Unsuspected Intrinsic Property of Melanin to Dissociate Water Can Be Used for the Treatment of CNS Diseases.

Retinal adhesion mechanisms in mammals are quite complex and multifactorial in nature. To date, these mechanisms are incompletely understood due to a variety of chemical, physical, and physiological forces impinging upon retinal tissue: retinal pigment epithelium, nearby tissues as sclera and vitreous, the subretinal space, and the highly complex interphotoreceptor matrix that fills subretinal space. The adhesion of the retina to the choroid, rather than anatomical, is a dynamic process, as the retina detaches a few minutes after life ceases. The adhesion mechanisms described in the literature, such as intraocular pressure and the oncotic pressure of the choroid that seems to push the retina towards the choroid, the delicate anatomical relationships between the rod and cone photoreceptors, the retinal pigment epithelium, the existence of a complex material called interphotoreceptor matrix, as well as other metabolic and structural factors, still cannot explain the remarkable features observed in the adhesion mechanisms between the photoreceptor layer and retinal pigment epithelium cells. The unexpected intrinsic property of melanin to absorb light energy and transform it into chemically based free energy can explain normal adhesion of the sensory retina to the pigment epithelium. In this article, we explore and highlight this explanation, which states that it is definitely able to provide a new treatment avenue against devastating neurodegenerative properties.

Microglial dependent protective effects of neuroactive steroids.

Microglial cells are extremely important for homeostasis of the CNS. Upon brain damage, microglia become reactive in response to inflammatory stimuli and lead to the secretion of inflammatory cytokines. Because microglia have the ability of adjusting their steady state to an active phenotype that modulates the CNS environment, chronic activation of microglia has an important role in mediating neuroinflammatory brain diseases. Depending upon the nature and degree of the injury stimulus, microglial activity may alternate, either to acute and mild responses -sometimes beneficial- or chronic and severe that may result in neurodegeneration. In this context, proper and controlled activation of microglia should be considered as a potential neuroprotective strategy against neurodegeneration. More recently, the use of estrogenic compounds to regulate microgliosis has shown promising results, and is currently being investigated due to their potential pharmacologic ability in the regulation of inflammation. In this review, we highlight the role of microgliamediated damage and discuss the effect of neurosteroids in reducing the adverse impact of inflammation in the brain.

A synopsis on the linkage between age-related dementias and vascular disorders.

The concept of age-related dementias and vascular disorders has now been recognized for over a century. In the present review, we have emphasized on the causes, consequences and the true bases for the treatment and prevention of these disorders. Systematic efforts have been put together to identify the aetiology in each case. Increased efforts have been targeted towards the concept and genetic factors responsible for vascular cognitive impairment and post-stroke dementia in relation with Alzheimer's disease, which is a consequence of age-related dementia, especially as they hold promise for early prevention and treatment. It has now been well accepted that vascular dementia is not a single disease but a group of conditions with different pathological correlations and pathophysiological mechanisms. The present review represents an amalgamation of several pathophysiological mechanisms producing a very heterogeneous clinical presentation for developing such consequences. We suggest current diagnostic categories and describe clinical parameters according to recently reported studies that document the demographic data in a standardized manner for age-related dementia disorders.

Nanoparticles as Alternative Strategies for Drug Delivery to the Alzheimer Brain: Electron Microscopy Ultrastructural Analysis.

One of the biggest problems and challenges for the development of new drugs and treatment strategies against Alzheimer Disease (AD) is the crossing of target drugs into the blood brain barrier. The use of nanoparticles in drug delivery therapy holds much promise in targeting remote tissues, and as a result many studies have attempted to study the ultrastructural localization of nanoparticles in various tissues. However, there are currently no in vivo studies demonstrating the ultrastructural distribution of nanoparticles in the brain. The aim of this study was to address how intraperitoneal injection of silver nanoparticles in the brain leads to leaking on the inter-endothelial contact and luminal plasma membrane, thus elucidating the possibility of penetrating into the most affected areas in the Alzheimer brain (vascular endothelium, perivascular, neuronal and glial cells). Our results show that the silver nanoparticles reached the brain and were found in hippocampal areas, indicating that they can be conjugated and used to deliver the drugs into the cell cytoplasm of the damaged brain cells. The present study can be useful for the development of novel drug delivering therapy and useful in understanding the delivery, distribution and effects of silver nanoparticles in AD brain tissue at cellular and subcellular level.

