The Rd group (n=12) received ginsenoside Rd (100 mg/kg) orally 48 hours before the induction of spinal cord ischemia. Spinal cord ischemia was induced by aortic occlusion using a Fogarty balloon catheter in the Rd and control groups. A neurological assessment according to the motor deficit index and a histological evaluation of the spinal cord were performed. To evaluate the antioxidant activity of ginsenoside Rd, malondialdehyde levels and superoxide dismutase activity were determined. Further, the tissue levels of tumor necrosis factor-alpha and interleukin-1 beta were measured. Results: The Rd group showed significantly lower motor deficit index scores than did the control group throughout the entire experimental period (P<0.001). The Rd group demonstrated significantly greater numbers of normal motor neurons than did the control group (P=0.039). The Rd group exhibited decreased malondialdehyde levels (P<0.001) and increased superoxide dismutase activity (P=0.029) compared to the control group. Tumor necrosis factor-alpha and interleukin-1 beta tissue levels were significantly decreased in the Rd group (P<0.001). Conclusion: Ginsenoside Rd pretreatment may be a promising treatment to prevent ischemia-reperfusion injury in patients who undergo thoracoabdominal aortic surgery.

RESUMEN

INTRODUCTION: Paraplegia may develop as a result of spinal cord ischemia-reperfusion injury in patients who underwent thoracoabdominal aortic surgery. The objective of this research is to determine the neuroprotective effects of ginsenoside Rd pretreatment in a rat model of spinal cord ischemia-reperfusion injury. METHODS: Sprague-Dawley rats (n=36) were randomly assigned to three groups. The sham (n=12) and control (n=12) groups received normal saline orally. The Rd group (n=12) received ginsenoside Rd (100 mg/kg) orally 48 hours before the induction of spinal cord ischemia. Spinal cord ischemia was induced by aortic occlusion using a Fogarty balloon catheter in the Rd and control groups. A neurological assessment according to the motor deficit index and a histological evaluation of the spinal cord were performed. To evaluate the antioxidant activity of ginsenoside Rd, malondialdehyde levels and superoxide dismutase activity were determined. Further, the tissue levels of tumor necrosis factor-alpha and interleukin-1 beta were measured. RESULTS: The Rd group showed significantly lower motor deficit index scores than did the control group throughout the entire experimental period (P<0.001). The Rd group demonstrated significantly greater numbers of normal motor neurons than did the control group (P=0.039). The Rd group exhibited decreased malondialdehyde levels (P<0.001) and increased superoxide dismutase activity (P=0.029) compared to the control group. Tumor necrosis factor-alpha and interleukin-1 beta tissue levels were significantly decreased in the Rd group (P<0.001). CONCLUSION: Ginsenoside Rd pretreatment may be a promising treatment to prevent ischemia-reperfusion injury in patients who undergo thoracoabdominal aortic surgery.

Asunto(s)

Fármacos Neuroprotectores , Daño por Reperfusión , Isquemia de la Médula Espinal , Ratas , Animales , Fármacos Neuroprotectores/farmacología , Interleucina-1beta , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa , Daño por Reperfusión/prevención & control , Superóxido Dismutasa , Malondialdehído , Modelos Animales de Enfermedad

RESUMEN

This report describes 2 events of degenerative myelopathy in 4- to 27-day-old piglets, with mortality rates reaching 40%. Sows were fed rations containing low levels of pantothenic acid. Piglets presented with severe depression, weakness, ataxia, and paresis, which were more pronounced in the pelvic limbs. No significant gross lesions were observed. Histologically, there were degeneration and necrosis of neurons in the spinal cord, primarily in the thoracic nucleus in the thoracic and lumbar segments, and motor neurons in nucleus IX of the ventral horn in the cervical and lumbar intumescence. Minimal-to-moderate axonal and myelin degeneration was observed in the dorsal funiculus of the spinal cord and in the dorsal and ventral nerve roots. Immunohistochemistry demonstrated depletion of acetylcholine neurotransmitters in motor neurons and accumulation of neurofilaments in the perikaryon of neurons in the thoracic nucleus and motor neurons. Ultrastructurally, the thoracic nucleus neurons and motor neurons showed dissolution of Nissl granulation. The topographical distribution of the lesions indicates damage to the second-order neurons of the spinocerebellar tract, first-order axon cuneocerebellar tract, and dorsal column-medial lemniscus pathway as the cause of the conscious and unconscious proprioceptive deficit, and damage to the alpha motor neuron as the cause of the motor deficit. Clinical signs reversed and no new cases occurred after pantothenic acid levels were corrected in the ration, and piglets received parenteral administration of pantothenic acid. This study highlights the important and practical use of detailed neuropathological analysis to refine differential diagnosis.

