Far beyond the motor neuron: the role of glial cells in amyotrophic lateral sclerosis / Muito além do neurônio motor: o papel das células da glia na esclerose lateral amiotrófica

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.

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.

Abnormal heart rate variability and atrial fibrillation after aortic surgery / Variabilidade anormal da frequência cardíaca e fibrilação atrial após cirurgia aórtica

Introduction: Complete denervation of transplanted heart exerts protective effect against postoperative atrial fibrillation; various degrees of autonomic denervation appear also after transection of ascending aorta during surgery for aortic aneurysm. Objective: This study aimed to evaluate if the level of cardiac denervation obtained by resection of ascending aorta could exert any effect on postoperative atrial fibrillation incidence. Methods: We retrospectively analysed the clinical records of 67 patients submitted to graft replacement of ascending aorta (group A) and 132 with aortic valve replacement (group B); all episodes of postoperative atrial fibrillation occurred during the 1-month follow-up have been reported. Heart Rate Variability parameters were obtained from a 24-h Holter recording; clinical, echocardiographic and treatment data were also evaluated. Results: Overall, 45% of patients (group A 43%, group B 46%) presented at least one episode of postoperative atrial fibrillation. Older age (but not gender, abnormal glucose tolerance, ejection fraction, left atrial diameter) was correlated with incidence of postoperative atrial fibrillation. Only among a subgroup of patients with aortic transection and signs of greater autonomic derangement (heart rate variability parameters below the median and mean heart rate over the 75th percentile), possibly indicating more profound autonomic denervation, a lower incidence of postoperative atrial fibrillation was observed (22% vs. 54%). Conclusion: Transection of ascending aorta for repair of an aortic aneurysm did not confer any significant protective effect from postoperative atrial fibrillation in comparison to patients with intact ascending aorta. It could be speculated that a limited and heterogeneous cardiac denervation was produced by the intervention, creating an eletrophysiological substrate for the high incidence of postoperative atrial fibrillation observed. .

Introdução: Denervação completa do coração transplantado exerce efeito protetor contra a fibrilação atrial no pós-operatório; vários graus de denervação autonômica aparecem também após a transecção da aorta ascendente durante a cirurgia de aneurisma da aorta. Objetivo: Este estudo teve como objetivo avaliar se o nível de denervação cardíaca obtida por ressecção da aorta ascendente poderia exercer algum efeito sobre a incidência de fibrilação atrial no pós-operatório. Métodos: Foram analisados retrospectivamente os prontuários de 67 pacientes submetidos a enxerto de substituição de aorta torácica (grupo A) e 132 com a substituição da valva aórtica (grupo B). Foram relatados todos os episódios de fibrilação atrial pós-operatória ocorridos durante 1 mês de seguimento. Parâmetros de variabilidade da frequência cardíaca foram obtidos a partir de 24 h de gravação do Holter; dados clínicos, ecocardiográficos e de tratamento também foram avaliados. Resultados: No geral, 45% dos pacientes (grupo A 43%, grupo B 46%) apresentaram pelo menos um episódio de fibrilação atrial no pós-operatório. Idade mais avançada (mas não gênero, tolerância à glicose anormal, fração de ejeção, diâmetro do átrio esquerdo) foi correlacionada com a incidência de fibrilação atrial pós-operatória. Apenas em um subgrupo de pacientes com transecção aórtica e sinais de maior desarranjo autonômico (parâmetros de variabilidade da frequência cardíaca abaixo da mediana e a média de frequência cardíaca acima do percentil 75), indicando possivelmente denervação autonômica mais profunda, foi observada menor incidência de fibrilação atrial pós-operatória (22% vs. 54%). Conclusão: Transecção da aorta ascendente para correção de um aneurisma da aorta não confere qualquer efeito protetor significativo de fibrilação atrial no pós-operatório em comparação com pacientes com aorta ascendente intacta. Pode-se especular que uma denervação cardíaca limitada e heterogênea foi produzida pela ...

Neurochemical phenotype and birthdating of specific cell populations in the chick retina

The chick embryo is one of the most traditional models in developing neuroscience and its visual system has been one of the most exhaustively studied. The retina has been used as a model for studying the development of the nervous system. Here, we describe the morphological features that characterize each stage of the retina development and studies of the neurogenesis period of some specific neurochemical subpopulations of retinal cells by using a combination of immunohistochemistry and autoradiography of tritiated-thymidine. It could be concluded that the proliferation period of dopaminergic, GABAergic, cholinoceptive and GABAceptive cells does not follow a common rule of the neurogenesis. In addition, some specific neurochemical cell groups can have a restrict proliferation period when compared to the total cell population.

