8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases.

We describe the development of quinolylnitrones (QNs) as multifunctional ligands inhibiting cholinesterases (ChEs: acetylcholinesterase and butyrylcholinesterase-hBChE) and monoamine oxidases (hMAO-A/B) for the therapy of neurodegenerative diseases. We identified QN 19, a simple, low molecular weight nitrone, that is readily synthesized from commercially available 8-hydroxyquinoline-2-carbaldehyde. Quinolylnitrone 19 has no typical pharmacophoric element to suggest ChE or MAO inhibition, yet unexpectedly showed potent inhibition of hBChE (IC50 = 1.06 ± 0.31 nmol/L) and hMAO-B (IC50 = 4.46 ± 0.18 µmol/L). The crystal structures of 19 with hBChE and hMAO-B provided the structural basis for potent binding, which was further studied by enzyme kinetics. Compound 19 acted as a free radical scavenger and biometal chelator, crossed the blood-brain barrier, was not cytotoxic, and showed neuroprotective properties in a 6-hydroxydopamine cell model of Parkinson's disease. In addition, in vivo studies showed the anti-amnesic effect of 19 in the scopolamine-induced mouse model of AD without adverse effects on motoric function and coordination. Importantly, chronic treatment of double transgenic APPswe-PS1δE9 mice with 19 reduced amyloid plaque load in the hippocampus and cortex of female mice, underscoring the disease-modifying effect of QN 19.

The Use of Classmates as a Self-Motivation Strategy From the Perspective of Self-Regulated Learning.

It can be stated that self-regulated learning (SRL) brings broad benefits to the process of students' learning and studying. However, research has yet to be undertaken in relation to one of its components, namely self-regulation of motivation and affectivity. The main objectives of this study are to examine the use of self-motivation strategies that involve classmates and to obtain models on the influence of academic goals and self-efficacy on such self-motivation strategies. To this end, was conducted a study using two different samples of students in the compulsory secondary education or baccalaureate stages in Spain (N = 613 and N = 910). The results obtained indicate that, with regard to gender, differences only exist in the use of the strategy of deception (t = 5.450, p < 0.001, d = 0.364). That the two pairs of strategies positively and significantly correlated with one another (r = 0.239, p < 0.01 and r = 0.355, p < 0.01). That only the strategy of annulation of others correlates with a more adaptive type of motivation. Thus, the group of students that reported the greatest level in its use also did so in relation to task and ego self-enhancing goals, to self-efficacy, and being negatively associated with the goal of work avoidance. Finally, were offered models on relationships between academic goals, self-efficacy and enhancement and annulation strategies [χ2(8) = 5.204, p = 0.736] and deception and annulation strategies [χ2(4) = 3.228, p = 0.520].

The proof-of-concept of ASS234: Peripherally administered ASS234 enters the central nervous system and reduces pathology in a male mouse model of Alzheimer disease.

BACKGROUND: The heterogeneity of Alzheimer disease requires the development of multitarget drugs for treating the symptoms of the disease and its progression. Both cholinergic and monoamine oxidase dysfunctions are involved in the pathological process. Thus, we hypothesized that the development of therapies focused on these targets might be effective. We have developed and assessed a new product, coded ASS234, a multipotent acetyl and butyrylcholinesterase/monoamine oxidase A-B inhibitor with a potent inhibitory effect on amyloid-ß aggregation as well as antioxidant and antiapoptotic properties. But there is a need to reliably correlate in vitro and in vivo drug release data. METHODS: We examined the effect of ASS234 on cognition in healthy adult C57BL/6J mice in a model of scopolamine-induced cognitive impairment that often accompanies normal and pathological aging. Also, in a characterized transgenic APPswe/PS1ΔE9 mouse model of Alzheimer disease, we examined the effects of short-term ASS234 treatment on plaque deposition and gliosis using immunohistochemistry. Toxicology of ASS234 was assessed using a quantitative high-throughput in vitro cytotoxicity screening assay following the MTT assay method in HepG2 liver cells. RESULTS: In vivo, ASS234 significantly decreased scopolamine-induced learning deficits in C57BL/6J mice. Also, reduction of amyloid plaque burden and gliosis in the cortex and hippocampus was assessed. In vitro, ASS234 exhibited lesser toxicity than donepezil and tacrine. LIMITATIONS: The study was conducted in male mice only. Although the Alzheimer disease model does not recapitulate all features of the human disease, it exhibits progressive monoaminergic neurodegeneration. CONCLUSION: ASS234 is a promising alternative drug of choice to treat the cognitive decline and neurodegeneration underlying Alzheimer disease.

