Cerebral and extracerebral distribution of radioactivity associated with oxytocin in rabbits after intranasal administration: Comparison of TTA-121, a newly developed oxytocin formulation, with Syntocinon.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with deficits in social interactions/communication. Despite the large number of ASD patients, there is no drug approved to treat its core symptoms. Recently, Syntocinon (oxytocin nasal spray) has been reported to have a therapeutic effect on ASD. However, the disadvantage of Syntocinon for ASD treatment is that 6 puffs/administration are required to achieve the effective pharmacological dose. Furthermore, there are no published reports evaluating the cerebral distribution profile of oxytocin after intranasal administration. TTA-121 is a newly developed intranasal oxytocin formulation with high bioavailability produced by optimizing the physicochemical properties. In this study, we prepared the same formula as Syntocinon as the control formulation (CF), and the cerebral and extracerebral distribution of oxytocin in rabbits after single intranasal administration of 3H-labeled oxytocin formulations-[3H]TTA-121 and [3H]CF were examined and compared. The area under the concentration-time curve to the time of the last quantifiable concentration (AUCt) in the whole brain was 3.6-fold higher in the [3H]TTA-121 group than in the [3H]CF group, indicating increased delivery of radioactivity to the brain by TTA-121 than by CF. Since the distribution profiles showed no notable differences in radioactivity between the olfactory bulb and trigeminal nerve, intranasally-administered oxytocin was probably transferred to the brain via both pathways. The results also showed an increase in radioactivity in the prefrontal area and the precuneus, which are probable sites of pharmacological action as shown in clinical studies using functional magnetic resonance imaging (fMRI), confirming that intranasally-administered oxytocin could reach these tissues.

Sex-Biased Gene Expression and Evolution in the Cerebrum and Syrinx of Chinese Hwamei (Garrulax canorus).

It is common that males and females display sexual dimorphisms, which usually result from sex-biased gene expression. Chinese hwamei (Garrulax canorus) is a good model for studying sex-biased gene expression because the song between the sexes is quite different. In this study, we analyze cerebrum and syrinx sex-biased gene expression and evolution using the de novo assembled Chinese hwamei transcriptome. In both the cerebrum and syrinx, our study revealed that most female-biased genes were actively expressed in females only, while most male-biased genes were actively expressed in both sexes. In addition, both male- and female-biased genes were enriched on the putative Z chromosome, suggesting the existence of sexually antagonistic genes and the insufficient dosage compensation of the Z-linked genes. We also identified a 9 Mb sex linkage region on the putative 4A chromosome which enriched more than 20% of female-biased genes. Resultantly, male-biased genes in both tissues had significantly higher Ka/Ks and effective number of codons (ENCs) than unbiased genes, and this suggested that male-biased genes which exhibit accelerated divergence may have resulted from positive selection. Taken together, our results initially revealed the reasons for the differences in singing behavior between males and females of Chinese hwamei.

Metabolism of [1,6-13 C]glucose in the cerebellum of 18-day-old rats: Comparison with cerebral metabolism.

There is little information on metabolism in developing cerebellum despite the known importance of this region in cognition and motor tasks. Ex vivo 1 H- and 13 C-NMR spectroscopy were used to determine metabolism during late postnatal development in cerebellum and cerebrum from 18-day-old rat pups after intraperitoneal (i.p.) injection of [1,6-13 C]glucose. The concentration of several metabolites in cerebellum was distinctly different than cerebrum; alanine, glutamine, creatine and myo-inositol were higher in cerebellum than cerebrum, the concentrations of lactate, GABA, aspartate and N-acetylaspartate (NAA) were lower in cerebellum than in cerebrum, and levels of glutamate, succinate, choline and taurine were similar in both brain regions. The incorporation of label from the metabolism of [1,6-13 C]glucose into most isotopomers of glutamate (GLU), glutamine (GLN), GABA and aspartate was lower in cerebellum than in cerebrum. Incorporation of label into the C2 position of lactate via the pyruvate recycling pathway was found in both brain regions. The ratio of newly synthesized GLN/GLU was significantly higher in cerebellum than in cerebrum indicating relatively active metabolism via glutamine synthetase in cerebellar astrocytes at postnatal day 18. This is the first study to determine metabolism in the cerebellum and cerebrum of male and female rat brain.

