Environmental enrichment reduces brain excitability in adult rats overnourished during lactation / Enriquecimento ambiental reduz excitabilidade cerebral em ratos adultos hipernutridos durante a lactação

ABSTRACT Objective: This study aimed to analyze whether exposure to environmental enrichment (EE) during the juvenile phase of life interferes with the electrical activity of the adult rat brain. In addition, the present research also investigated whether this putative effect on brain electrical activity could be affected by prior overnutrition during lactation. Electrophysiology was measured through cortical spreading depression (CSD), a phenomenon related to brain excitability. Methods: Wistar rats were suckled in litters of either nine or three pups, forming the nourished (N) or overnourished (ON) groups, respectively. At 36 days old, half of the animals from each nutritional condition were exposed to EE. The other half was kept in the standard environment (SE). At 90-120 days of life, each animal was anesthetized for CSD recordings. Results: Overnutrition during lactation caused increases (p < 0.05) in body and brain weights. The EE decelerated CSD propagation velocity regardless of nutritional state during lactation (p < 0.001). The CSD deceleration in the N-EE group was 23.8% and in the ON-EE group was 15% in comparison with the N-SE and ON-SE groups, respectively. Conclusion: Our data demonstrated that EE exposure in the juvenile phase of the rat's life reduced brain excitability, and this effect was observed even if animals were overnourished during lactation. An EE could be considered an adjuvant therapeutic resource to modulate brain excitability.

RESUMO Objetivo: Este estudo analisou se a exposição ao ambiente enriquecido durante a fase juvenil da vida interferiria na atividade elétrica do cérebro de ratos adultos. Além disso, a presente pesquisa também investigou se esse provável efeito na atividade elétrica cerebral poderia ser afetado pela hipernutrição durante a lactação. A eletrofisiologia foi medida através da depressão alastrante cortical, um fenômeno relacionado à excitabilidade cerebral. Métodos: Ratos Wistar foram amamentados em ninhadas de nove ou três filhotes, formando os grupos nutridos ou hipernutridos, respectivamente. Aos 36 dias, metade dos animais de cada condição nutricional foram expostos ao ambiente enriquecido. A outra metade foi mantida na condição de ambiente padrão. Aos 90-120 dias de vida, foram obtidos os registros da depressão alastrante cortical. Resultados: A hipernutrição durante a lactação causou incrementos (p < 0,05) nos pesos corporal e cerebral.O Ambiente Enriquecido desacelerou a velocidade de propagação da depressão alastrante cortical independentemente do estado nutricional durante a lactação (p < 0,001). A desaceleração da depressão alastrante cortical no grupo nutrido/ambiente enriquecido foi de 23,8% e no grupo hipernutrido/ambiente enriquecido foi de 15% em comparação com os grupos nutrido/ambiente padrão e hipernutrido/ambiente padrão, respectivamente. Conclusão: Nossos dados demonstram que a exposição ao ambiente enriquecido na fase juvenil da vida do rato reduz a excitabilidade cerebral, e esse efeito pode ser observado mesmo se os animais estiverem hipernutridos durante a lactação. O ambiente enriquecido pode ser considerado um recurso terapêutico adjuvante para modular a excitabilidade cerebral.

Antioxidant extract counteracts the effects of aging on cortical spreading depression and oxidative stress in the brain cortex

Abstract Purpose: To investigate the effects of Murici extract on the brain excitability-dependent phenomenon known as cortical spreading depression (CSD) and on brain oxidative stress. Methods: Adult and aged Wistar rats were supplemented with murici extract (150 mg/kg/day or 300 mg/kg/day) by gavage for fifteen days. Afterwards, the animals were submitted to a CSD electrophysiological recording and to brain oxidative stress evaluation. Results: Our results showed that aging decreased CSD propagation velocity, catalase activity and glutathione/oxidized glutathione ratio (GSH/GSSG) in the brain cortex of the rats, and increased malondialdehyde (MDA) concentrations and superoxide dismutase (SOD) activity. The highest dose (300 mg/kg/day) of murici extract accelerated CSD, whereas the lowest (150mg/kg/day) decelerated, in both adult and aged animals. In contrast, aged animals supplemented with murici extract in both doses presented low MDA levels and high GSG/GSSG ratio in comparison to the control-aged animals. Conclusion: Murici extract supplementation seems to revert detrimental effects in aged brains and could be considered as a strategy in the treatment of pathologies related to aging and cortical spreading depression.