Overview of research on teacher self-efficacy in social cognitive perspective / Panorama de las pesquisas sobre autoeficacia docente en la perspectiva social cognitiva

The objective of this study was to present an overview of existing researches on self-efficacy teaching. Therefore, researches on articles in the CAPES-Journals and in the SCIELO database were carried out from 2009 to 2013. The survey resulted in 26 articles which consider the inclusion criteria previously established. The results indicate that in relation to the analysis of the frequency words, the following expressions are highlighted: teaching self-efficacy, job satisfaction and students’ performance. Self-efficacy is influenced by factors such as emotional exhaustion, depersonalization, job satisfaction, relationship with parents, use of violence, time pressure, academic performance, class management, collective efficacy, among others. These results contribute to signal the direction of the researches which are conducted in the area, indicating some trends and highlighting gaps to be investigated such as a great number of studies that verify the relation between self-efficacy and academic performance as well as self-efficacy teaching and public policy that favour the teaching and learning process

El objetivo de este trabajo fue presentar un panorama de las pesquisas existentes sobre autoeficacia docente. Para tanto, se buscaron artículos en la base de datos de la CAPES y SCIELO periódicos llevado a cabo desde 2009 hasta 2013. Esto resultó en 26 artículos que contemplaban los criterios de inclusión antes establecidos. Los resultados indican que en el análisis de frecuencia de palabras se destacaron los siguientes termos: autoeficacia docente, satisfacción laboral y rendimiento de alumnos. La autoeficacia es influenciada por factores como agotamiento emocional, despersonalización, satisfacción laboral, relación con los padres, uso de la violencia, presión del tiempo, rendimiento académico, manejo de clase, eficacia colectiva entre otros. Tales resultados contribuyen enseñando el sentido de las pesquisas hechas en el área, indicando algunas tendencias y evidenciando lagunas por investigar, por ejemplo, más estudios que verifiquen la relación entre autoeficacia y rendimiento académico, y además, autoeficacia docente y políticas públicas que favorezcan el proceso de enseñanza-aprendizaje

Revisão sistemática de pesquisas sobre eficácia coletiva docente / Systematic review on researches about collective teacher efficacy

A eficácia coletiva docente é a percepção compartilhada pelos professores sobre a capacidade do corpo docente de organizar e executar ações necessárias a um efeito positivo no desempenho acadêmico dos alunos. Este artigo tem o objetivo de construir um panorama das pesquisas sobre eficácia coletiva de professores, analisando seus principais resultados. Para tanto, foram realizadas buscas de artigos publicados entre 2000 e 201 3, na base de dados Portal de Periódicos Capes. Os resultados indicam que a eficácia coletiva de professores está diretamente relacionada ao desempenho acadêmico dos alunos.Notou-se ainda que outras variáveis podem influenciar as crenças coletivas, tais como a autoeficácia e a situação socioeconômica da escola

Satisfação no trabalho docente: uma análise a partir do modelo social cognitivo de satisfação no trabalho e da eficácia coletiva docente / The teacher job satisfaction: an analysis from the social cognitive model of job satisfaction and collective efficacy from teachers / La satisfacción en el trabajo docente: un análisis desde el modelo cognitivo social de la satisfacción en el trabajo y de la eficacia colectiva de los profesores