Cerebral nitric oxide and mitochondrial function in patients suffering aneurysmal subarachnoid hemorrhage-a translational approach.

BACKGROUND: Cerebral ischemia and neuroinflammation following aneurysmal subarachnoid hemorrhage (SAH) are major contributors to poor neurological outcome. Our study set out to investigate in an exploratory approach the interaction between NO and energy metabolism following SAH as both hypoxia and inflammation are known to affect nitric oxide (NO) metabolism and NO in turn affects mitochondria. METHODS: In seven patients under continuous multimodality neuromonitoring suffering poor-grade aneurysmal SAH, cerebral metabolism and NO levels (determined as a sum of nitrite plus nitrate) were determined in cerebral microdialysate for 14 days following SAH. In additional ex vivo experiments, rat cortex homogenate was subjected to the NO concentrations determined in SAH patients to test whether these NO concentrations impair mitochondrial function (determined by means of high-resolution respirometry). RESULTS: NO levels showed biphasic kinetics with drastically increased levels during the first 7 days (74.5 ± 29.9 µM) and significantly lower levels thereafter (47.5 ± 18.7 µM; p = 0.02). Only during the first 7 days, NO levels showed a strong negative correlation with brain tissue oxygen tension (r = - 0.78; p < 0.001) and a positive correlation with cerebral lactate (r = 0.79; p < 0.001), pyruvate (r = 0.68; p < 0.001), glutamate (r = 0.65; p < 0.001), as well as the lactate-pyruvate ratio (r = 0.48; p = 0.01), suggesting mitochondrial dysfunction. Ex vivo experiments confirmed that the increase in NO levels determined in patients during the acute phase is sufficient to impair mitochondrial function (p < 0.001). Mitochondrial respiration was inhibited irrespectively of whether glutamate (substrate of complex I) or succinate (substrate of complex II) was used as mitochondrial substrate suggesting the inhibition of mitochondrial complex IV. The latter was confirmed by direct determination of complex IV activity. CONCLUSIONS: Exploratory analysis of our data suggests that during the acute phase of SAH, NO plays a key role in the neuronal damage impairing mitochondrial function and facilitating accumulation of mitochondrial substrate; further studies are required to understand mechanisms underlying this observation.

Toxicology of tramadol following chronic exposure based on metabolomics of the cerebrum in mice.

Tramadol is an opioid used as an analgesic for treating moderate or severe pain. The long-term use of tramadol can induce several adverse effects. The toxicological mechanism of tramadol abuse is unclear. Metabolomics is a very useful method for investigating the toxicology of drug abuse. We investigated the impact of chronic tramadol administration on the cerebrum of mice, focusing on the metabolites after tramadol administration. The mice received 20 or 50 mg/kg body weight tramadol dissolved in physiological saline daily for 5 weeks via oral gavage. Compared with the control group, the low dose tramadol group showed seven potential biomarkers, including gamma-hydroxybutyric acid, succinate semialdehyde, and methylmalonic acid, which were either up- or down-regulated. Compared with the control group, the high dose tramadol group showed ten potential biomarkers, including gamma-hydroxybutyric acid, glutamine, and O-phosphorylethanolamine, which were either up- or down-regulated. The up-regulated gamma-hydroxybutyric acid and the down-regulated succinate semialdehyde revealed that the neurotransmitter system was disrupted after tramadol abuse. Compared with the low dose tramadol group, there were twenty-nine potential biomarkers in the high dose tramadol group, mainly related to the pentose phosphate pathway and glycerophospholipid metabolism. In conclusion, metabolomics in the tramadol abuse group demonstrated that long-term tramadol abuse can result in oxidative damage, inflammation, and disruption of the GABA neurotransmitter system, which will help to elucidate the toxicology of tramadol abuse.

A single meal has the potential to alter brain oxylipin content.