O embrião de galinha é um dos mais tradicionais modelosde estudos da neurociência do desenvolvimento e seu sistema visual tem sido um dos mais exaustivamente estudado. Aretina tem sido utilizada como modelo para estudar o desenvolvimento do sistema nervoso. Aqui, nós descrevemos as características morfológicas que caracterizam cada estádio da retina em desenvolvimento e os estudos do período de neurogênese de algumas subpopulações de células neuroquímicamente específicas da retina usando uma combinação de imunohistoquímica e autoradiografia de timidina-tritiada. Conclui-se que o período de proliferação das células dopaminérgicas, GABAérgicas, colinoceptivas e GABAceptivas não segue uma regra comum. Além disso, alguns grupos celulares neuroquimicamente distintos podem ter um período de proliferaçãomais restrito quando comparado ao da população total destas células.

effects of ascorbic acid injection in to locus ceruleus and ventral tegmental area and PGi on morphine withdrawal signs in rats

Recent studies indicate that the glutamatergic and dopaminergic systems are involved in morphine withdrawal syndrome. Ascorbic acid [ascorbate] is an antioxidant vitamin released from glutamatergic neurons and modulates the synaptic action of dopamine and glutamate in the locus ceruleus, ventral tegmental area and PGi as well as behavior. To determine the effects of ascorbic acid injection into locus ceruleus, ventral tegmental area and PGi on morphine withdrawal signs in rats [MWS]. This was an experimental study in which a total of 80 male rats [250-300gr] divided into two were tested. The first group marked as control received 3% sucrose in tap water [n=10] and the second group [dependent group] received morphine and 3% sucrose in tap water [0.1, 0.2, 0.3, 0.4mg/ml each for 48h, and 0.4mg/ml for the remaining days up to day 21]. The latter was further divided into 7 subgroups as follows: [1] morphine group; [2, 3, and 4] sham operated groups which were surgically implanted with cannula at the locus ceruleus [LC], ventral tegmental area [VTA], and PGi; [5, 6, 7] morphine-ascorbic acid groups injected with AA [8 microg/microl] into LC, VTA, and PGi at day 21 and 5 min before naloxone administration. At the end of the training day, all groups received naloxone [2mg/kg I.P] and MWS was studied for 30 minute. Our results showed that the injection of ascorbate into LC and PGi caused a higher decrease in morphine withdrawal syndrome signs compared to VTA. Glutamatergic system is more effective than dopaminergic system in attenuation of MWS by acute injection of ascorbate

Niveles extracelulares de glutamato y aspartato en el fluido gingival en la periodontitis / Extracellular glutamate and aspartate levels in the gingival crevicular fluid of periodontitis patients

El objetivo de este trabajo fue comparar los niveles extracelulares de glutamato y aspartato en el fluido del surco gingival (GCF) de personas adultas, en la periodontitis crónica localizada inducida por placa (PCIP) y la gingivitis inducida por placa (GIP). La enfermedad periodontal produce cambios inflamatorios en los tejidos de sostén de las piezas dentales afectadas. El análisis químico del GCF, con diferentes métodos de colección y análisis, ha sido usado para determinar la presencia de algunos elementos inflamatorios que aparecen en la enfermedad periodontal, tales como diversas enzimas, aminoácidos, etc.Las muestras del GCF se tomaron con la técnica de microdiálisis en las zonas dentales con PCIP con una profundidad del surco > 3 mm; pérdida de soporte > 2mm y en las zonas dentales con GIP en el mismo paciente (n=10) Total de muestras: 100. Para medir el glutamato y aspartato en el GCF se usó la técnica de electroforesis capilar acoplada a laser con detección inducida por fluorescencia (CZE-LIFD). Los resultados mostraron que en los dientes con PCIP el glutamato disminuyó (p<0.05) y el aspartato aumentó (p< 0.02) en comparación con los dientes con GIP.