Considerando que a satisfação no trabalho é um aspecto que tem efeito sobre os estados motivacionais dos professores, faz-se necessário investigar suas implicações na docência. Neste sentido, este estudo tem como objetivo: identificar fatores relacionados à satisfação no trabalho a partir da avaliação das dimensões do Modelo Social Cognitivo de Satisfação no Trabalho (MSCST) e da eficácia coletiva. Para tanto, realizou-se pesquisa numa amostra de 495 professores de uma rede privada de ensino, utilizando abordagem mista (quantitativa-qualitativa). As técnicas estatísticas de análise dos dados foram aplicadas nas informações coletadas referentes à amostra total (495). A análise de conteúdo (abordagem qualitativa) foi aplicada nas respostas abertas de 40 professores pertencentes à amostra. Os resultados indicaram que as crenças de eficácia (autoeficácia e eficácia coletiva) não têm efeito sobre a satisfação no trabalho docente e que outros fatores, como os econômicos, podem estar mais relacionados à satisfação.

Whereas job satisfaction is an aspect that has an effect on the motivational states of teachers, it is necessary to investigate its implications for teaching. Thus, this study aims to: identify factors related to job satisfaction based on the assessment of the dimensions of the Social Cognitive Model of Job Satisfaction (MSCST) and collective efficacy. For this, research was conducted on a sample of 495 teachers of private schools using mixed approach (quantitative and qualitative). Technical data analysis statistics were applied to the information collected concerning the total sample (495). The content analysis (qualitative approach) was applied at the open of 40 teachers from the sample answers. The results indicated that the efficacy beliefs (self-efficacy and collective efficacy) has no effect on satisfaction in teaching and other factors such as economic, may be more related to satisfaction.

Mientras que la satisfacción en el trabajo es un aspecto que tiene un efecto sobre la motivación de los profesores, es necesario investigar sus implicaciones en la enseñanza. En este sentido, el objetivo de este estudio fue identificar los factores relacionados con la satisfacción en el trabajo de la evaluación de las dimensiones del modelo social de la satisfacción en el trabajo cognitivo (MSCST) y la eficacia colectiva. Por tanto, la investigación se llevó a cabo sobre una muestra de 495 profesores de una red privada de enseñanza, utilizando el enfoque mixto (cuantitativo y cualitativo). Las técnicas estadísticas de análisis de datos se aplican a la información recopilada en relación con el total de la muestra (495). El análisis de contenido (enfoque cualitativo) fue aplicado a las respuestas abiertas de 40 profesores pertenecientes a la muestra. Los resultados indicaron que las creencias de eficacia (eficacia y la eficacia colectiva) no tiene efecto sobre la satisfacción en el trabajo de enseñanza y que otros factores, tales como la económica, pueden estar más relacionados con la satisfacción.

Satisfação no trabalho docente: Uma análise a partir do modelo social cognitivo de satisfação no trabalho e da eficácia coletiva docente / The teacher job satisfaction: An analysis from the social cognitive model of job satisfaction and collective efficacy from teachers / La satisfacción en el trabajo docente: Un análisis desde el modelo cognitivo social de la satisfacción en el trabajo y de la eficacia colectiva de los profesores

Resumo Considerando que a satisfação no trabalho é um aspecto que tem efeito sobre os estados motivacionais dos professores, faz-se necessário investigar suas implicações na docência. Neste sentido, este estudo tem como objetivo: identificar fatores relacionados à satisfação no trabalho a partir da avaliação das dimensões do Modelo Social Cognitivo de Satisfação no Trabalho (MSCST) e da eficácia coletiva. Para tanto, realizou-se pesquisa numa amostra de 495 professores de uma rede privada de ensino, utilizando abordagem mista (quantitativa-qualitativa). As técnicas estatísticas de análise dos dados foram aplicadas nas informações coletadas referentes à amostra total (495). A análise de conteúdo (abordagem qualitativa) foi aplicada nas respostas abertas de 40 professores pertencentes à amostra. Os resultados indicaram que as crenças de eficácia (autoeficácia e eficácia coletiva) não têm efeito sobre a satisfação no trabalho docente e que outros fatores, como os econômicos, podem estar mais relacionados à satisfação.