Análise da relação entre o estilo de vida da população economicamente ativa e a prevalência da depressão / Analysis of the relationship between the lifestyle of the economically active population and the prevalence of depression

A depressão é caracterizada como um distúrbio multifatorial da área afetiva ou do humor, exerce impacto funcional e envolve inúmeros aspectos da de ordem biológica, psicológica e social. A depressão representa, atualmente, um importante problema de saúde pública. A pesquisa foi desenvolvida com o objetivo de analisar a relação entre o estilo de vida da população economicamente ativa e a prevalência da depressão. Tratase de uma análise empírica desenvolvida com dados secundários, sob enfoque quantitativo, tendo como unidade de análise a Região Nordeste. Realizou-se estatística descritiva Regressão de Poisson nas análises bi e multivariada para testar a associação entre a variável resposta e explicativas. A prevalência da depressão para população da Região Nordeste, na faixa etária de 18 anos ou mais, foi de 5,6%. As variáveis que, no modelo multivariado final, apresentaram-se como fatores associados ao risco de depressão, foram mulheres, a faixa etária de 40-59 anos, separadas (os) ou divorciadas (os)/judicialmente, ensino médio completo/superior incompleto, fumantes, que não consomem bebidas alcoólicas abusivamente, consomem frutas três vezes ou mais ao dia e que consideram seu estado de saúde regular. Os resultados do estudo apontam que a depressão é uma doença que incide mais significativamente na população em idade produtiva e fornece evidências sobre fatores associados, alguns potencialmente modificáveis, o que poderá contribuir para o planejamento de políticas públicas.(AU)

The depression is characterized as a multifactorial disorder of the affective area or from the mood, exerts functional impact and involves innumerable aspects of the biological, psychological and social order. The depression currently represents a significant public health problem. The research was developed with the objective of analyzing the relationship between the lifestyle of the economically active population and the prevalence of the depression. It is an empirical analysis developed with secondary data, under a quantitative approach, having as unit of analysis the Northeast Region. Poisson Regression descriptive statistics were performed Poisson regression in the bi and multivariate analyzes to test the association between the response variable and explanatory variables. Poisson Regression descriptive statistics were performed in the bi and multivariate analyzes to test the association between the variable response and explanatory. The prevalence of depression for the population of the Northeast Region, in the age group of 18 years or more, was 5.6%. The variables that in the final multivariate model presented themselves as factors associated to the risk of depression were women, in a age grouo of 40-59 years, separated or judicially divorced, complete high school / incomplete university, smokers who do not consume alcoholic beverages abusively, consume fruit three times or more a day and that consider their health condition as regular. The results of the study indicate that depression is a disease that affects more significantly the population of productive age and provides evidence on associated factors, some potentially modifiable, what will may contribute to the planning of public policies.(AU)

Cortical spreading depression in migraine-time to reconsider? / Depressão alastrante cortical na enxaqueca – hora de reconsiderar?

New evidence concerning the pathophysiology of migraine has come from the results of therapeutic transcranial magnetic stimulation (tTMS). The instantaneous responses to single pulses applied during the aura or headache phase, together with a number of other observations, make it unlikely that cortical spreading depression is involved in migraine. tTMS is considered to act by abolishing abnormal impulse activity in cortical pyramidal neurons and a suggestion is made as to how this activity could arise.

Novas evidências referentes à fisiopatologia da enxaqueca são o resultado de estimulação magnética transcraniana terapêutica (tTMS). As respostas imediatas a pulsos simples aplicados durante as fases de aura ou de cefaleia, em associação a diversas outras observações, tornam improvável a ideia de que a depressão alastrante esteja envolvida na enxaqueca. Considera-se que tTMS tenha sua ação abolindo atividade anormal de impulsos em neurônios corticais piramidais, sugerindo que esta atividade tenha um papel desencadeante.

Aristides Leão: a birth centennial homage with comments on his spreading depression / Aristides Leão: homenagem ao centenário de nascimento com comentários sobre sua depressão alastrante

The year of 2014 is the birth centenary of Aristides Azevedo Pacheco Leão (1914-1993), and also marks seventy years of the publication of his discovery of the novel electrophysiological phenomenon, named by him “spreading depression” (SD), soon designated “Leão’s wave” or “Leão’s spreading depression”. This was a remarkable scientific milestone, and the author must be celebrated for this achievement, as the studies he triggered proceeded worldwide, with new concepts, as spreading depolarization, until the present days. Robust experimental and clinical evidence emerged to suggest that these and related electrophysiological phenomena are involved in the mechanisms of migraine aura, acute cerebrovascular diseases, traumatic brain injury, transient global amnesia, epileptic seizures, and their pathophysiological characteristics come to offer new therapeutic perspectives. He was a remarkable and complex personality, and the authors remit the readers to a paper where his personal life is contemplated.