Asunto(s)

Enfermedades de la Médula Espinal , Enfermedades de los Porcinos , Animales , Porcinos , Femenino , Ácido Pantoténico/metabolismo , Médula Espinal/patología , Neuronas/patología , Bulbo Raquídeo/patología , Enfermedades de la Médula Espinal/veterinaria , Enfermedades de la Médula Espinal/metabolismo , Enfermedades de la Médula Espinal/patología , Enfermedades de los Porcinos/patología

RESUMEN

Non-cell-autonomous mechanisms contribute to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), in which astrocytes release unidentified factors that are toxic to motoneurons (MNs). We report here that mouse and patient iPSC-derived astrocytes with diverse ALS/FTD-linked mutations (SOD1, TARDBP, and C9ORF72) display elevated levels of intracellular inorganic polyphosphate (polyP), a ubiquitous, negatively charged biopolymer. PolyP levels are also increased in astrocyte-conditioned media (ACM) from ALS/FTD astrocytes. ACM-mediated MN death is prevented by degrading or neutralizing polyP in ALS/FTD astrocytes or ACM. Studies further reveal that postmortem familial and sporadic ALS spinal cord sections display enriched polyP staining signals and that ALS cerebrospinal fluid (CSF) exhibits increased polyP concentrations. Our in vitro results establish excessive astrocyte-derived polyP as a critical factor in non-cell-autonomous MN degeneration and a potential therapeutic target for ALS/FTD. The CSF data indicate that polyP might serve as a new biomarker for ALS/FTD.

Asunto(s)

Esclerosis Amiotrófica Lateral , Demencia Frontotemporal , Esclerosis Amiotrófica Lateral/genética , Animales , Astrocitos , Proteína C9orf72/genética , Medios de Cultivo Condicionados/farmacología , Demencia Frontotemporal/genética , Humanos , Ratones , Neuronas Motoras , Polifosfatos

RESUMEN

Purpose: Various postoperative protocols have been proposed to improve outcomes and accelerate nerve regeneration. Recently, the use of physical exercise in a post-surgical neurorraphy procedure has shown good results when started early. We experimentally investigated the hypothesis that post-operative exercise speeds up results and improves clinical and morphologic parameters. Methods: Isogenic rats were randomly divided into four groups: 1 SHAM; 2 SHAM submitted to the exercise protocol (EP); 3 Grafting of the sciatic nerve; and 4 Grafting of the sciatic nerve associated with the EP. The EP was based on aerobic activities with a treadmill, with a progressive increase in time and intensity during 6 weeks. The results were evaluated by the sciatic functional index (SFI), morphometric and morphologic analysis of nerve distal to the lesion, and the number of spinal cord motor neurons, positive to the marker Fluoro-Gold (FG), captured retrogradely through neurorraphy. Results: Functional analysis (SFI) did not show a statistical difference between the group grafted with (­50.94) and without exercise (-65.79) after 90 days. The motoneurons count (Spinal cord histology) also showed no diference between these groups (834.5 × 833 respectively). Although functionally there is no difference between these groups, morphometric study showed a greater density (53.62) and larger fibers (7.762) in GRAFT group. When comparing both operated groups with both SHAM groups, all values were much lower. Conclusions: The experimental model that this aerobic treadmill exercises protocol did not modify nerve regeneration after sciatic nerve injury and repair with nerve graft.

Asunto(s)

Animales , Ratas , Nervio Peroneo , Neuropatías Peroneas/terapia , Prueba de Esfuerzo , Regeneración Nerviosa , Hipertensión/veterinaria , Neuronas Motoras/fisiología

RESUMEN

Advanced age and amyotrophic lateral sclerosis (ALS) are both associated with a loss of motor neurons resulting in muscle fiber atrophy and muscle weakness. Aging associated muscle fiber atrophy and weakening is termed sarcopenia, but the association with motor neuron loss is not as clearly established as in ALS, probably related to the prolonged time course of aging-related changes. Although aging and ALS effects on limb muscle strength and neuromotor performance are serious, such effects on the diaphragm muscle can be life threatening. Converging evidence indicates that larger phrenic motor neurons, innervating more fatigable type IIx and/or IIb diaphragm muscle fibers (fast fatigue intermediate, FInt and fast fatigable, FF motor units) are more susceptible to degeneration with both aging and ALS compared to smaller phrenic motor neurons innervating type I and IIa diaphragm muscle fibers (slow and fast fatigue resistant motor units, respectively). The etiology of ALS and age-related loss of motor neurons appears to involve mitochondrial function and neuroinflammation, both chronic and acute exacerbation. How mitochondrial dysfunction, neuroinflammation and motor neuron size intersect is the focus of continuing investigation.