Abstract Whereas job satisfaction is an aspect that has an effect on the motivational states of teachers, it is necessary to investigate its implications for teaching. Thus, this study aims to: identify factors related to job satisfaction based on the assessment of the dimensions of the Social Cognitive Model of Job Satisfaction (MSCST) and collective efficacy. For this, research was conducted on a sample of 495 teachers of private schools using mixed approach (quantitative and qualitative). Technical data analysis statistics were applied to the information collected concerning the total sample (495). The content analysis (qualitative approach) was applied at the open of 40 teachers from the sample answers. The results indicated that the efficacy beliefs (self-efficacy and collective efficacy) has no effect on satisfaction in teaching and other factors such as economic, may be more related to satisfaction.

Resumen Mientras que la satisfacción en el trabajo es un aspecto que tiene un efecto sobre la motivación de los profesores, es necesario investigar sus implicaciones en la enseñanza. En este sentido, el objetivo de este estudio fue identificar los factores relacionados con la satisfacción en el trabajo de la evaluación de las dimensiones del modelo social de la satisfacción en el trabajo cognitivo (MSCST) y la eficacia colectiva. Por tanto, la investigación se llevó a cabo sobre una muestra de 495 profesores de una red privada de enseñanza, utilizando el enfoque mixto (cuantitativo y cualitativo). Las técnicas estadísticas de análisis de datos se aplican a la información recopilada en relación con el total de la muestra (495). El análisis de contenido (enfoque cualitativo) fue aplicado a las respuestas abiertas de 40 profesores pertenecientes a la muestra. Los resultados indicaron que las creencias de eficacia (eficacia y la eficacia colectiva) no tiene efecto sobre la satisfacción en el trabajo de enseñanza y que otros factores, tales como la económica, pueden estar más relacionados con la satisfacción.

Adrenomedullin Expression in Alzheimer's Brain.

Adrenomedullin (AM) is a potent vasodilator peptide highly expressed throughout the brain and originally isolated from pheochromocytoma cells. In addition to its vasoactive properties, AM is considered a neuromodulator that possesses antiapoptotic and antioxidant properties that suggest that this peptide can protect the brain from damage. In a previous study, we found that AM exerts a neuroprotective action in the brain and that this effect may be mediated by regulation of nitric oxide synthases, matrix metalloproteases, and inflammatory mediators. AM upregulation contributes to neuroprotection, but understanding the precise roles played by AM and its receptor (RAMP2) in neurodegenerative diseases including Alzheimer's disease (AD), awaits further research. In search of Alzheimer's biomarkers, the expression levels of peptides with endothelial vasodilatory action, including AM, were found to be significantly altered in mild AD or during pre-dementia stage of mild cognitive impairment. These studies concluded that ratio of AM or its precursor fragment mid-regional proAM in blood hold promise as diagnostic marker for AD. We are now presenting a study regarding the hypothesis that the AMRAMP2 system might be implicated in the pathophysiology of AD.

Caracterização das Pesquisas sobre Eficácia Coletiva Docente na Perspectiva da Teoria Social Cognitiva / Characterization of studies on collective teacher efficacy from a Social Cognitive Theory perspective

RESUMO A eficácia coletiva de professores refere-se ao modo como os membros do corpo docente julgam as capacidades desse grupo para realizar as tarefas específicas de sua função. Este estudo objetivou revisar sistematicamente pesquisas sobre a eficácia coletiva docente, na perspectiva social cognitiva. Para tanto, foram realizadas buscas de artigos publicados entre 2010 a 2014, na base de dados da CAPES. O levantamento resultou em 12 artigos que contemplavam os critérios de inclusão pré-estabelecidos. Os resultados indicaram, por meio da análise dos objetivos dos artigos selecionados, que as variáveis mais utilizadas para estudar a eficácia coletiva foram: autoeficácia e satisfação no trabalho. Notou-se ainda que a maioria das pesquisas utilizou abordagem quantitativa, sendo necessário ampliar os estudos, aplicando técnicas qualitativas.

ABSTRACT Collective efficacy of teachers refers to the way faculty members judge the capabilities of this group to perform the specific tasks of the ir function. This study aimed to systematic ally review studies on collective teacher efficacy from a social cognitive perspective. The refore, articles in the CAPES database published between 2010 to 2014were reviewed .The survey resulted in 12 articles which contemplated pre-established inclusion criteria. The results indicated by means of analysis of the objectives of the articles that the variables most commonly used to study the collective teacher efficacy were: self-efficacy and job satisfaction. It was also noted that the majority of the studies useda quantitative approach, indicating a necessity to expand the studies applying qualitative techniques.