Our objective was to determine whether consumption of a single meal has the potential to alter brain oxylipin content. We examined the cerebrum of mice fed a single high-fat/high-sucrose Western meal or a low-fat/low-sucrose control meal, as well as fasted mice. We found no changes in fatty acid composition of cerebrum across the groups. The cerebral oxylipin profile of mice fed a Western meal is distinct from the profile of mice fed a low-fat/low-sucrose meal. Cerebral gene expression of cyclooxygenase 1, cyclooxygenase 2, and epoxide hydrolase 1 were elevated in Western meal-fed mice compared to low-fat/low-sucrose meal-fed mice. Mice that consumed either meal had lower gene expression of cytochrome P450, family 2, subfamily j, polypeptide 12 than fasted mice. Our data in this hypothesis-generating study indicates that the composition of a single meal has the potential to alter brain oxylipins and the gene expression of the enzymes responsible for their production.

Frequency-resolved analysis of coherent oscillations of local cerebral blood volume, measured with near-infrared spectroscopy, and systemic arterial pressure in healthy human subjects.

We report a study on twenty-two healthy human subjects of the dynamic relationship between cerebral hemoglobin concentration ([HbT]), measured with near-infrared spectroscopy (NIRS) in the prefrontal cortex, and systemic arterial blood pressure (ABP), measured with finger plethysmography. [HbT] is a measure of local cerebral blood volume (CBV). We induced hemodynamic oscillations at discrete frequencies in the range 0.04-0.20 Hz with cyclic inflation and deflation of pneumatic cuffs wrapped around the subject's thighs. We modeled the transfer function of ABP and [HbT] in terms of effective arterial (K(a)) and venous (K(v)) compliances, and a cerebral autoregulation time constant (τ(AR)). The mean values (± standard errors) of these parameters across the twenty-two subjects were K(a) = 0.01 ± 0.01 µM/mmHg, K(v) = 0.09 ± 0.05 µM/mmHg, and τ(AR) = 2.2 ± 1.3 s. Spatially resolved measurements in a subset of eight subjects reveal a spatial variability of these parameters that may exceed the inter-subject variability at a set location. This study sheds some light onto the role that ABP and cerebral blood flow (CBF) play in the dynamics of [HbT] measured with NIRS, and paves the way for new non-invasive optical studies of cerebral blood flow and cerebral autoregulation.

Changes in MAP-2 and GFAP immunoreactivity in pup hippocampus during prepubertal and pubertal periods caused by maternal subclinical hypothyroidism

An absence of the thyroid hormone during the critical period of brain development causes delayed maturation of glial cells and neurons and decreases the number of hippocampal cells. This study aims to examine the impact of maternal subclinical hypothyroidism (SCH) on pup hippocampus during the prepubertal and pubertal periods by means of assessing the histopathological changes in astrocytes and neurons.Twelve Wistar albino pregnant rats were divided into two groups, Group H and Group C. Group C was designated as the control group and nothing was added to their drinking water. SCH was induced in Group H by administering 6-propyl-2-thiouracil (PTU) at a final concentration of 0.01% in the drinking water of pregnant rats for 21 days. Male pups for each group were divided evenly and evaluated on either day 15 (prepubertal) or 60 (pubertal) (7 pups in each group). At the end of the experimental period, the rats were sacrificed for analysis of brain tissue. Immunoreactivity intensities of MAP-2 and GFAP were evaluated in hippocampus tissue. Thyroid function was determined using ELISA. The structure of hippocampus was evaluated by hematoxylin-eosin staining. Finally, the TUNEL method was utilized to show apoptosis of hippocampus tissue. The results were analyzed statistically.The findings show that maternal SCH causes disruption in hippocampal cytoskeleton and dendritic organization, especially during the pubertal period, as well as a decrease in MAP-2 expression. We observed structural deformation in astrocytes, reduced astrocyte survival and GFAP expression. Finally, we found that the number of neuronal apoptotic cells tended to increase in the pubertal period

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Detection of elevated ketone bodies by postmortem 1H-MRS in a case of fetal ketoacidosis.