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La edad avanzada y la esclerosis lateral amiotrofica (ALS) están asociadas con una pérdida de neuronas motoras que produce atrofia de las fibras musculares y debilidad muscular. El envejecimiento asociado a atrofia y debilitamiento de las fibras musculares se denomina sarcopenia, pero la asociación con la pérdida de neuronas motoras no está tan claramente establecida como en la ALS, hecho probablemente relacionado con el curso prolongado de los cambios que ocurren durante el envejecimiento. Aunque el envejecimiento y los efectos de la ALS sobre la fuerza muscular de las extremidades y el rendimiento neuromotor son graves, tales efectos sobre el músculo del diafragma pueden ser potencialmente mortales. La evidencia convergente indica que las neuronas motoras frénicas más grandes, que inervan fibras musculares de diafragma tipo IIx y / o IIb más fatigables (unidades motoras FF de fatiga rápida intermedia, FInt y fatigable rápida) son más susceptibles a la degeneración con el envejecimiento y la ALS en comparación con las neuronas motoras más pequeñas del nervio frénico que inervan las fibras musculares del diafragma tipo I y IIa (unidades motoras lentas y rápidas resistentes a la fatiga, respectivamente). La etiología de la ALS y la pérdida de neuronas motoras relacionadas con la edad parece implicar la función mitocondrial y la neuroinflamación, tanto la exacerbación crónica como la aguda. La forma en que se cruzan la disfunción mitocondrial, la neuroinflamación y el tamaño de la neurona motora es el foco de una continua investigación.

RESUMEN

In vitro modeling of neurodegenerative diseases is now possible by using patient-derived induced pluripotent stem cells (iPS). Through them, it is nowadays conceivable to obtain human neurons and glia, and study diseases cellular and molecular mechanisms, an attribute that was previously unavailable to any human condition. Amyotrophic lateral sclerosis (ALS) is one of the diseases that has gained a rapid advance with iPS technology. By differentiating motor neurons from iPS cells of ALS- patients, we are studying the mechanisms underlying ALS- disease onset and progression. Here, we introduce a cellular platform to help maintain longevity of ALS iPS-motor neurons, a cellular feature relevant for most late-onset human diseases. Long term cultures of patient-derived iPS cells might prove to be critical for the development of personalized-drugs.

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Actualmente es posible modelar in vitro enfermedades neurodegenerativas humanas mediante el uso de células madre pluripotentes inducidas (iPS) derivadas del paciente. A través de ellas, es hoy concebible obtener neuronas y glía humanas, y estudiar mecanismos celulares y moleculares de enfermedades, un atributo que anteriormente no era posible para ninguna condición humana. La esclerosis lateral amiotrófica (ELA) es una de las enfermedades que se ha beneficiado con la tecnología de iPS. Al diferenciar neuronas motoras de células iPS obtenidas de pacientes con ELA, hemos iniciado estudios sobre los mecanismos que subyacen a la aparición y progresión de la enfermedad. Aquí, presentamos el desarrollo de una plataforma celular que permite extender la longevidad de las neuronas motoras derivadas de iPS, una característica relevante para la mayoría de las enfermedades humanas de inicio tardío. Los cultivos a largo plazo de células iPS provenientes de pacientes pueden ser determinantes en el desarrollo de terapias asociadas a la medicina de precisión.

Asunto(s)

Humanos , Animales , Ratones , Células Madre Pluripotentes Inducidas/citología , Esclerosis Amiotrófica Lateral/metabolismo , Inmunohistoquímica , Línea Celular , Técnicas de Cocultivo , Esclerosis Amiotrófica Lateral/patología , Esclerosis Amiotrófica Lateral/terapia

RESUMEN

Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of upper and lower motor neurons accompanied by proliferation of reactive microglia in affected regions. However, it is unknown whether the hematopoietic marker CD34 can identify a subpopulation of proliferating microglial cells in the ALS degenerating spinal cord. Immunohistochemistry for CD34 and microglia markers was performed in lumbar spinal cords of ALS rats bearing the SOD1G93A mutation and autopsied ALS and control human subjects. Characterization of CD34-positive cells was also performed in primary cell cultures of the rat spinal cords. CD34 was expressed in a large number of cells that closely interacted with degenerating lumbar spinal cord motor neurons in symptomatic SOD1G93A rats, but not in controls. Most CD34+ cells co-expressed the myeloid marker CD11b, while only a subpopulation was stained for Iba1 or CD68. Notably, CD34+ cells actively proliferated and formed clusters adjacent to damaged motor neurons bearing misfolded SOD1. CD34+ cells were identified in the proximity of motor neurons in autopsied spinal cord from sporadic ALS subjects but not in controls. Cell culture of symptomatic SOD1G93A rat spinal cords yielded a large number of CD34+ cells exclusively in the non-adherent phase, which generated microglia after successive passaging. A yet unrecognized CD34+ cells, expressing or not the microglial marker Iba1, proliferate and accumulate adjacent to degenerating spinal motor neurons, representing an intriguing cell target for approaching ALS pathogenesis and therapeutics.