Envolvimento parental na tarefa escolar / Parental involvement in homework / Envolvimiento parental en la tarea escolar

O objetivo deste trabalho foi investigar os sentimentos e percepções dos pais em relação ao envolvimento na tarefa escolar dos filhos. Foi utilizada pesquisa qualitativa, com ênfase na utilização do grupo focal. Participaram do estudo 12 responsáveis de adolescentes que cursavam o 7º, 8º e 9º anos do Ensino Fundamental de uma escola privada. Os dados foram analisados através da análise de conteúdo. Os resultados indicaram que os pais veem a tarefa escolar como elemento constituinte da dinâmica das atividades escolares, a despeito dos sentimentos negativos que permeiam seu envolvimento na referida tarefa.

In this work we investigate the feelings and perceptions of the parents towards their involvement in the homework of their children. A qualitative research was made with emphasis on the use of the focal group. The study had 12 participants : people responsible for teenagers who were in the 7th, 8th and 9th grade of the basic education from a private school. The data were analyzed by content analysis. The results indicated that the parents see the homework as an element which belongs to the dynamics of school activities, despite the negative feelings that permeate their involvement in the mentioned schoolwork.

El objetivo de este estudio fue investigar los sentimientos y percepciones de los padres en relación al envolvimiento en la tarea escolar de los hijos. Se utilizó investigación cualitativa, con énfasis en la utilización del grupo focal. Participaron del estudio 12 responsables de adolescentes que cursaban el 7º, 8º y 9º años de la Enseñanza Fundamental de una escuela privada. Los datos fueron analizados por intermedio del análisis de contenido. Los resultados indicaron que los padres ven la tarea escolar como elemento constituyente de la dinámica de las actividades escolares, a respecto de los sentimientos negativos que permean su envolvimiento en la referida tarea.

Envolvimento parental na tarefa escolar / Parental involvement in homework / Envolvimiento parental en la tarea escolar

O objetivo deste trabalho foi investigar os sentimentos e percepções dos pais em relação ao envolvimento na tarefa escolar dos filhos. Foi utilizada pesquisa qualitativa, com ênfase na utilização do grupo focal. Participaram do estudo 12 responsáveis de adolescentes que cursavam o 7º, 8º e 9º anos do Ensino Fundamental de uma escola privada. Os dados foram analisados através da análise de conteúdo. Os resultados indicaram que os pais veem a tarefa escolar como elemento constituinte da dinâmica das atividades escolares, a despeito dos sentimentos negativos que permeiam seu envolvimento na referida tarefa.(AU)

In this work we investigate the feelings and perceptions of the parents towards their involvement in the homework of their children. A qualitative research was made with emphasis on the use of the focal group. The study had 12 participants : people responsible for teenagers who were in the 7th, 8th and 9th grade of the basic education from a private school. The data were analyzed by content analysis. The results indicated that the parents see the homework as an element which belongs to the dynamics of school activities, despite the negative feelings that permeate their involvement in the mentioned schoolwork.(AU)

El objetivo de este estudio fue investigar los sentimientos y percepciones de los padres en relación al envolvimiento en la tarea escolar de los hijos. Se utilizó investigación cualitativa, con énfasis en la utilización del grupo focal. Participaron del estudio 12 responsables de adolescentes que cursaban el 7º, 8º y 9º años de la Enseñanza Fundamental de una escuela privada. Los datos fueron analizados por intermedio del análisis de contenido. Los resultados indicaron que los padres ven la tarea escolar como elemento constituyente de la dinámica de las actividades escolares, a respecto de los sentimientos negativos que permean su envolvimiento en la referida tarea.(AU)

Donepezil + propargylamine + 8-hydroxyquinoline hybrids as new multifunctional metal-chelators, ChE and MAO inhibitors for the potential treatment of Alzheimer's disease.