Proteína LIC10494 de Leptospira interrogans serovar Copenhageni: modelo estructural y regiones funcionales asociadas / Protein LIC10494 of Leptospira interrogans serovar Copenhageni: structural model and associated functional regions / Proteína LIC10494 de Leptospira interrogans serovar Copenhageni: modelo estrutural e regiões funcionais associadas

Objetivo. Predecir computacionalmente la estructura tridimensional de la proteína antigénica LIC10494 e inferir las regiones funcionales asociadas importantes para su antigenicidad e inmunogenicidad. Materiales y métodos. Se realizó un análisis computacional de la estructura primaria de LIC10494 a partir de los servidores BLAST, PROTPARAM, PROTSCALE, DAS, SOSUI, TOPPRED, TMAP, TMPRED, SPLIT4, PHDHTM, TMHMM2, HMMTOP2, GLOBPLOT y PROSITE. La estructura secundaria se obtuvo por consenso de los algoritmos SOPM, PREDATOR GOR4, DPM y DSC. La aproximación a la estructura terciaria se obtuvo con el algoritmo MUSTER. La minimización de energía se obtuvo a partir del campo de fuerza AMBER94 de la suite de análisis molecular SCHRODINGER, y la validación tanto estereoquímica como energética del modelo se realizó con el servidor RAMPAGE. El modelo final fue visualizado con el programa PyMol v.0,98. Resultados. En el presente estudio se propone un modelo computacional que detalla la estructura tridimensional de la lipoproteína hipotética LIC10494 y está de acuerdo con reportes experimentales previos; el estudio demuestra la existencia de patrones que podrían tener un papel importante en la patogenicidad y la protección de la bacteria frente al sistema inmune del hospedero; la presencia de una región desordenada entre los aminoácidos 80 y 140; y la presencia de un segmento transmembrana entre los aminoácidos 8 y 22. Conclusión. La coincidencia entre segmentos estructurales y funcionales sugiere que el modelo puede usarse para predecir ciertos aspectos del comportamiento biológico de la proteína en cuanto a la patogenicidad e inmunogenicidad de la bacteria.

Objective. Predict by computational means the 3D structure of the antigenic protein LIC10494 and report associated important functional regions for its pathogenicity and immunogenicity. Materials and methods. We performed a computational analysis of the primary structure of LIC10494 using the servers BLAST, PROTPARAM, PROTSCALE, DAS, SOSUI, TOPPRED, TMAP, TMpred, SPLIT4, PHDHTM, TMHMM2, HMMTOP2, GLOBPLOT and PROSITE. The secondary structure was obtained by consensus of the algorithms SOPM, PREDATOR GOR4, DPM and DSC. The approach to the tertiary structure was obtained using the algorithm MUSTER. The energy minimization was done using the AMBER94 force field of the Schrodinger suite of molecular analysis, and the stereochemistry and energy model validation was performed by the RAMPAGE server. The final model was visualized using PyMol V.0,98. Results. This study proposes a computational model that describes the 3D structure of the hypothetical lipoprotein LIC10494 and agrees with previous experimental reports; thus, our study demonstrates the existence of patterns that could play an important role in the pathogenicity and protection of the bacteria against the host immune system; the presence of a disorganized region between amino acids 80 and 140, and of a transmembrane segment between amino acids 8 and 22. Conclusion. The coincidence between structural and functional segments suggests that our model can be used to predict certain aspects of the biological behaviour of the protein according to the pathogenic and immunogenic characteristics of the bacteria.

Objetivo. Predizer computacionalmente a estrutura tridimensional da proteína antigênica LIC10494 e inferir as regiões funcionais associadas importantes para a sua antigenicidade e imunogenicidade. Materiais e métodos. Foi realizada uma análise computacional da estrutura primária da LIC10494 nos servidores, BLAST, PROTPARAM, PROTSCALE, DAS, SOSUI, TOPPRED, TMAP, TMPRED, SPLIT4, PHDHTM, TMHMM2, HMMTOP2, GLOBPLOT e PROSITE. A estrutura secundária foi obtida por consenso dos algoritmos SOPM, PREDATOR GOR4, DPM e DSC. A aproximação para a estrutura terciária foi obtida com o algoritmo MUSTER. A minimização de energia foi obtida a partir do campo de força AMBER94 do conjunto de análise molecular SCHRODINGER, e a validação estereoquímica e energética do modelo foi realizada utilizando o servidor RAMPAGE. O modelo final foi visualizado com o programa PyMol V. 0,98. Resultados. Este estudo propõe um modelo computacional que descreve a estrutura tridimensional da lipoproteína hipotética LIC10494 e concorda com anteriores relatórios experimental; o estudo demonstra a existência de padrões que poderiam desempenhar um papel importante na patogenicidade e na proteção da bactéria ao sistema imune do hospedeiro; a presença de uma região desordenada entre os aminoácidos 80 e 140, e a presença de um segmento transmembrana entre os aminoácidos 8 e 22. Conclusão. A coincidência entre os segmentos estruturais e funcionais sugere que o modelo pode ser utilizado para prever determinados aspectos do comportamento biológico da proteína na patogenicidade e imunogenicidade da bactéria.

Long-lasting effects of perinatal asphyxia on exploration, memory and incentive downshift.