Asunto(s)

Esclerosis Amiotrófica Lateral/patología , Antígenos CD34/análisis , Microglía/patología , Neuronas Motoras/patología , Esclerosis Amiotrófica Lateral/genética , Animales , Proliferación Celular , Células Cultivadas , Humanos , Masculino , Microglía/citología , Mutación Puntual , Pliegue de Proteína , Ratas , Médula Espinal/patología , Superóxido Dismutasa-1/análisis , Superóxido Dismutasa-1/genética

RESUMEN

Age is a recognized risk factor for amyotrophic lateral sclerosis (ALS), a paralytic disease characterized by progressive loss of motor neurons and neuroinflammation. A hallmark of aging is the accumulation of senescent cells. Yet, the pathogenic role of cellular senescence in ALS remains poorly understood. In rats bearing the ALS-linked SOD1G93A mutation, microgliosis contribute to motor neuron death, and its pharmacologic downregulation results in increased survival. Here, we have explored whether gliosis and motor neuron loss were associated with cellular senescence in the spinal cord during paralysis progression. In the lumbar spinal cord of symptomatic SOD1G93A rats, numerous cells displayed nuclear p16INK4a as well as loss of nuclear Lamin B1 expression, two recognized senescence-associated markers. The number of p16INK4a-positive nuclei increased by four-fold while Lamin B1-negative nuclei increased by 1,2-fold, respect to non-transgenic or asymptomatic transgenic rats. p16INK4a-positive nuclei and Lamin B1-negative nuclei were typically localized in a subset of hypertrophic Iba1-positive microglia, occasionally exhibiting nuclear giant multinucleated cell aggregates and abnormal nuclear morphology. Next, we analyzed senescence markers in cell cultures of microglia obtained from the spinal cord of symptomatic SOD1G93A rats. Although microglia actively proliferated in cultures, a subset of them developed senescence markers after few days in vitro and subsequent passages. Senescent SOD1G93A microglia in culture conditions were characterized by large and flat morphology, senescence-associated beta-Galactosidase (SA-ß-Gal) activity as well as positive labeling for p16INK4a, p53, matrix metalloproteinase-1 (MMP-1) and nitrotyrosine, suggesting a senescent-associated secretory phenotype (SASP). Remarkably, in the degenerating lumbar spinal cord other cell types, including ChAT-positive motor neurons and GFAP-expressing astrocytes, also displayed nuclear p16INK4a staining. These results suggest that cellular senescence is closely associated with inflammation and motor neuron loss occurring after paralysis onset in SOD1G93A rats. The emergence of senescent cells could mediate key pathogenic mechanisms in ALS.

RESUMEN

Ethanol (EtOH) consumption is a risk factor for central nervous system damage, especially during adolescence. This study aimed to investigate the possible effects of chronic EtOH forced administration on gray and white matter of the spinal cord, from adolescence to adulthood. For this, male Wistar rats were administered EtOH by gavage (6.5 g/kg/day; 22.5% w/v) from the 35th to the 90th day of life, while control animals received only distilled water. After exposure, animals were euthanized and their spinal cords processed to obtain cervical and thoracic segments for histological analyses. Quantitative analyses of total cell density and motor neurons of white and gray matter from the ventral horns were evaluated. Forced EtOH administration model showed a decrease in the motoneuron density in the spinal cord in both segments evaluated. Analyses of total cell density showed that the cervical segment was more susceptible to damages promoted by EtOH, with a significant decrease in cell density. Our results showed that chronic EtOH exposure during adolescence could promote injuries to the spinal cord, with neurodegeneration of motoneurons and other cell types present in neural parenchyma.