We report a fetal loss following maternal ketoacidosis in a case of cryptic pregnancy. Biochemical analysis of peripheral blood revealed highly elevated levels of beta-hydroxybutyrate (BHB) in the mother (9.2 mmol/l) and the fetus (4.2 mmol/l). Fetal ketoacidosis with hypoxic-ischemic brain damage was determined to be the cause of death. 1H-MRS of the right cerebral hemisphere presented with distinctive resonances of BHB and acetone. Acetoacetate and glucose were not detected. Due to reported chronic abuse of ethanol and a period of fasting, alcoholic ketoacidosis was concluded to be the cause of the metabolic disorder. 1H-MRS is a viable examination for the postmortem detection of ketone bodies and may be a key supplement to noninvasive fetal autopsy for the diagnosis of ketoacidosis.

Suppressive effects of neonatal bisphenol A on the neuroendocrine system.

The aim of this study was to assess the effects of neonatal bisphenol A (BPA) administration on neuroendocrine features (the thyroid-brain axis). BPA (20 or 40 µg/kg) was orally administered to juvenile male albino rats ( Rattus norvegicus) from postnatal days (PNDs) 15 to 30. Both doses resulted in lower serum thyroxine (T4), triiodothyronine (T3), and growth hormone levels and higher thyrotropin level than the control levels at PND 30. In the neonatal cerebellum and cerebrum, vacuolation, pyknosis, edema, degenerative changes, and reductions in the size and number of the cells were observed in both treated groups. Alternatively, elevations in oxidative markers (lipid peroxidation, nitric oxide, and hydrogen peroxide [H2O2]) at both dose levels were recorded at PND 30, along with decreased activities of antioxidant markers (ascorbic acid, total thiol [t-SH], glutathione, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, and catalase) with respect to control levels. Thus, the BPA-induced hypothyroid state may disturb the neonatal thyroid-brain axis via production of free radicals, and this could damage the plasma membrane and cellular components, delaying cerebrum and cerebellum development.

A rapid method for identification and quantification of prostaglandins in cerebral tissues by UHPLC-ESI-MS/MS for the lipidomic in vivo studies.

An analytical method utilizing liquid chromatography coupled to mass spectrometry with electrospray ionization has been developed for the identification of prostaglandins (PGs) in cerebral tissues. The five compounds identified (thromboxane B2, prostaglandin E2, prostaglandin D2, 6-keto-prostaglandin F1 alpha and prostaglandin F2 alpha) are cellular mediators of inflammation and are involved in a variety of physiological and pathological processes by acting on membrane receptors on the surfaces of target cells. The parameters of the electrospray ionization interface were optimized to obtain the highest possible sensitivity for all compounds studied. The limits of detection ranged from 0.25 to 1.09 µg L-1, and the limits of quantification ranged from 0.83 to 3.64 µg L-1. The method was validated and applied to samples of brain tissue from five mice. The sample concentrations of the four prostaglandins quantified ranged from 375 ȵg L-1for prostaglandin E2 to 6602 µg L-1 for prostaglandin D2. An advantage of this work that should be emphasized is the fast response of the method, which allows to obtaining the lipid profile after a 3 min chromatographic run.

Tracking Effects of SIL1 Increase: Taking a Closer Look Beyond the Consequences of Elevated Expression Level.

SIL1 acts as a co-chaperone for the major ER-resident chaperone BiP and thus plays a role in many BiP-dependent cellular functions such as protein-folding control and unfolded protein response. Whereas the increase of BiP upon cellular stress conditions is a well-known phenomenon, elevation of SIL1 under stress conditions was thus far solely studied in yeast, and different studies indicated an adverse effect of SIL1 increase. This is seemingly in contrast with the beneficial effect of SIL1 increase in surviving neurons in neurodegenerative disorders such as amyotrophic lateral sclerosis and Alzheimer's disease. Here, we addressed these controversial findings. Applying cell biological, morphological and biochemical methods, we demonstrated that SIL1 increases in various mammalian cells and neuronal tissues upon cellular stress. Investigation of heterozygous SIL1 mutant cells and tissues supported this finding. Moreover, SIL1 protein was found to be stabilized during ER stress. Increased SIL1 initiates ER stress in a concentration-dependent manner which agrees with the described adverse SIL1 effect. However, our results also suggest that protective levels are achieved by the secretion of excessive SIL1 and GRP170 and that moderately increased SIL1 also ameliorates cellular fitness under stress conditions. Our immunoprecipitation results indicate that SIL1 might act in a BiP-independent manner. Proteomic studies showed that SIL1 elevation alters the expression of proteins including crucial players in neurodegeneration, especially in Alzheimer's disease. This finding agrees with our observation of increased SIL1 immunoreactivity in surviving neurons of Alzheimer's disease autopsy cases and supports the assumption that SIL1 plays a protective role in neurodegenerative disorders.