O ano de 2014 é o centenário de nascimento de Aristides Azevedo Pacheco Leão (1914-1993), e também assinala setenta anos da publicação de sua descoberta, que ele denominou “depressão alastrante” (DA), logo designada “onda de Leão” ou “depressão alastrante de Leão”. Foi um notável marco científico e o autor deve ser celebrado por esse feito, considerando que estudos que desencadeou continuaram no mundo todo, com novos conceitos, como a despolarização alastrante, até os dias atuais. Evidência experimental e clínica robusta emergiram sugerindo que esses fenômenos eletofisiológicos e outros relacionados encontram-se envolvidos nos mecanismos da aura da enxaqueca, doenças cerebrovasculares agudas, lesão cerebral traumática, amnésia global transitória, crises epiléticas, sendo que suas características fisiopatológicas vêm oferecer novas perspectivas terapêuticas. Foi uma personalidade complexa e notável, e os autores remetem os leitores para um artigo no qual sua vida pessoal é contemplada.

Brimonidine tartrate effect on retinal spreading depression depends on Müller cells / O efeito do tartarato de brimonidina sobre a depressão alastrante retiniana depende das células de Müller

Objective: Demonstrate the Brimonidine effect over Retinal Spreading Depression (SD). Brimonidine is an alpha-2–adrenergic receptor agonist, used in the management of glaucoma. Alpha2-agonists have been shown to be neuroprotective in various experimental models, however the molecular and cellular targets leading to these actions are still poorly defined. The SD of neuronal electric activity is a wave of cellular massive sustained depolarization that damages the nervous tissue. Local trauma, pressure, ischemic injuries and other chemical agents as high extracellular potassium concentration or glutamate, can trigger SD, leading to exaggerated focal electrical followed by an electrical silence. Methods: Using chicken retina as model, we performed alpha2-receptor detection by Western Blotting and Immunohistochemistry. After that we obtained electrical signals of SD by microelectrodes on retina in the absence or presence of Brimonidine. For in vivo visualization we observed retina with optical coherence tomography on normal state, with SD passing, and with SD + Brimonidine. Results: Our data demonstrated that: (1) alpha2-adrenergic receptors are present in Müller cells, (2) the treatment with Brimonidine decreases the SD‘s velocity as well as the voltage of SD waves and (3) OCT revealed that SD creates a hyper reflectance at inner plexiform layer, but on retinal treatment with brimonidine, SD was not visualized. Conclusions: Our study about brimonidine possible pathways of neuroprotection we observed it reduces SD (a neuronal damage wave), identified a new cellular target – the Müller cells, as well as, firstly demonstrated SD on OCT, showing that the inner plexiform layer is the main optically affected layer on SD. .

Objetivo: Demonstrar o efeito do Tartarato de Brimonidina, um alfa2-agonista usado no manejo do glaucoma, sobre a depressão alastrante (DA) retiniana. Esses agonistas têm demonstrado ser neuroprotetores em vários modelos experimentais, contudo seus alvos celulares e moleculares continuam indefinidos. A DA da atividade elétrica neuronal é uma onda de despolarização celular massiva e sustentada que leva ao dano no tecido nervoso. Trauma local, pressão, isquemia e outros agentes químicos como o aumento do potássio extracelular e o glutamato podem disparar a DA, levando a uma atividade elétrica exagerada seguida de silêncio elétrico. Métodos: Usando a retina de pinto como modelo, realizamos a detecção do alfa2-receptor por Western Blotting e ensaio Imunohistoquímico. Após isso, obtivemos os sinais elétricos da DA através de microeletrodos inseridos na retina durante sua passagem na presença ou ausência de Brimonidina. Para visualização do tecido utilizamos o tomógrafo de coerência optica (OCT), analisando como é a retina no seu estado de repouso, durante a passagem da DA, e a DA + brimonidina. Resultados: Nossos dados demonstraram que: (1) os receptores alfa adrenérgicos presentes na retina são do subtipo-2A e estão localizados nas células de Müller; (2) o tratamento com Brimonidina diminui a velocidade e a voltagem da onda de DA; (3) A OCT demonstrou que a DA retiniana possui um sinal óptico de maior reflectância na camada plexiforme interna, fato não observado quando foi associada à Brimonidina. Conclusão: A Brimonidina foi capaz de reduzir a DA (uma onda de lesão neuronal) e identificamos um novo possível alvo celular – a célula de Müller e demonstramos pela primeira vez uma OCT da DA, visualizando a camada plexiforme interna como a mais afetada opticamente pelo fenômeno. .

Persistência de imagem de hiperintensidade no hipocampo após episódio de amnésia global transitória / Persistence of hyperintensity image in the hippocampus after an episode of transient global amnesia

A patogenia da amnésia global transitória (AGT) continua obscura. Estudos recentes demonstraram que, em alguns pacientes, a sequência de difusão (DWI) da ressonância magnética pode revelar apresença de sinal pequeno e pontual hipersinal no hipocampo, após a fase aguda do episódio. Esse sinal é principalmente visualizado nas primeiras 6 horas do início do evento, sendo 114 horas o tempo máximo que foi registrado até o momento. Estamos apresentando um caso em que essa imagem persistiu por 11 dias após o episódio. Discutem-se as conhecidas causas, as teorias da patogenia da AGT e a possível conexão entre um efeito vascular e a depressão alastrante, como relatada na enxaqueca com aura.