Asunto(s)

Consumo de Bebidas Alcohólicas/efectos adversos , Recuento de Células , Etanol/farmacología , Neuronas Motoras/efectos de los fármacos , Médula Espinal/efectos de los fármacos , Animales , Recuento de Células/métodos , Masculino , Neuronas Motoras/citología , Ratas Wistar , Médula Espinal/citología , Agua , Sustancia Blanca/efectos de los fármacos , Sustancia Blanca/patología

RESUMEN

Introduction: Information about the neuroanatomical details of the ascendant transport of the rabies virus through the spinal cord is scarce. Objective: To identify the neuroanatomical route of dissemination of the rabies virus at each of the levels of the spinal cord of mice after being inoculated intramuscularly. Materials and methods: Mice were inoculated with the rabies virus in the hamstrings. After 24 hours post-inoculation, every eight hours, five animals were sacrificed by perfusion with paraformaldehyde. Then, the spinal cord was removed, and transverse cuts were made at the lumbosacral, thoracic, and cervical levels. These were processed by immunohistochemistry for the detection of viral antigens. Results: The first antigens of rabies were observed as aggregated particles in the lumbar spinal cord at 24 hours post-inoculation, within the ventral horn in the same side of the inoculated limb. At 32 hours post inoculation the first motoneurons immunoreactive to the virus became visible. At 40 hours postinoculation the first immunoreactive neurons were revealed in the thoracic level, located on lamina 8 and at 48 hours post-inoculation in the cervical cord, also on lamina 8. At 56 hours post-inoculation the virus had spread throughout the spinal cord, but the animals still did not show signs of the disease. Conclusion: In the mouse model we used, the rabies virus entered the spinal cord through the motoneurons and probably used the descending propriospinal pathway for its retrograde axonal transport to the encephalus.

Asunto(s)

Virus de la Rabia/fisiología , Médula Espinal/virología , Animales , Femenino , Ratones , Médula Espinal/anatomía & histología

RESUMEN

Resumen Introducción. Es escasa la información sobre los detalles neuroanatómicos del transporte del virus de la rabia en su ascenso por la médula espinal. Objetivos. Identificar la ruta neuroanatómica de diseminación del virus de la rabia en cada uno de los niveles de la médula espinal de ratón, después de ser inoculado por vía intramuscular. Materiales y métodos. Se inocularon ratones en los músculos isquiotibiales, con virus de la rabia. A partir de las 24 horas después de la inoculación, cada ocho horas se sacrificaron cinco animales por perfusión con paraformaldehído, se les extrajo la médula espinal y se hicieron cortes transversales en los niveles lumbosacro, torácico y cervical. Estos se procesaron mediante inmunohistoquímica para detectar antígenos virales. Resultados. Los primeros antígenos de la rabia se observaron como partículas agregadas, en la médula espinal lumbar, a las 24 horas después de la inoculación, dentro del asta ventral ipsilateral a la extremidad inoculada. A las 32 horas después de la inoculación, se hicieron visibles las primeras motoneuronas inmunorreactivas al virus. A las 40 horas después de la inoculación, se revelaron las primeras neuronas inmunorreactivas en la médula torácica, localizadas en la lámina 8 y, a las 48 horas después de la inoculación en la médula cervical, también en la lámina 8. A las 56 horas después de la inoculación, el virus se había diseminado por toda la médula espinal pero los animales aún no revelaban signos de la enfermedad. Conclusión. En el modelo de ratón aquí utilizado, el virus de la rabia ingresó a la médula espinal por las motoneuronas y, probablemente, utilizó la vía propioespinal descendente para su transporte axonal retrógrado hasta el encéfalo.

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Abstract Introduction: Information about the neuroanatomical details of the ascendant transport of the rabies virus through the spinal cord is scarce. Objective: To identify the neuroanatomical route of dissemination of the rabies virus at each of the levels of the spinal cord of mice after being inoculated intramuscularly. Materials and methods: Mice were inoculated with the rabies virus in the hamstrings. After 24 hours post-inoculation, every eight hours, five animals were sacrificed by perfusion with paraformaldehyde. Then, the spinal cord was removed, and transverse cuts were made at the lumbosacral, thoracic, and cervical levels. These were processed by immunohistochemistry for the detection of viral antigens. Results: The first antigens of rabies were observed as aggregated particles in the lumbar spinal cord at 24 hours post-inoculation, within the ventral horn in the same side of the inoculated limb. At 32 hours post inoculation the first motoneurons immunoreactive to the virus became visible. At 40 hours post-inoculation the first immunoreactive neurons were revealed in the thoracic level, located on lamina 8 and at 48 hours post-inoculation in the cervical cord, also on lamina 8. At 56 hours post-inoculation the virus had spread throughout the spinal cord, but the animals still did not show signs of the disease. Conclusion: In the mouse model we used, the rabies virus entered the spinal cord through the motoneurons and probably used the descending propriospinal pathway for its retrograde axonal transport to the encephalus.