In vivo neurochemical measurements in cerebral tissues using a droplet-based monitoring system.

Direct collection of extracellular fluid (ECF) plays a central role in the monitoring of neurological disorders. Current approaches using microdialysis catheters are however drastically limited in term of temporal resolution. Here we show a functional in vivo validation of a droplet collection system included at the tip of a neural probe. The system comprises an advanced droplet formation mechanism which enables the collection of neurochemicals present in the brain ECF at high-temporal resolution. The probe was implanted in a rat brain and could successfully collect fluid samples organized in a train of droplets. A microfabricated target plate compatible with most of the surface-based detection methods was specifically developed for sample analysis. The time-resolved brain-fluid samples are analyzed using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). The results provide a time evolution picture of the cerebral tissues neurochemical composition for selected elements known for their involvement in neurodegenerative diseases.

Intracerebral Distribution of a-Pinene and the Anxiolytic-like Effect in Mice Following Inhaled Administration of Essential Oil from Chamaecyparis obtuse.

The anxiolytic-like and stress reduction effects following inhaled administration of essential oil from Chamaecyparis obtusa (EOCO) have been reported. Volatile components are thought to produce these effects of EOCO by neurological transfer and pharmacological transfer. The regions of the brain in which inhaled compounds are found due to pharmacological transfer of EOCO are not known. This research was undertaken to clarify the relationship between the intracerebral distribution of α-pinene, which is the main component of EOCO, and emotional behavior. α-Pinene was detected as the main component of volatile EOCO. The amount of α-pinene in each region of the brain was measured following inhaled administration of EOCO. The amount of α-pinene was different in each region of the brain. With inhaled administration of 32 µL/L air EOCO, a high concentration of α-pinene was observed. However, no significant differences in the concentration of α-pinene among brain regions were found. A therapeutic concentration of α-pinene (8 µL/L air EOCO) in each region of the brain may induce an anxiolytic-like effect, and a high concentration of α-pinene (32 µL/L air EOCO) in each region of the brain may induce an excitatory-like effect. The increases in the concentration of α-pinene from 8 to 32 µL/L air EOCO in the striatum and the hippocampus were significantly lower compared with the increases in other brain regions. These results indicate that regions besides the striatum and the hippocampus participated in the increase in locomotor activity due to the high concentration of α-pinene in the brain.

A rare case of malignant pediatric ectomesenchymoma arising from the cerebrum.

Malignant ectomesenchymoma is a rare tumor that contains both ectodermal and mesenchymal elements. So far, only 7 patients with a manifestation in the cerebrum (with confirmed clinicopathological data) have been reported. A 4-year-old girl was present at our hospital with a 3-week history of intermittent sudden dizzy with no apparent cause. MRI showed an irregular enhanced lesion in the left frontal-parietal lobe and lateral ventricle with peripheral gadolinium-enhancement with a significant surrounding edema. Total removal of the tumor was performed. Histological examination of the resected tumor revealed a mixed astrocytoma and anaplastic ependymoma component with undifferentiated mesenchymal spindle cell component. Generally speaking, the main malignant part in most cases of malignant ectomesenchymoma (MEM) is the mesenchymal component. In the present case, the malignant component was both in the mesenchymal and ectodermal part. In particular, the mesenchymal part was mainly composed of spindle cells, and the ectodermal part primarily consisted of gliomatous component and anaplastic ependymoma component. The patient was then treated with chemotherapy and as regard to the prognosis, there was no evidence of tumor recurrence at the 5 months' follow-up. The long term follow-up is still in progress.