The pathogenesis of transient global amnesia (TGA) remains obscure.Recent studies revealed that small and punctate signal on diffusion-weighted imaging (DWI) in the hippocampus after the post-acute phase. This signal is mainly seen in the first 6 hours of the onset of the event, and so far the maximum time registered was 114 hours. We present one case where this image persisted for 11 days after the episode. Known causes, theories on pathogenesis of TGA and a possible relation between a vascular mechanism and the spreading depression, as reported in migraine with aura, are discussed.

Signos de liberación cortical en pacientes con esquizofrenia, trastornos depresivos, trastorno afectivo bipolar, demencia y enfermedad cerebrovascular / Cortical Release Signs in Patients with Schizophrenia, Depressive Disorders, and Bipolar Affective Disorder

Resumen Introducción y objetivos: Determinar la presencia de signos de liberación cortical, asociada a daño de sustancia blanca, es un método clínico de fácil realización. El objetivo es deter minar la presencia de signos de liberación cortical en pacientes con enfermedades mentales y enfermedad cerebrovascular y determinar su utilidad clínica, dado que indica daño cortical. Material y métodos: Se realiza búsqueda de signos de liberación cortical en pacientes hospitalizados en clínica psiquiátrica y hospital general con diagnósticos de trastorno afectivo bipolar (40), depresión (37), esquizofrenia (33), enfermedad cardiovascular (33) y demencia (37). Resultados: Los signos de liberación cortical no tienen igual importancia en la determinación de daño cortical; por ejemplo, se encontró reflejo glabelar en todos los grupos; el de paratonía, especialmente en el grupo con esquizofrenia, y más signos, en el grupo de pacientes con demencia. Conclusiones: Se formula que estos signos implican daño de sustancia blanca subcortical; la aparición de estos signos supone la necesidad de seguimiento de pacientes con diagnósticos de trastorno afectivo bipolar, depresión y esquizofrenia.

Abstract Background and objectives: Determining the presence of cortical release signs associated with white matter damage, is a clinically easy method to perform. The objective of this study is to determine the presence of cortical release signs in patients with mental illnesses and cerebrovascular disease, as well as its clinical usefulness, given that it indicates cortical damage. Material and methods: A review was made of cortical release signs in patients hospitalized in clinical psychiatry and general hospitals with bipolar affective disorder (40), depression (37), schizophrenia (33), cardiovascular disease (33) and dementia (37). Results: The signs of cortical release do not have the same importance as cortical damage. For example, the glabellar reflex was found in all the groups, that of paratonia, particularly in the group with schizophrenia, and others signs in the group of patients with dementia. Conclusions: It is suggested that these signs imply subcortical white matter damage. The appearance of these signs shows the need for a follow up of patients diagnosed with bipolar affective disorder, depression and schizophrenia.

Depressão alastrante cortical e seu possível papel na lesão neuronal subsequente à hemorragia subaracnóide aneurismática / The role of cortical spreading depolarizations in delayed cerebral ischemia after aneurysmal subarachnoid hemorhage

Isquemia cerebral tardia (delayed cerebral ischemia; DCI)é a principal causa potencialmente tratável de mortalidade e incapacidade em pacientes com hemorragia subaracnóide aneurismática (HSA). No entanto, não existe tratamento eficaz para esta condição até o momento. A recente demonstração da falta de resposta clínica à reversão farmacológica do espasmo arterial após HSA estimulou uma reavaliação dos conceitos fisiopatológicos na DCI que segue a HSA,que foram por muito tempo creditados ao espasmo arterial observado em doentes com HSA. Desde a demonstração de resultados eletrocorticográficos de depressão cortical generalizada(“cortical spreading depressions”, CSD) em pacientes com HSA, um crescente interesse foi despertado sobre opapel destes fenômenos na fisiopatologia da DCI observados em pacientes com HSA. Quando induzida em um cérebro saudável, a CSD está associada com aumento do fluxo sanguíneo cerebral, facilitando a distribuição de substratos de energia necessários para repolarização celular cerebral.Em um cérebro lesado, no entanto, CSDs estão associados a uma redução do fluxo sanguíneo cerebral, que, no contexto de aumento das necessidades da energia, leva à falha de energia e hipóxia, acentuando a gravidade da lesão cerebral. Esta resposta inversa hemodinâmica à CSD foi descoberta pela primeira vez em um modelo animal, replicando as condições de HSA e, posteriormente, demonstrado em pacientes com HSA. A isquemia leva à escassez de substratos energéticos e propagação da hipóxia, resultando em lesões corticais, e podem explicar os padrões de lesão, semelhantemente ao que ocorre em pacientes com HSA. Estas observações sugerem que o déficit de energia produzida por CSD é um fator chave na patogênese dos DCI observados como resultado da HSA.Este artigo detalha as principais características de CSDs e sua potencial relevância na fisiopatologia das complicações isquêmicas da HSA.