Asunto(s)

Animales , Femenino , Ratones , Virus de la Rabia/fisiología , Médula Espinal/virología , Médula Espinal/anatomía & histología

RESUMEN

ABSTRACT The X-linked spinal and bulbar muscular atrophy (Kennedy's disease) is a rare X-linked, recessive, lower motor neuron disease, characterized by weakness, atrophy, and fasciculations of the appendicular and bulbar muscle. The disease is caused by an expansion of the CAG repetition in the androgen receptor gene. Patients with Kennedy's disease have more than 39 CAG repetitions. We report a case of 57-year-old man, resident of Monte Dourado (PA, Brazil) who complained of brachiocrural paresis evolving for 3 years along with fasciculations and tremors of extremities. In addition, he also developed dysarthria, dysphagia, and sexual dysfunction. The patient clinical picture included gait impairment, global hyporeflexia, proximal muscle atrophy of upper limbs, deviation of the uvula to right during phonation and tongue atrophy with fasciculations. The patient reported that about 30 years ago he had undergone gynecomastia surgery. His electroneuromyography suggested spinal muscular atrophy, and nuclear magnetic resonance imaging showed tapering of the cervical and thoracic spinal cord. Patient's creatine kinase level was elevated. In view of the findings, an exam was requested to investigate Kennedy's disease. The exam identified 46 CAG repetitions in the androgen receptor gene, which confirmed the diagnostic suspicion. This was the first case of Kennedy's disease diagnosed and described in the Brazilian Amazon. To our knowledge only other four papers were published on this disease in Brazilian patients. A brief review is also provided on etiopathogenic, clinical and diagnostic aspects.

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RESUMO A atrofia muscular bulboespinhal ligada ao cromossomo X (doença de Kennedy) é uma rara doença de neurônio motor inferior, recessiva, ligada ao X, e caracterizada por fraqueza, atrofia e fasciculações da musculatura apendicular e bulbar. É causada por uma expansão da repetição CAG no gene do receptor de androgênio. Pacientes com doença de Kennedy apresentam mais de 39 repetições CAG. O paciente deste relato era do sexo masculino, 57 anos, morador de Monte Dourado (PA, Brasil), com queixa de paresia braquiocrural há 3 anos, acompanhada de fasciculações e tremores de extremidades. Em seguida, ele desenvolveu disartria, disfagia e disfunção sexual. Também apresentava comprometimento da marcha, hiporreflexia global, atrofia muscular proximal dos membros superiores, desvio da úvula para direita à fonação e atrofia de língua com fasciculações. Foi realizada cirurgia para tratamento de ginecomastia há 30 anos. A eletroneuromiografia sugeriu quadro de atrofia muscular espinhal. Imagens de ressonância magnética demonstraram afilamento da medula espinhal cervical e torácica. A creatina quinase estava elevada. Diante dos achados, solicitou-se investigação para doença de Kennedy, e foram identificadas 46 repetições CAG no gene do receptor de androgênio, o que confirmou a suspeita diagnóstica. Este foi o primeiro caso de doença de Kennedy diagnosticado e descrito na Amazônia brasileira. Existem, além deste relato, apenas outros quatro trabalhos publicados sobre a doença em pacientes do Brasil. Também realizamos breve revisão de aspectos etiopatogênicos, clínicos e diagnósticos.

Asunto(s)

Humanos , Masculino , Persona de Mediana Edad , Atrofia Bulboespinal Ligada al X/diagnóstico , Brasil/epidemiología , Familia , Bosques , Atrofia Bulboespinal Ligada al X/genética , Atrofia Bulboespinal Ligada al X/epidemiología , Enfermedades Asintomáticas

RESUMEN

Amyotrophic Lateral Sclerosis (ALS) is one of the most common adult-onset motor neuron disease causing a progressive, rapid and irreversible degeneration of motor neurons in the cortex, brain stem and spinal cord. No effective treatment is available and cell therapy clinical trials are currently being tested in ALS affected patients. It is well known that in ALS patients, approximately 50% of pericytes from the spinal cord barrier are lost. In the central nervous system, pericytes act in the formation and maintenance of the blood-brain barrier, a natural defense that slows the progression of symptoms in neurodegenerative diseases. Here we evaluated, for the first time, the therapeutic effect of human pericytes in vivo in SOD1 mice and in vitro in motor neurons and other neuronal cells derived from one ALS patient. Pericytes and mesenchymal stromal cells (MSCs) were derived from the same adipose tissue sample and were administered to SOD1 mice intraperitoneally. The effect of the two treatments was compared. Treatment with pericytes extended significantly animals survival in SOD1 males, but not in females that usually have a milder phenotype with higher survival rates. No significant differences were observed in the survival of mice treated with MSCs. Gene expression analysis in brain and spinal cord of end-stage animals showed that treatment with pericytes can stimulate the host antioxidant system. Additionally, pericytes induced the expression of SOD1 and CAT in motor neurons and other neuronal cells derived from one ALS patient carrying a mutation in FUS. Overall, treatment with pericytes was more effective than treatment with MSCs. Our results encourage further investigations and suggest that pericytes may be a good option for ALS treatment in the future. Graphical Abstract ᅟ.