The objective of this work was to compare glutamate and aspartate levels in periodontal chronic localized disease (PCIP) and dental zones with gingivitis (GIP) in the gingival crevicular fluid (GCF). Periodontal inflammation produces histological changes, increase of blood irrigation and also increase of subgingival fluid. GCF was recognized as an inflammatory exudes derived from the periodontal tissue. Different methods to collect and analyze GCF samples had been used to identify some substances in the GCF, such as the proteinglycans metabolite, to be a possible marker of active periodontal disease. A combination of microdialysis in situ in dental zones with PCIP (probing depth > 3 mm; attachment level > 2 mm) and dental zones with GIP (n=10), total samples: 100, and capillary zone electrophoresis coupled to a laser induced fluorescence detection (CZE-LIFD) was used to measure extracellular concentrations of amino acids: glutamate and aspartate in the GCF in adult patients The results showed that glutamate decrease (p<0.05) and aspartate increase (p<0.02) in PCIP disease zones compared with dental zones with GIP. We observed chemical in vivo evidence that differentiate the GIP zones and PCIP zones.

Sistema glutamatergico, primera parte: sinaptologia, homeostasis y muerte celular / Glutamatergic system (firts part)

El ácido glutámico es el neurotransmisor más abundante del sistema nervioso. Las neuronas glutamatérgicas extienden su acción a lo largo del eje encefalomedular. Dos tercios de las neuronas de la corteza cerebral son glutamatérgicas. Las terminales glutamatérgicas establecen contactos en alta proporción con espinas dendríticas, estructuras sobre las cuales existen mayores indicios de plasticidad morfofuncional y que se asocian a los procesos integrativos más complejos. El papel del ácido glutámico y su disfunción ha ganado importancia en neurología y en psiquiatría, en la medida en que se ha profundizado en el conocimiento sobre su metabolismo, tipos de receptores, transportadores y mecanismos de homeostasis, cuya disfunción puede llevar a muerte neuronal

Learning may provide neuroprotection against dementia

A number of studies attempting to identify specific risk factors for dementia have noted an inverse relationship between educational background and the likelihood of developing dementia. This idea has been somewhat controversial as educational background can introduce a number of confounding factors that generally affect health and lifestyle. Despite these reservations, there is mounting evidence to support the concept of education (or increased mental activity) producing a functional reserve in the brain, a process that provides some protection against the clinical manifestation of dementia. Long-term potentiation (LTP) is a recognized neural correlate of learning and memory. We have shown recently that LTP reduces the sensitivity of hippocampal neurons to agonists of the neurotransmitter glutamate; additionally, we have reported that LTP protects the neurons from the effects of acute hypoxia. Given that the effect of hypoxia on neurons involves over-stimulation by glutamate, and hypoxia has been implicated in the aetio-pathology of some types of dementia, our observations suggest that LTP has a protective effect on neuronal tissue. Such an interaction offers a physiological basis for the epidemiological evidence that lifelong learning can protect a person from some types of dementia.

Changes in acidic amino acid efflux from rat brain with maturation

Our previous studies have shown a greater uptake of acidic amino acids from the blood into the brain of neonatal when compared to that of adult rats. The aim of this study is to investigate whether a developmental change exists in the brain to blood efflux of this group of amino acids. The whole brain was perfused in situ with Ringer's solution containing 14C-aspartate or 14C-glutamate for 10 min. The perfusion was then continued with 14C-free perfusate for a further 20 min and samples of jugular venous outflow were taken at 30-second intervals. The amount of radioactivity [in ln dpm] in each sample was then plotted against the sampling time, and the half-time [t1/2] for 14C-efflux was calculated. Paper chromatography of the outflow samples revealed that more than 91% of the 14C-labelled acidic amino acid present in the effluent samples for up to 30 min of perfusion was chemically intact. The t1/2 for aspartate efflux in neonatal rats was 16.16 +/- 0.76 min which was significantly slower [p < 0.05] than that for the adults, 10.06 +/- 0.46 min [means +/- SEM, n = 3 and 4]. The t1/2 for glutamate efflux was also small in the adult brain where it was 50% the value seen in the neonates. The above results indicate that the systems involved in the efflux of acidic amino acids out of the brain favour retention and increased levels of this group of amino acids in the developing brain

Los mecanismos pre y postsinápticos que intervienen en la inducción y mantenimiento de la potenciación a largo plazo / Pre and post synaptic mechanisms involved in the inductment and maintainance of long-term potentiation