The synthesis, biochemical evaluation, ADMET, toxicity and molecular modeling of novel multi-target-directed Donepezil + Propargylamine + 8-Hydroxyquinoline (DPH) hybrids 1-7 for the potential prevention and treatment of Alzheimer's disease is described. The most interesting derivative was racemic α-aminotrile4-(1-benzylpiperidin-4-yl)-2-(((8-hydroxyquinolin-5-yl)methyl)(prop-2-yn-1-yl)amino) butanenitrile (DPH6) [MAO A (IC50 = 6.2 ± 0.7 µM; MAO B (IC50 = 10.2 ± 0.9 µM); AChE (IC50 = 1.8 ± 0.1 µM); BuChE (IC50 = 1.6 ± 0.25 µM)], an irreversible MAO A/B inhibitor and mixed-type AChE inhibitor with metal-chelating properties. According to docking studies, both DPH6 enantiomers interact simultaneously with the catalytic and peripheral site of EeAChE through a linker of appropriate length, supporting the observed mixed-type AChE inhibition. Both enantiomers exhibited a relatively similar position of both hydroxyquinoline and benzyl moieties with the rest of the molecule easily accommodated in the relatively large cavity of MAO A. For MAO B, the quinoline system was hosted at the cavity entrance whereas for MAO A this system occupied the substrate cavity. In this disposition the quinoline moiety interacted directly with the FAD aromatic ring. Very similar binding affinity values were also observed for both enantiomers with ChE and MAO enzymes. DPH derivatives exhibited moderate to good ADMET properties and brain penetration capacity for CNS activity. DPH6 was less toxic than donepezil at high concentrations; while at low concentrations both displayed a similar cell viability profile. Finally, in a passive avoidance task, the antiamnesic effect of DPH6 was tested on mice with experimentally induced amnesia. DPH6 was capable to significantly decrease scopolamine-induced learning deficits in healthy adult mice.

New synthesis and promising neuroprotective role in experimental ischemic stroke of ONO-1714.

In an experimental permanent stroke model, we report here the contribution of ONO-1714 to brain damage prevention. Daily drug administration, twenty-one days prior to and two days after an experimental infarct, was performed by using mini-osmotic pumps (ALZET). Infarct volumes were assessed by image analysis of sequential coronal brain 1 mm(3) sections stained following the 2,3,5-triphenyltetrazolium chloride histological staining technique. Results of this study provide evidence of a significant reduction of the brain lesion size, suggesting ONO-1714 as a potential neuroprotective agent in stroke patients. ONO-1714 was prepared in our laboratory following a procedure which resulted in the supply of the desired compound in an easy and excellent yield.

Evaluación de las estrategias de autorregulación afectivo-motivacional de los estudiantes: Las EEMA-VS / Assessment of students´ affective-motivational self-regulatory strategies: The EEMA-VS

Este artículo informa del estudio de las Escalas de Estrategias Motivacionales del Aprendizaje-Versión Secundaria (EEMA-VS) como instrumento para evaluar la utilización de diferentes tipos de estrategias de autorregulación afectivo-motivacional, desde una perspectiva autorreguladora de la motivación y el aprendizaje en estudiantes de secundaria. El instrumento está formado por tres escalas: expectativas, valor y afecto. La primera incluye las subescalas de autoconcepto/autoestima y de expectativas/atribuciones. La escala de valor incluye las subescalas de interés/valor y generación de metas. Finalmente, la escala de afecto incluye una única subescala. Los resultados sugieren que las EEMA-VS ofrecen una fiabilidad relativamente buena. Las escalas parecen ser válidas dados los resultados de los tres análisis factoriales exploratorios y confirmatorios. Se examina la utilización de estas estrategias (AU)

This article reports the study of the learning motivational strategies scales–secondary version (EEMA-VS) as an instrument to assess the use of different types of affective-motivational self-regulatory strategies, based on a self-regulatory perspective on student motivation and learning in secondary school. The instrument is comprised of three scales: expectancy, value and affect. Expectancy scale includes self-concept/self-esteem and expectancies/attributions subscales. Value scale includes interest/value and goal generation subscales. Finally, affect scale includes an unique subscale. The results suggest that the EEMA-VS have relatively good reliability. The scales seem to be valid given the results of the three exploratory and confirmatory factor analyses. Use of these strategies is examined (AU)

Hypothermia prevents nitric oxide system changes in retina induced by severe perinatal asphyxia.