Delayed cerebral ischemia (DCI) is the leading potentially treatable cause of mortality and disability in patients with aneurysmal subarachnoid hemorrhage (SAH). However, to date there is no effective treatment for this entity. The recently demonstrated lack of clinical response to pharmacologic reversal of arterial spasm as a result of SAH has spurred a reassessment of the pathophysiological concepts on DCI that follows SAH.DCI was long believed the consequence of the angiographically visible arterial spasm observed in patients with SAH. Since themeasurement of cortical spreading depolarizations (CSD) inpatients with SAH, increasing evidence has suggested a role for these phenomena in the pathophysiology of DCI. When induced in a healthy brain, CSDs are associated with an increase in regional cerebral blood flow that facilitates the delivery of the necessary energy substrates for cellular repolarization. Ina brain that has been injured, however, CSDs can induce microvascular constriction, or cortical spreading ischemia. This inverse hemodynamic response to CSD was first discovered in an animal model replicating the conditions following SAH, and later demonstrated in patients with SAH. The spreading ischemia leads to energy substrates shortage and hypoxia, resulting in cortical lesions, and may explain similar lesion patterns which occur in SAH patients. This review describes the salient characteristics of CSD and its potential relevance in the pathophysiology, monitoring, and treatment of ischemic complications following SAH.

Depresiones corticales propagadas y su posible rol en la fisiopatología del daño neuronal subsecuente a la hemorragia subaracnoidea / Cortical spreading depressions and their role in the pathophysiology of neuronal damage subsequent to aneurysmal subarachnoid hemorrhage

El vasoespasmo cerebral es la principal causa potencialmente tratable de mortalidad e incapacidad en pacientes que sufren hemorragia subaracnoidea aneurismática (HSA). Sin embargo, a la fecha no existe un tratamiento eficaz para el mismo. La reciente demostración de la falta de respuesta clínica a la reversión farmacológica del espasmo arterial a consecuencia de HSA ha obligado un replanteo de los fundamentos fisiopatológicos de los déficits neurológicos isquémicos tardíos (“delayed ischemic neurologic déficit”, DIND) a consecuencia de HSA, los cuales se creían en relación al espasmo arterial observado en pacientes con HSA. Desde la demostración de hallazgos electrocorticográficos de depresión cortical propagada (“cortical spreading depression”, CSD) en pacientes con HSA, un interés creciente se ha despertado respecto del rol de estos fenómenos en la fisiopatología de los DIND observados en pacientes con HSA. Cuando inducidas en un cerebro saludable, las CSD se asocian con un aumento del flujo sanguíneo cerebral, facilitando la entrega del cerebro de los sustratos energéticos necesarios. En un cerebro que ha sido lesionado, sin embargo, la CSD se asocia con una reducción en flujo sanguíneo cerebral, lo cual, en el contexto de un aumento de las necesidades de energía, conduce a la insuficiencia energética y la hipoxia, empeorando así el daño cerebral. Estas observaciones sugieren que el déficit de energía producida por la CSD es un factor clave en la patogénesis de los DIND observados a consecuencia de HSA. Este resumen detalla características sobresalientes de las CSD y su potencial relevancia en la fisiopatología del vasoespasmo.

Cerebral vasospasm is the leading potentially treatable cause of mortality and disability in patients with aneurysmatic subarachnoid hemorrhage (SAH). However, to date there is no effective treatment for this entity. The recently demonstrated lack of clinical response to pharmacologic reversal of arterial spasm as a result of SAH has spurred a reassessment of the pathophysiological concepts on delayed ischemic neurologic deficits (DIND) that follow SAH, which were long believed the effect of the arterial spasm observed in patients with SAH. Since the discovery of electrocorticographic cortical spreading depressions (CSD) in patients with SAH, increasing interest has been shown on the role of these phenomena in the pathophysiology of DIND observed in patients with HSA. When induced in a healthy brain, CSD are associated with an increase in cerebral blood flow by facilitating the delivery of the necessary energy substrates. In a brain that has been injured, however, CSD are associated with a reduction in cerebral blood flow, which, in the context of increased energy requirements leads to energy shortage and hypoxia, thus worsening brain damage. These observations suggest that the energetic deficit produced by the CSD is a key factor in the pathogenesis of DIND observed as a result of HSA. This review details striking characteristics of CSD and their potential relevance in the pathophysiology of vasospasm.