Asunto(s)

Esclerosis Amiotrófica Lateral/terapia , Células Madre Pluripotentes Inducidas/patología , Neuronas Motoras/patología , Pericitos/trasplante , Superóxido Dismutasa-1/genética , Tejido Adiposo/citología , Tejido Adiposo/metabolismo , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/mortalidad , Esclerosis Amiotrófica Lateral/patología , Animales , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Tronco Encefálico/metabolismo , Tronco Encefálico/patología , Catalasa/genética , Catalasa/metabolismo , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Masculino , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Ratones , Ratones Transgénicos , Neuronas Motoras/metabolismo , Mutación , Pericitos/citología , Pericitos/metabolismo , Proteína FUS de Unión a ARN/genética , Proteína FUS de Unión a ARN/metabolismo , Médula Espinal/metabolismo , Médula Espinal/patología , Superóxido Dismutasa-1/deficiencia , Análisis de Supervivencia

RESUMEN

Amyotrophic lateral sclerosis (ALS) is described as a neurodegenerative disorder. However, neuroinflammation and chemokine expression are prominent pathological finding at sites of injury. Adipsin and adiponectin are molecules that are implicated in the pathogenesis of neurodegenerative and neuroimmune disorders. Adipsin and adiponectin concentrations were determined in the CSF of ALS patients and controls and the relationship of these chemokines with clinical severity and disease duration in ALS was determined. Seventy-seven ALS patients (mean age 49.5 ± 10.4 years) (mean body mass index 23.5 ± 4.5) were included. Twenty patients had bulbar, 53 spinal, and four bulbospinal onset ALS. Median adipsin CSF level was 12,650.94 pg/ml in ALS patients and 3290.98 pg/ml in controls (p < 0.001). Median adiponectin CSF level was 4608 pg/ml in ALS patients and 3453 pg/ml in controls (p = 0.1). No differences were observed in disease duration, progression rate or disease severity. There was a significant positive correlation between adipsin and adiponectin concentrations (r = 0.379, p = 0.01). No correlation with age, body mass index or ALFRS-R score was found. Adipsin was significantly elevated in CSF, suggesting that this chemokine might have a role in ALS pathogenesis. Adiponectin showed a trend towards higher concentrations, but failed to reach statistical significance. Due to the clinical heterogeneity in our cohort, these chemokines do not appear to be associated with disease duration or severity.

Asunto(s)

Adiponectina/líquido cefalorraquídeo , Esclerosis Amiotrófica Lateral/líquido cefalorraquídeo , Factor D del Complemento/líquido cefalorraquídeo , Adulto , Anciano , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad

RESUMEN

Amyotrophic Lateral Sclerosis (ALS) is a paradigmatic neurodegenerative disease, characterized by progressive paralysis of skeletal muscles associated with motor neuron degeneration. It is well-established that glial cells play a key role in ALS pathogenesis. In transgenic rodent models for familial ALS reactive astrocytes, microglia and oligodendrocyte precursors accumulate in the degenerating spinal cord and appear to contribute to primary motor neuron death through a non-cell autonomous pathogenic mechanism. Furthermore in rats expressing the ALS-linked SOD1G93A mutation, rapid spread of paralysis coincides with emergence of neurotoxic and proliferating aberrant glia cells with an astrocyte-like phenotype (AbA cells) that are found surrounding damaged motor neurons. AbAs simultaneously express astrocytic markers GFAP, S100ß and Connexin-43 along with microglial markers Iba-1, CD11b and CD163. Studies with cell cultures have shown that AbAs originate from inflammatory microglial cells that undergo phenotypic transition. Because AbAs appear only after paralysis onset and exponentially increase in parallel with disease progression, they appear to actively contribute to ALS progression. While several reviews have been published on the pathogenic role of glial cells in ALS, this review focuses on emergence and pro-inflammatory activity of AbAs as part of an increasingly complex neurodegenerative microenvironment during ALS disease development.