One-third of asphyctic neonates develop long-term neurological injuries, including several degrees of ischemic proliferative retinopathy (IPR) such as retinopathy of prematurity (ROP). Given that the retina is altered by perinatal asphyxia, our aim was to study the effects of nitric oxide (NO) in the retina in order to analyze its impact on the retinal injury. Application of hypothermia was evaluated as preventive treatment. Sprague-Dawley rats were subjected to perinatal asphyxia [either at 37°C (PA group) or at 15°C (HYP group)]. Full-term rats were used as controls (CTL). A significantly increased activity of both constitutive NO synthase (nNOS, Ca(2+)-dependent) and inducible NO synthase (iNOS, Ca(2+)-independent) was observed in PA retinas from 21 days old up to 60 days old with respect to age-matched CTL, with a significant increase along the time course in the PA. nNOS was immunolocalized at amacrine, horizontal, and ganglion cells of the PA group, with a significant increase in relative optical density (R.O.D.), cellular area, and number of cells. iNOS immunoreactivity was observed in the inner nuclear layer and in the internal Müller cell processes of PA, with a significant increase in R.O.D. and colocalizing with GFAP in the 60-day-old PA group. Six nitrated protein species were increased in retinas from PA rats. Nitrotyrosine immunoreactivity showed a localization similar to that of iNOS, with increased R.O.D. in the PA group and colocalization with GFAP in 60-day-old animals. HYP prevented all the changes observed in PA rats. Although the NO system displays changes induced by hypoxia-ischemia, hypothermia application shows a strong protective effect.

Adrenomedullin expression is up-regulated by acute hypobaric hypoxia in the cerebral cortex of the adult rat.

Hypobaric hypoxia can produce neuropsychological disorders such as insomnia, dizziness, memory deficiencies, headache and nausea. Here we report the changes in adrenomedullin (AM) expression observed in rats exposed to hypobaric hypoxia and different times of reoxygenation. AM immunoreactivity was transiently elevated in the cerebral cortex after 7 h of exposure to a simulated altitude of 8325 m (27 000 ft). This higher expression was seen in all pyramidal cells and in a subset of small interneurons. AM-positive nonpyramidal neurons contained also calbindin and calretinin, but no parvalbumin immunoreactivity, thus identifying them as bipolar and double bouquet cells. Small blood vessels and related astroglia also became immunoreactive following the hypobaric insult. AM up-regulation decreased progressively with the time of reoxygenation, reaching almost control levels after 5 days. Real-time PCR quantification of AM mRNA and Western blotting confirmed the up-regulation of AM expression following hypobaria. In addition, hypobaria modulates alternative splicing of the AM gene resulting in a higher production of AM. Our data show that AM expression regulation constitutes a cortical response to hypobaria, suggesting that AM modulation may provide new therapeutic avenues to prevent and/or treat the symptoms produced by hypobaria.

Cardiovascular and renal alterations on the nitric oxide pathway in spontaneous hypertension and ageing.

We have assessed the NO system in the cardiovascular and renal systems of young, adult and old normotensive (WKY) and hypertensive rats (SHR). The NO pathway was assessed analytically, by measuring the concentration of nitrate in plasma as well as the activity of NO synthases in the left ventricle and kidney; and functionally, by measuring the isometric forces generated upon addition of the NO blocker, L-NAME, to aortic segments. All these procedures consistently revealed that the NO pathway is upregulated in hypertension or senescence. In addition, we have performed immunohistochemical studies of NO synthases in the kidney of adult animals (WKY and SHR). NO synthases are expressed throughout the kidney in both rat strains. Immunoreactivity of neuronal NOS was higher in the tubular cells of the renal medulla of the SHR. Staining with the inducible and endothelial NOS antibodies was similar in normo- and hypertension. In summary, hypertension and ageing upregulate the NO pathway in structures involved in the regulation of blood pressure (heart, vessels and kidney).

