Para além do combate à ancilostomíase: o diário do médico norte-americano Alan Gregg / Looking beyond the campaign to eradicate ancylostomiasis: the diary of the American physician Alan Gregg

Entre 1916 e 1923, o Distrito Federal e 11 estados brasileiros estabeleceram acordos de cooperação com a divisão internacional de saúde – International Health Board – da Fundação Rockefeller para combater uma endemia rural, a ancilostomíase. Este breve texto apresenta o diário de Alan Gregg, um dos médicos norte-americanos que trabalharam no Brasil entre 1919-1922. Fonte interessante para discutir questões relativas à história da saúde pública no Brasil, o diário do médico, além das informações sobre as atividades de combate à ancilostomíase desenvolvidas pela Fundação Rockefeller no país, apresenta suas impressões relativas à natureza, à cultura, à política e à sociedade brasileiras. Na seleção de trechos do diário ora apresentado, priorizamos, porém, aspectos relativos às atividades profissionais realizadas por Gregg.

Between 1916 and 1923, the Federal District and 11 Brazilian states entered into cooperation agreements with the International Health Board of the Rockefeller Foundation to combat a rural endemic disease, namely ancylostomiasis. This paper presents the diary of Alan Gregg, one of the American physicians who worked in Brazil from 1919 to 1922. An interesting source to discuss issues relating to the history of public health in Brazil, in addition to information about the activities to combat ancylostomiasis developed by the Rockefeller Foundation in the country, the diary of the physician presents his impressions concerning nature, culture, politics and society in Brazil. In the diary excerpts presented here, however, aspects related to the professional activities performed by Gregg are prioritized.

ERKs and mitochondria-related pathways are essential for glycyrrhizic acid-mediated neuroprotection against glutamate-induced toxicity in differentiated PC12 cells

The present study focuses on the neuroprotective effect of glycyrrhizic acid (GA, a major compound separated from Glycyrrhiza Radix, which is a crude Chinese traditional drug) against glutamate-induced cytotoxicity in differentiated PC12 (DPC12) cells. The results showed that GA treatment improved cell viability and ameliorated abnormal glutamate-induced alterations in mitochondria in DPC12 cells. GA reversed glutamate-suppressed B-cell lymphoma 2 levels, inhibited glutamate-enhanced expressions of Bax and cleaved caspase 3, and reduced cytochrome C (Cyto C) release. Exposure to glutamate strongly inhibited phosphorylation of AKT (protein kinase B) and extracellular signal-regulated kinases (ERKs); however, GA pretreatment enhanced activation of ERKs but not AKT. The presence of PD98059 (a mitogen-activated protein/extracellular signal-regulated kinase kinase [MEK] inhibitor) but not LY294002 (a phosphoinositide 3-kinase [PI3K] inhibitor) diminished the potency of GA for improving viability of glutamate-exposed DPC12 cells. These results indicated that ERKs and mitochondria-related pathways are essential for the neuroprotective effect of GA against glutamate-induced toxicity in DPC12 cells. The present study provides experimental evidence supporting GA as a potential therapeutic agent for use in the treatment of neurodegenerative diseases.

Consumo de aminoácido de cadeia ramificada na esclerose lateral amiotrófica: suplemento proteico ou substância neurotóxica? / Branched-chain amino acid consumption in amyotrophic lateral sclerosis: protein supplement or neurotoxic substance?

Estudos demonstraram efeito positivo principalmente no ganho ponderalem pacientes com esclerose lateral amiotrófica (ELA), suplementadoscom aminoácidos de cadeia ramificada (AACR). Achados recentes têm mostrado que o consumo excessivo e crônico de AACR pode contribuir para a progressão da doença, provavelmente devido a estes serem precursores do glutamato. O objetivo deste estudo foi avaliar a evidência acerca da utilização dos AACR por pacientes com ELA, a fim de elucidar questões pertinentes a sua ingestão. Foi feita busca em base de dados de artigos científicos relacionados ao consumo de AACR na ELA, no período de 1988 a 2013. Foram encontrados seis artigos relacionados ao consumo de AACR por pacientes com ELA. Desses, um referiu melhora da força, enquanto os outros relataram ganho ponderal ou não mostraram resultados significativosem relação aos desfechos. Além disso, foi possível observar uma estreita relação entre o consumo excessivo e crônico dos AACR com o agravamento da doença. À luz dos conhecimentos ora disponíveis, a suplementação com AACR não é recomendada devido aos possíveis efeitos nocivos. O consumo adequado de alimentos proteicos, fontes desses aminoácidos, deve ser utilizado pelos pacientes, respeitando as recomendações estabelecidas. No entanto, estudos adicionais devem ser desenvolvidos em virtude do escasso número de publicações disponíveis.

Studies have shown positive effect mainly in weight gain inpatients with amyotrophic lateral sclerosis (ALS) supplemented with branched chain amino acids (BCAA). However, recent studies have shown that excessive and chronic intake has contributed to the worsening of the disease progression, probably because the amino acids are glutamate precursors. The objective of this study was to assess the evidence about the use of BCAA by patients with ALS, with the aim to clarify pertinent issues for its intake. A search was conducted in data bases for scientific papers related to the intake of BCAA in ALS, between 1988 and 2013. For these review six articles related to the use of BCAA in ALS were found. Of these, one described strength improvement, while the remaining reported weight gain or no significant effects in relation to the outcome. Additionally, it waspossible to observe a close relationship between the excessive and chronic BCAA intake with the worsening of the disease. Considering the presente day available knowledge BCAA supplementation should not be indicated due to the possible harmful effect. The intake of appropriated protein foods should be consumed by these patients, respecting the suggested recommendation. However, more studies are necessary due to the scarce papers in this area.