Acute tryptophan administration impairs cortical spreading depression propagation in REM sleep deprived and non-deprived adult rats

The enhanced availability of tryptophan in the brain, as a consequence of exogenous tryptophan administration, can increase neuronal serotonin synthesis and this can interfere with brain function. REM sleep deprivation (D) constitutes another external factor that can change brain excitability, facilitating, in some cases, the manifestation of neurological diseases like epilepsy. Here we used cortical spreading depression (CSD) as a neurophysiological parameter to investigate the effects of a single L-tryptophan intraperitoneal injection combined or not with 72h D-condition (water-tank technique) in rats. A 1h baseline CSD-recording was performed under urethane+chloralose (1g/kg + 40mg/kg) anesthesia and revealed increased CSD propagation velocities in D rats, as compared with non-deprived (ND), or pseudo-deprived (Pseudo) controls. After the baseline CSD recording, L-tryptophan was immediately injected (125 mg/kg ip, dissolved in water at pH about 3) and this was followed by a significant decrease of CSD propagation velocities, as compared to the baseline values in the same animals of the Pseudo, ND and D condition. In an additional control group (ND rats injected with the vehicle), no CSD propagation change was seen. Our findings indicate an important acute antagonistic influence of tryptophan on CSD propagation, which is not affected by REM sleep deprivation. We suggest that this tryptophan effect may be due to a serotonin-mediated action, probably caused by increased serotonin synthesis as a consequence of enhanced tryptophan availability in the brain.

Depressão alastrante cortical em ratos adultos tratados com L-arginina durante o aleitamento / Cortical spreading depression in adult rats treated with L-arginine during lactation

Como um precursor essencial para a síntese de moléculas proteícas com grande importância biológica, a arginina apresenta marcável versatilidade metabólica e regulatória. O Óxido Nítrico (NO), gerado a partir da arginina exerce papel multifuncional no sistema nervoso, incluindo modulação da liberação de neurotransmissores, regulação do fluxo sanguíneo local cerebral e plasticidade sináptica. Estudo recente tem sugerido que a sinalização mediada pelo óxido está envolvida na depressão alastrante cortical (DA; Wang et al., Neuropharmacol. 44:949-957, 2003). Nós investigamos em ratos o efeito da administração de L-arginina (ARG) combinado ao estado nutricional, durante o período do aleitamento, na propagação da depressão alastrante crtical (DA), em ratos adultos. Ratos Wistar foram amentados em ninhadas de 6 ou 12 filhotes por mãe (respectivamente N6 e N12). Nesse período os filhotes receberam, por gavagem, ou solução contendo o aminoácido ARG (5, 10, 20 mg/dia respectivamente, durante a primeira, segunda e terceira semana de tratamento) ou água destilada (C). Os pesos corporais foram obtidos nos dias 7/14/21/25/30/60/90 e no dia do registro eletrofisiológico. Os animais foram submetidos ao registro da DA, por 4 horas, quando tornaram-se adultos (90-110 dias). A DA foi deflagrada a cada 20 min pela aplicação de KCI a 2 por cento, por 1 min, na região do córtex frontal, e registrada durante 4 horas em 2 pontos do córtex parietal, através do eletrocorticograma e da variação lenta de voltagem (VLV) que acompanha a DA. Ao final do registro, foram determinados os pesos encefálicos úmidos. Os animais N12 apresentaram pesos corporais e encefálicos menores e velocidades menores e velocidades da DA maiores do que os respectivos grupos N6. Aos 90 dias de vida, os animais ARG-N6 apresentaram pesos corporais estatisticamente superiores aos dos grupos HIS-N6 e C-N6...

Wave onset in central gray matter - its intrinsic optical signal and phase transitions in extracellular polymers

The brain is an excitable media in which excitation waves propagate at several scales of time and space. ''One-dimensional'' action potentials (millisecond scale) along the axon membrane, and spreading depression waves (seconds to minutes) at the three dimensions of the gray matter neuropil (complex of interacting membranes) are examples of excitation waves. In the retina, excitation waves have a prominent intrinsic optical signal (IOS). This optical signal is created by light scatter and has different components at the red and blue end of the spectrum. We could observe the wave onset in the retina, and measure the optical changes at the critical transition from quiescence to propagating wave. The results demonstrated the presence of fluctuations preceding propagation and suggested a phase transition. We have interpreted these results based on an extrapolation from Tasaki's experiments with action potentials and volume phase transitions of polymers. Thus, the scatter of red light appeared to be a volume phase transition in the extracellular matrix that was caused by the interactions between the cellular membrane cell coat and the extracellular sugar and protein complexes. If this hypothesis were correct, then forcing extracellular current flow should create a similar signal in another tissue, provided that this tissue was also transparent to light and with a similarly narrow extracellular space. This control tissue exists and it is the crystalline lens. We performed the experiments and confirmed the optical changes. Phase transitions in the extracellular polymers could be an important part of the long-range correlations found during wave propagation in central nervous tissue