Asunto(s)

Esclerosis Amiotrófica Lateral/patología , Neuroglía/patología , Esclerosis Amiotrófica Lateral/metabolismo , Animales , Astrocitos/patología , Encéfalo/patología , Microambiente Celular , Humanos , Microglía/patología , Neuronas Motoras/patología , Mutación , Fenotipo , Médula Espinal/patología , Superóxido Dismutasa-1/genética , Superóxido Dismutasa-1/metabolismo

RESUMEN

OBJECTIVE: To determine the association between the amplitude of vastus medialis (VM) Hoffmann reflex (H-reflex) and pain level, self-reported physical function, and chronicity of pain in women with patellofemoral pain (PFP). DESIGN: Cross-sectional study. SETTING: Laboratory of biomechanics and motor control. PARTICIPANTS: Women diagnosed with PFP (N=15) aged 18 to 35 years. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Data on worst pain level during the previous month, self-reported physical function, and symptom duration (chronicity) were collected from the participants. Maximum evoked responses were obtained by electrical stimulation applied to the femoral nerve and peak-to-peak amplitudes of normalized maximal H-reflexes (maximal Hoffmann reflex/maximal motor wave ratios) of the VM were calculated. A Pearson product-moment correlation matrix (r) was used to explore the relations between the amplitude of VM H-reflex and worst pain during the previous month, self-reported function, and chronicity of pain. RESULTS: Strong negative correlations were found between the amplitude of VM H-reflex and worst pain in the previous month (r=-.71; P=.003) and chronicity (r=-.74; P=.001). A strong positive correlation was found between the amplitude of VM H-reflex and self-reported physical function (r=.62; P=.012). CONCLUSIONS: The strong and significant relations reported in this study suggest that women with PFP showing greater VM H-reflex excitability tend to have lower pain, better physical function, and more recent symptoms. Therefore, rehabilitation strategies designed to increase the excitability of the monosynaptic stretch reflex should be considered in the treatment of women with PFP if their effectiveness is demonstrated in future studies.

Asunto(s)

Síndrome de Dolor Patelofemoral/fisiopatología , Músculo Cuádriceps/fisiopatología , Reflejo Anormal/fisiología , Adolescente , Adulto , Enfermedad Crónica , Estudios Transversales , Estimulación Eléctrica , Electromiografía , Femenino , Nervio Femoral , Humanos , Dimensión del Dolor , Síndrome de Dolor Patelofemoral/rehabilitación , Autoinforme , Adulto Joven

RESUMEN

ABSTRACT Motor neuron disease is one of the major groups of neurodegenerative diseases, mainly represented by amyotrophic lateral sclerosis. Despite wide genetic and biochemical data regarding its pathophysiological mechanisms, motor neuron disease develops under a complex network of mechanisms not restricted to the unique functions of the alpha motor neurons but which actually involve diverse functions of glial cell interaction. This review aims to expose some of the leading roles of glial cells in the physiological mechanisms of neuron-glial cell interactions and the mechanisms related to motor neuron survival linked to glial cell functions.

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RESUMO A doença do neurônio motor constitui um dos principais grupos de doenças neurodegenerativas, representadas principalmente pela esclerose lateral amiotrófica. Apesar dos amplos dados genéticos e bioquímicos em relação aos seus mecanismos fisiopatológicos, a doença do neurônio motor se desenvolve sob uma complexa rede de mecanismos não restritos às funções particulares dos neurônios motores alfa, mas, na verdade, envolvendo diversas funções interativas das células da glia. Esta revisão tem como objetivo expor alguns dos principais papéis das células da glia nos mecanismos fisiológicos de interações neurônio-glia e os mecanismos relacionados à sobrevivência do neurônio motor ligados a funções das células da glia.

Asunto(s)

Humanos , Neuroglía/fisiología , Esclerosis Amiotrófica Lateral/fisiopatología , Esclerosis Amiotrófica Lateral/patología , Neuronas Motoras/fisiología , Neuroglía/química , Ácido Glutámico/fisiología , Ilustración Médica , Neuronas Motoras/química , Factores de Crecimiento Nervioso/fisiología

RESUMEN

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive muscular atrophy and death within 3-5 years after its onset. Despite the significant advances in knowledge of ALS pathology, no effective treatment is available. Therefore, it is imperative to search for new alternatives to treat ALS. Cell therapy, especially using bone-marrow cells, has showed to be very useful to protect the neural tissue in different brain disease or traumatic lesions. In ALS, most published results show beneficial effects of the use bone marrow cells, especially mesenchymal stromal cells. However, until now, the best outcome extends animal's lifespan by only a few weeks. It is essential to continue the search for a really effective therapy, testing different cells, routes and time-windows of administration. Studying the mechanisms that initiate and spread the degenerative process is also important to find out an effective therapy. Therefore, we discussed here some progresses that have been made using bone-marrow cell therapy as a therapeutic tool for ALS.