Neuroprotective effect of total and sequential extract of Scrophularia striata boiss. in rat cerebellar granule neurons following glutamate-induced neurotoxicity: an in-vitro study

Neuroprotective effect of the extract from aerial parts of Scrophularia striata Boiss [Scrophulariaceae] was investigated against glutamate-induced neurotoxicity on cultured rat pups Cerebellar Granule Neurons [CGNs]. CGNs from 8 days old Sprague-Dawley rat were prepared and cultured. The experiments were performed after 8 days in culture. The plant was collected from the northeastern part [Ruin region] of Iran and air-dried at room temperature. The total extract was prepared with maceration of prepared powder in ethanol 80% for three times. Sequential extracts were obtained using dried and powdered aerial parts with increasingly polar solvents: petroleum ether, chloroform, ethyl acetate and methanol 80% solution. Cultured cells were exposed to 125 micro M of glutamate for 12 h following a 24 h of incubation with test fractions at concentration of 10 mcg/mL. Morphological assay was performed using invert light microscope after fixation and staining with haematoxylin. Neuronal viability was measured using MTT assay. Statistical analysis was done using SPSS software. One way analysis of variance [ANOVA] was performed by Tukey post-hoc test. Values were considered statistically significant when p-value < = 0.05. Results of this study showed a significant neuroprotective activity of high polarity methanolic fraction of aerial parts of Scrophularia striata against glutamate-induced neurotoxicity in a dosedependent manner. Treatment with 10 mcg/mL of the fractions showed the best result

Toxicidade retiniana do gás hexafluoreto de enxofre, líquido perfluorocarbono, ar e solução salina balanceada em olhos de coelhos / Sulfur hexafluoride gas, perfluorocarbon liquid, air and balanced salt solution retinal toxicity in rabbit eyes

OBJETIVOS: Determinar a toxicidade retiniana do gás hexafluoreto de enxofre, líquido perfluorocarbono e solução salina balanceada em olhos de coelhos. MÉTODOS: Foram analisados 22 olhos de 16 coelhos albinos da raça Nova Zelândia divididos em grupos: solução salina balanceada (7 olhos); hexafluoreto de enxofre (4 olhos), líquido perfluorocarbono (5 olhos) e controle (6 olhos). Após aspiração de 0,3 ml de humor vítreo, foi injetado a mesma quantidade de solução salina balanceada ou hexafluoreto de enxofre a 100 por cento ou líquido perfluorocarbono na cavidade vítrea. O grupo controle não foi submetido a nenhum procedimento. Três semanas depois o humor vítreo foi coletado para análise bioquímica e o olho enucleado para análise histológica. RESULTADOS: Os olhos dos animais que receberam injeção de hexafluoreto de enxofre e líquido perfluorocarbono mostraram significativo aumento da concentração vítrea de glutamato quando comparado aos grupos solução salina balanceada e controle (p<0,05). A análise histológica confirmou os achados bioquímicos mostrando alterações como disrupção do segmento externo dos fotorreceptores, afilamento das camadas plexiforme interna e externa, diminuição do número de núcleos na camada ganglionar e nuclear interna, edema e presença de macrófagos nas camadas superficiais. Estas alterações foram mais acentuadas no grupo líquido de perfluorocarbono em relação ao grupo hexafluoreto de enxofre. Não foram observadas alterações histológicas retinianas significativas nos grupos solução salina balanceada e controle. CONCLUSAO: A presença de gás hexafluoreto de enxofre e líquido perfluorocarbono na câmara vítrea se mostrou potencialmente tóxica para a retina de coelhos quando comparado ao grupo controle e solução salina balanceada.

Anti-apoptotic role of phospholipase D isozymes in the glutamate-induced cell death

Abstract Phospholipase D (PLD) plays an important role as an effector in a variety of physiological processes that reveal it to be a member of the signal transducing phospholipases. Recently, PLD2 was reported as a necessary intermediate in preventing apoptosis induced by hydrogen peroxide or hypoxia in rat pheochromocytoma (PC12) cells. The data presented here show that both PLD isozymes, PLD1 and PLD2 are also required in attenuating glutamate-induced cell death in PC12 cells. Treatment of PC12 cells with glutamate resulted in induction of apoptosis in these cells, which is accompanied by decreased PLD activity and increased ceramide concentration. Incubation of PC12 cells with exogenous C6-ceramide showed a time-dependent decrease of PLD activity. When cDNAs of PLD1 and PLD2 were transfected into PC12 cells respectively, overexpression of PLD1 or PLD2 resulted in inhibition of glutamate-induced apoptotic cell death. These data indicate that both PLD1 and PLD2 play a protective role against glutamate-induced cell death in PC12 cells.

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.

Exitotoxicidad, bases fisiopatológicas e implicancias clínicas / Excitotoxicity: physiopathological basis and clinical implicancies

El sistema glutamatérgico es el principal sistema de neurotransmisión por aminoácidos exitatorios. Su sobreestimulación se ha involucrado en diversas patologías neurológicas tales como: epilepsia, injuria neuronal por isquemia e hipoglicemia y enfermedades neurodegenerativas tales como: el Corea de Huntington. Se revisan las bases bioquímicas y fisiopatológicas de los sistemas glutamatérgicos y sus probables implicaciones en la clínica