Spreading depression is facilitated in adult rats previously submitted to short episodes of malnutrition during the lactation period

Lactating rat dams were submitted to short episodes (1,2 or 3 weeks) of nutritional restriction by receiving the "regional basic diet" (RBD), with 8 percent protein) of low-income human population of Northeast Brazil. Their pups were then studied regarding the developmental effects on body and brain weights. When the rats reached adulthood, cortical susceptibility to the phenomenon of spreading depression (SD) was evaluated by performing electrophysiological recordings on the surface of the cerebral cortex. SD was elicited at 20-min intervals by applying 2 percent KCL for 1 min to a site on the frontal cortex and its occurrence was monitored at 2 sites in the parietal region by recording the electrocorticogram and the slow potential change of SD. When compared to control rats fed a commercial diet with 23 percent protein, early malnourished rats showed deficits in body and brain weights (10 percent to 60 percent and 3 percent to 15 percent, respectively), as well as increases in velocity of SD propagation (10 percent to 20 percent). these effects were directly related to the duration of maternal dietary restriction, with pups malnourished for 2 ou 3 weeks presenting more intense weight and SD changes than those malnourished for 1 week. The effects of 1-week restrictions on SD were less evident in the pups malnourished during the second week of lactation and were more evident in pups receiving the RBD during the third week. The results indicate that short episodes of early malnutrition during the suckling period can affect body and brain development, as well as the cortical susceptibility to SD during adulthood. The data also suggest that the third week of lactation is the period during which the brain is most sensitive to malnutrition, concerning the effects on SD.

Malnutrition and brain function: experimental studies using the phenomenon of cortical spreading depression

Depending on its intensity and duration, nutritional deficiency can disrupt the structure and function of the nervous system of humans and other mammals, with consequences more or less devastating for the whole organism, particularly in the early postnatal life, when body growth is very rapid and the need for proteins, calories and other nutrients is greatest. In this review, electrophysiological data are presented regarding the use of the phenomenon of cortical spreading depression (CSD) to study effects of malnutrition on the brain. Several conditions of clinical importance and that are known to alter brain function are shown also to influence CSD features in experimental animals. Some of these conditions, (e.g., phamacological manipulation of neurotransmitter systems, dietary treatment with Lithium, acute hyperglycemia, hypothyroidism, aging and environmental stimulation) decrease CSD susceptibility, while other conditions increase it, as, for example, systemic reduction of extracellular chloride levels, deprivation of REM-sleep, acute hypoglycemia, treatment with diazepam, consumption of ethanol and malnutrition. Particular emphasis is laid on the effect of early environmental enrichment on CSD in normal and malnourished animals. Our results suggest that such effect is more evident in the malnourished brain, as compared to the wellnourished one. The data also show that malnutrition alters the brain responsivity to some CSD-facilitatory or inhibitory agents. The underlying mechanisms to explain the observed effects are discussed.

Effect of aging on cortical spreading depression

The effects of aging on spreading depression (SD) were investigated in the Mongolian gerbil (G; age range 1.5 to 58 months; N = 35) and in the albino rat (R; 2.5 to 24 months; N = 100). Two strains of rats were studied: Wistar (W; N = 35) and Sprague-Dawley (SDAW; N = 65). SDAW rats were divided into two groups: one group was fed a commercial lab chow diet (CD) containing 22 per cent protein (N = 47), and the other was fed a 22 per cent casein diet (CAS; N = 18). SD was elicited on the frontal cortical surface by 1-min application of 2 per cent KCl and its appearance was recorded (ECoG and DC potential) at two points in the parieto-occipital area of the same hemisphere. SD propagation velocity was measured on the basis of the time spent for an SD "wave" to cross the distance between the two recording points. Within the age range studied, older animals displayed significantly lower SD velocities than the younger ones, independent of the species, strain or diet (velocity ranges, in mm/min: G, 2.22-5.99; W, 2.47-4.12; SDAW-CD, 2.32-4.42 and SDAW-CAS, 2.65-4.14). The correlation coefficients between age and SD velocity were: G, -0.78; W, -0.45; SDAW-CD, -0.68 and SDAW-CAS, -0.72 (P<0.05 in all cases). As a rule, at each time point the gerbils presented higher SD velocities than the rats of the same age. In another set of experiments, in order to test the role of free radicals in SD, 7 gerbils (14-51 months old) and 13 W rats (3-24 months old) were fed a 22 per cent casein diet free of the antioxidant vitamins C and E for 4-6 weeks before the experiments. No correlation was found between age and SD propagation in these animals fed a diet free of vitamins C and E, although gerbils displayed higher SD velocities than age-matched rats (velocities: G, 3.70-5.34; R, 3.25-4.44 mm/min; correlation coefficients: G, -0.39; W, -0.29; P>0.05). These data indicate that gerbils have higher SD susceptibility than rats of the same age, and that this susceptibility decreases with aging in both species. The lack of correlation between age and SD velocity in the animals fed a diet free of antioxidant vitamins suggests a possible role of free radicals in cortical SD, in accordance with evidence from other laboratories obtained in the isolated retina.