La modificación en la fortaleza de las conexiones sinápticas es una variable crítica que contribuye en varios aspectos al funcionamiento del sistema nervioso, incluyendo al aprendizaje, a la memoria (24,34,40), y en algunas neuropatologías. Cualquier modelo que presente una modificación sotenida en la respuesta sináptica representa posibilidad de analizar los mecanismos plásticos y adaptativos del sistema nervioso, así como el efecto de ciertas drogas de uso psiquiátrico sobre estos mecanismos o de sus características bajo condiciones patológicas. La Potenciación a Largo Plazo (LTP, del inglés Long-term potentiation), se ubica actualmente como uno de los modelos más útiles de plasticidad neuronal. En general, existe el acuerdo de que la LTP, definida como un incremento de larga duración en la eficacia sináptica, presenta dos fases: inducción y mantenimiento. Diversos estudios han sugerido que los principales mecanismos que intervienen en la inducción de la LTP incluyen la participación (principalmente en el giro dentado y en el área CA1 del hipocampo) de los receptores tipo NMDA(N-metil-D-aspartato) y no-NMDA, del calcio, etc. La dinámica de estos mecanismos explica algunas de las características principales de la LTP: la especificidad sináptica, la cooperatividad y la asociatividad. Con respecto a la fase de mantenimiento, hay controversia acerca de si los mecanismos responsables de la persistencia del fenómeno son exclusivamente presinápticos, postsinápticos o si comprenden a ambos sitios de la sinapsis(12), aunque, al parecer, esta última opción es la más viable. En múltiples investigaciones se ha referido que la inducción o el mantenimiento de la LTP pueden verse alterados bajo diversas situaciones: ya sea por la presencia de agonistas o antagonistas del glutamato, del GABA, de la estructura anatómica donde se estudia o por los parámetros de estimulación eléctrica utilizada para la inducción. En aspectos realcionados con la práctica clínica se ha señalado que la LTP puede modificarse por sustancias empleadas en la farmacoterapia psiquiátrica, en modelo experimentales de epilepsia, o que algunos de los mecanismo celulares importantes en la LTP se presentan alterados mientras que otros se preservan en el cerebro de pacientes con trastornos neurodegenerativos como la enfermedad de Alzheimer

Cerebellar granule cell membranes and glutamate mediates transactivation of glutamine synthetase promoter.

Potential region of glutamine synthetase promoter driving astrocyte-specific transactivation, mediated by cerebellar granule cell membrane and glutamate has been identified by deletion analysis of promoter and transient transfection. The promoter region from -420 to -765 was found to be potentially important for this transactivation. These results provided further evidence for importance of neuronal-glial and glutamate-glial interactions in regulation of glial gene expression.

Release and uptake of glutamate as related to excitatoxicity

It has been established that neurons exposed to high concentrations of glutamate or other excitatory amino acids degenerate and die. Neuronal damage appears to be due to the activation of different types of glutamate receptors, among which the ionotropic N-methyl-D-aspartate (NMDA) type seems particularly involved, since its channel is permeable to Ca2+ and an increase in the cytoplasmic concentration of this cation promotes a chain of events leading to cell death. The mechanism of such glutamate receptor-mediated neurodegeneration has been defined as excitotoxicity, and several pieces of evidence suggest that this mechanism might contribute to the neuronal death associated with certain neurological disorders, such as ischemia, cerebral trauma and some chronic neurodegenerative diseases. A relevant question is whether the origin of endogenous extracellular glutamate is important for the induction of excitotoxicity. An excess of glutamate release, or a deficiency in its clearance from the synaptic cleft, which depends mainly on its transport by high affinity carriers, are potential sources for the accumulation of extracellular glutamate. In the present article some experimental results from our laboratory, aimed at obtaining information on this question, are reviewed. These experiments include the use of 4-aminopyridine, a convulsant drug that enhances the release of glutamate, and of some inhibitors of glutamate transport, in vivo and in neuronal cell cultures. The results obtained indicate that an increase of endogenous extracellular glutamate due to these procedures is not sufficient to induce neuronal death, at least under the experimental condition used.

The role of glutamic acid in the pathogenesis of stroke and the development of neuroprotective drugs

The role of glutamic acid (glutamate) in the pathogenesis of stroke is now fairly well established. As a result, many drugs which act on glutamate receptors are currently under investigation for their ability to prevent the damage induced by glutamate under ischaemic conditions. The efficacy of these compounds in protecting central neurones from the effects of stroke may be indicative of the importance of the role that glutamate plays in this process