Changes in the expression pattern of the nitrergic system of ovine cerebellum affected by scrapie.

The constitutive and inducible isoforms of nitric oxide synthase (NOS) and the end-product of nitration, nitrotyrosine, were analyzed by immunohistochemistry, Western blotting, and enzymatic activity in sheep at different stages of the prion disease, scrapie. Four groups were studied: 1) nonaffected (control), 2) preclinical, 3) clinical, and 4) terminal. Constitutive neuronal NOS (nNOS) was the most abundant isoform present in cerebellar neurons of the sheep. Expression of nNOS increased in preclinical animals but diminished in the late stages of the disease. The Purkinje cells that usually are not immunoreactive for this protein became immunopositive in the clinical phase. In unaffected sheep, the inducible isoform (iNOS) was slightly positive in the Purkinje cells. As the disease progressed, the immunoreactivity of Purkinje neurons for iNOS increased. At the final stages, numerous iNOS-positive microglial cells were found in the molecular layer. There was a basal level of protein nitration in the cerebellum of unaffected sheep, especially in the molecular layer. As the disease progressed, the distal prolongations of the Purkinje cells and the astroglia became immunoreactive for nitrotyrosine. Our results suggest that the nitrergic system reacts to the progression of spongiform diseases and may be part of their pathogenesis mechanism.

Características neuropatológicas y moleculares de la enfermedad de Alzheimer / Neuropathological and molecular characteristics of Alzheimer's disease

La enfermedad de Alzheimer (EA) es la enfermedad neurodegenerativa más prevalente entre las personas mayores de 65 años. Su impacto sanitario y social es extraordinario, ya que el número de mayores aumenta inexorablemente en nuestra sociedad. Por el momento sólo disponemos de hipótesis para explicar la etiología de la EA. Tales hipótesis se basan fundamentalmente en el análisis de las lesiones patológicas características de la EA, las placas seniles con su componente betaamiloide y los ovillos neurofibrilares constituidos por la proteína tau. En esta revisión queremos dar una visión actualizada del estado de conocimientos disponibles prestando atención a las primeras etapas asintomáticas del desarrollo de la enfermedad

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease among the elderly. Due to the significant increase in the number of older people in our society, the social and health impact of AD is enormous. Current explanations of the aetiology of AD are hypothetical, based mainly on the characteristic neuropathological lesions observed in this disease (senile plaques with the beta-amyloid peptide as the main component and neurofibrillary tangles due to abnormal hyperphosphorylation of the tau protein). The present review aims to provide an up-to-date overview of current knowledge of AD with particular emphasis on the asymptomatic initial stages of the disease

The nitric oxide donor LA 419 decreases brain damage in a focal ischemia model.

Stroke affects a large number of people, especially in developed countries, but treatment options are limited. Over the years, it has become clear that nitric oxide (NO) plays a major role in this pathology and that treatments that either reduce or increase NO presence may provide an alternative route for reducing the sequelae of brain ischemia. The NO donor LA 419 previously has been shown to protect the brain tissue from ischemic damage in an experimental model of global brain ischemia. Here we study whether this holds true for focal ischemia, a condition closer to the more common form of human stroke. Ischemia was induced in rats by a stereotaxic injection of endothelin-1, a potent vasoconstrictor, in the striatum. Seven days after the injection, magnetic resonance imaging (MRI) found a significant elevation in apparent diffusion coefficient (ADC) in the injected striatum of untreated rats, due to ischemia-induced vascular edema. Animals that received LA 419 prior to injection with endothelin-1 showed an ADC undistinguishable from the contralateral striatum or from the striatum of rats not treated with LA 419. In addition, immunohistochemistry with antibodies against neuronal nitric oxide synthase (nNOS), inducible NOS (iNOS), and nitrotyrosine showed a marked increase in the expression of these markers of NO production following ischemic treatment that was dampened by treatment with LA 419. In summary, our results clearly show that the NO donor LA 419 may be a useful compound for the prevention and/or treatment of focal brain ischemia.