Perinatal asphyxia remains as one of the most important causes of death and disability in children, without an effective treatment. Moreover, little is known about the long-lasting behavioral consequences of asphyxia at birth. Therefore, the main aim of the present study was to investigate the motor, emotional and cognitive functions of adult asphyctic rats. Experimental subjects consisted of rats born vaginally (CTL), by cesarean section (C+), or by cesarean section following 19 min of asphyxia (PA). At three months of age, animals were examined in a behavioral test battery including elevated plus maze, open field, Morris water maze, and an incentive downshift procedure. Results indicated that groups did not differ in anxiety-related behaviors, although a large variability was observed in the asphyctic group and therefore, the results are not completely conclusive. In addition, PA and C+ rats showed a deficit in exploration of new environments, but to a much lesser extent in the latter group. Spatial reference and working memory impairments were also found in PA rats. Finally, when animals were downshifted from a 32% to a 4% sucrose solution, an attenuated suppression of consummatory behavior was observed in PA rats. These results confirmed and extended those reported previously about the behavioral alterations associated with acute asphyxia around birth.

Investigation of toxic factors affecting cells of rat brains exposed to 3-methylcatechol

The aim of this work was to study the effects of 3MC on the peroxidation of biomolecules in nuclear fractions and nonsynaptic mitochondrial respiration in organelles obtained from rat brains. The cytotoxicity towards rat primary astrocytes in vitro was also tested. 3MC at 1mM oxidized consuming oxygen at a rate of 1.98 ± 0.19 µM.min-1 and formed reactive quinones. At the same concentration, 3MC induced peroxidation of biomolecules in nuclear fractions obtained from rat brain homogenates and inhibited state 2 FADH2-linked respiration in nonsynaptic mitochondria. Furthermore, 3MC oxidized in the culture medium, leading to the formation of quinones. This toluene metabolite was cytotoxic to rat primary astrocytes. The concentration that killed 50 percent of cells after 72 h was 107 mM. The results of the study indicated a direct relationship between cytotoxicity and 3MC oxidation.

O 3-metilcatecol (3MC) é um metabólito do tolueno. Para esclarecer se o 3MC seria tóxico para o sistema nervoso central, examinou-se seus efeitos sobre a peroxidação de biomoléculas em frações nucleares e a respiração mitocondrial em organelas obtidas de cérebros de ratos. Também se testou a citotoxicidade para astrócitos primários de ratos. O 3MC a 1mM oxida-se consumindo oxigênio a uma taxa de 1,98 ± 0,19 mM.min-1, formando quinonas reativas. Nessa mesma concentração o 3MC peroxidou biomoléculas nas frações nucleares. Esse composto também inibiu o estado 2 da respiração mitocondrial associada ao FADH2. Além disso, o 3MC também se oxida em meio de cultura levando à formação de quinonas. Esse metabólito do tolueno foi citotóxico para astrócitos de ratos. A concentração que matou 50 por cento das células após 72 horas foi 107 mM. Os resultados desse estudo indicam uma relação direta entre a citotoxicidade e a oxidação do 3MC.

Catechol inhibits FADH2-linked respiration in rat liver mitochondrial fraction.

PURPOSE: The aim of this work was to investigate the hypothesis that catechol inhibits FADH -linked basal respiration in mitochondria isolated from rat liver homogenates. Moreover, catechol ability to induce peroxidation of biomolecules in liver nuclear fractions was also studied. METHODS: Rat liver homogenates were incubated with 1mM 1,2-dihydroxybenzene (catechol) at pH 7.4 for up to 30 minutes. After that, mitochondrial fractions were isolated by differential centrifugation. Basal oxygen uptake was measured using a Clark-type electrode after the addition of 10 mM sodium succinate. Nuclear fractions were incubated in the presence of 1 mM catechol for 17 hours at room temperature and the peroxidation of biomolecules was investigated by the reaction with thiobarbituric acid, which was determined spectrophotometrically at 535 nm. RESULTS: Catechol induced a time-dependent partial inhibition of FADH -linked basal mitochondrial respiration, however this substance was unable to induce a direct peroxidation of biomolecules in hepatic nuclear fractions. CONCLUSION: Catechol produced an inhibition of basal respiration associated to FADH2 in isolated liver mitochondria that could lead to cytotoxicity, ROS generation and cell death.

Catechol inhibits FADH2-linked respiration in rat liver mitochondrial fraction

OBJETIVO: Testar a hipótese do catecol inibir a respiração basal associada ao FADH2 em frações mitocondriais hepáticas de rato. Além disso, estudou-se também a capacidade do catecol de induzir peroxidação de biomoléculas nas frações nucleares. MÉTODOS: Os homogeneizados de fígado de ratos foram incubados com catecol a 1 mM em pH fisiológico. Depois disso, as frações mitocondriais foram isoladas por centrifugação diferencial. O consumo basal de oxigênio foi medido com um eletrodo do tipo Clark após injeção de succinato a 10 mM. Frações nucleares foram incubadas com catecol por 17 horas à temperatura ambiente e a peroxidação de biomoléculas foi investigada pela reação com o ácido tiobarbitúrico e mensurada espectrofotometricamente. RESULTADOS: O catecol induziu uma inibição parcial da respiração basal mitocondrial associada ao FADH2 de forma dependente do tempo, contudo essa substância não induziu peroxidação direta das biomoléculas presentes nas frações nucleares hepáticas. CONCLUSÃO: O catecol produz inibição da respiração basal associada ao FADH2 em mitocôndrias isoladas de fígado, o que pode levar à toxicidade, produção de espécies reativas e morte celular.