Descriçäo compartimentalizada das dinâmicas iônicas intra e extracelulares de tecidos neuronais / Compartment description of intracellular and extracellular ionic dynamics of neuronal tissues

Em geral, a modelagem realística de sistemas neuronais considera os circuitos elétricos análogos aos mecanismos de geração de correntes elétricas, potenciais e campos elétricos, não considerando os de difusão e eletrodifusão. Entretanto, na simulação de fenômenos que envolvem grandes fluxos iônicos, tais como o fenômeno da Depressão Alastrante de Leão, onde esses mecanismos são comprovadamente essenciais, faz-se necessária a descrição das dinâmicas iônicas envolvidas. Com esse objetivo, este trabalho apresenta o desenvolvimento de uma representação compartimentalizada para as dinâmicas intra e extracelulares em tecidos neuronais, a qual pode ser verificada como representativa de um modelo analítico, de onde leis básicas, tais como a lei de Fick e a equação de Nerst, podem ser deduzidas.

A depressäo alastrante sob o efeito de bário / Spreading depression under the effect of barium

Apresentamos aqui os resultados de medidas ópticas e eletro-fisiológicas obtidas durante a ocorrência de ondas de depressão alastrante (DA) na retina de galinha in vitro. Adquirindo simultaneamente os sinais supracitados foi possível analisar a sua relaçäo temporal e espacial durante a DA. As ondas foram elicitadas sob condiçöes de controle e com a aplicaçäo de cloreto de bário à soluçäao de perfusäo. Algumas das características mais afetadas foram a variaçäo lenta do potencial extra-celular, a velocidade e o valor absoluto do pico da derivada do sinal de tensäo. A onda óptica intrínseca (IOS) também foi afetada. Apesar disso, o pico da derivada (do potencial) ocorreu senpre no momento da chegada da onda óptica à ponta da micropipeta. Como o bário é um bloqueador de células gliais, os resultados dos experimentos evidenciam a relaçäo entre a despolarizaçäo glial e outros fenômenos comcomitantes tais como a onda de tensäo e o IOS, o que deverá ser objeto de investigaçöes futuras

Abstract - ln this paper we present the results of optical and electro-physiological measurements carried out during the occurrence of spreading depression waves in the in vitro chicken retina. Simultaneously acquiring the optical and electrical signals, we could verify the temporal and spatial relationship between them. The waves have been elicited under control conditions and with the application of barium chloride to the perfusing solution. Some of the most affected features of the waves were the negative slow potential shift, the velocity and the peak absolute value of the derivative of the potential wave. The intrinsic optical signal (IOS) was also affected. Nevertheless, the peak value ofthe derivative occurred always when the !OS was exactly on the tip ofthe micropipette. As longas bariurn is a K-channel blocker specific for glial cells, the results of these experiments pennit to conclude that the relationship between the glial depolarization and the concornitant phenomena such as the potential wave and the !OS exists and should be the subject offurther investigation

Biphasic effects of gap junctional uncoupling agents on the propagation of retinal spreading depression

The spreading depression wave of Leäo (SD) propagates in the nervous tissue at 3-10 mm/min and is a accompanied by an increase of intracellular Ca²+ concentration and a decrease in the extracellular milieu. Recently the spread of Ca²+ waves with propagating velocities of the same order of magnitude has been detected in cultures of nerve cells. It has been suggested that these waves, which can be blocked by gap junctional agents, are related to SD. The present experiments describe some effects of heptanol and octanol (10µM to 10mM), well-known uncoupling agents of gap junctions, on the slow voltage changes and the velocity of propagation of Leäo's phenomenon in isolated chick retina: 1) a 50 to 700 µM concentration of these alcohols in the superfusate solutions increased the velocity, whereas high concentration (1 to 10 mM) decreased and subsequently halted the spread; 2) the recovery period of the slow voltage changes of SD was shorter in the presence of alcohol and its amplitude was larger during faster SD waves. These effects were observed in the retina during successive individual waves as well as in the course of circling SD. All of these effects were reversible, without any sign of damage to the retina. In the concentration range of 50 µM, methanol, ethanol, butanol and cyclo-hexanol had no effect on retinal SD. These data suggest the involvement of gap junctions in Leäo's wave. This involvement is complex and its functional effects together with other factors that influence the velocity of propagation of SD sre being investigated