Dairy intake is associated with brain glutathione concentration in older adults.

BACKGROUND: A reduction in key antioxidants such as glutathione has been noted in brain tissue undergoing oxidative stress in aging and neurodegeneration. To date, no dietary factor has been linked to a higher glutathione concentration. However, in an earlier pilot study, we showed evidence of a positive association between cerebral glutathione and dairy intake. OBJECTIVE: We tested the hypothesis that dairy food consumption is associated with cerebral glutathione concentrations in older adults. DESIGN: In this observational study, we measured cerebral glutathione concentrations in 60 healthy subjects (mean ± SD age: 68.7 ± 6.2 y) whose routine dairy intakes varied. Glutathione concentrations were measured by using a unique, noninvasive magnetic resonance chemical shift imaging technique at 3 T and compared with dairy intakes reported in 7-d food records. RESULTS: Glutathione concentrations in the frontal [Spearman's rank-order correlation (rs) = 0.39, P = 0.013], parietal (rs = 0.50, P = 0.001), and frontoparietal regions (rs = 0.47, P = 0.003) were correlated with average daily dairy servings. In particular, glutathione concentrations in all 3 regions were positively correlated with milk servings (P ≤ 0.013), and those in the parietal region were also correlated with cheese servings (P = 0.015) and calcium intake (P = 0.039). Dairy intake was related to sex, fat-free mass, and daily intakes of energy, protein, and carbohydrates. However, when these factors were controlled through a partial correlation, correlations between glutathione concentrations and dairy and milk servings remained significant. CONCLUSIONS: Higher cerebral glutathione concentrations were associated with greater dairy consumption in older adults. One possible explanation for this association is that dairy foods may serve as a good source of substrates for glutathione synthesis in the human brain.

Análise proteômica em cérebro de ratos submetidos a tratamento subcrônico com chumbo: influência da suplementação com ferro / Proteomic analysis of brain in rats submitted to subchronic treatment with lead: influence of iron supplementation

O chumbo (Pb) é um metal pesado que pode ocasionar alterações em todos os sistemas. Porém os maiores danos à saúde ocorrem quando este acomete o sistema nervoso central (SNC). Muitos estudos demonstram as alterações clinicas/comportamentais causadas pela ação do Pb no SNC. Entretanto, ainda são necessários estudos que demonstrem as alterações bioquímicas causadas pelo Pb neste sistema. Por outro lado, tem sido relatado que o ferro (Fe) parece ter um efeito protetor na toxicidade cerebral causada pelo Pb. Assim, o objetivo deste estudo foi analisar a concentração de Pb no tecido cerebral, bem como realizar análise proteômica em cérebro de ratos intoxicados por Pb, submetidos à suplementação com Fe ou não. O experimento foi realizado com 30 ratos recém-desmamados (Rattus norvegicus, variedade Wistar) divididos em 6 grupos (n=5/grupo), de acordo com o tratamento recebido por 6 semanas, a saber: Controle (não exposto ao Pb ou Fe), Controle Fe (exposto à administração de 20 mg/Kg p.c. de FeSO4 a cada 2 dias, por gavagem gástrica), Pb 100 (exposto à água contendo 100 mg/L de Pb), Pb 400 (exposto à água contendo 400 mg/L de Pb) Pb100 + Fe (exposto à água contendo 100 mg/L de Pb e à gavagem com FeSO4) e Pb400 + Fe (exposto à água contendo 400 mg/L de Pb e à gavagem com FeSO4). Decorrido o período experimental, os animais foram eutanasiados e o cérebro dos animais foi removido, sendo descartados o cerebelo e o tronco encefálico. O restante foi submetido à concentração de Pb e à análise proteômica. Foi observada uma dose-resposta em relação à concentração de Pb no cérebro. A administração de FeSO4 reduziu os níveis de Pb no cérebro, embora sem significância estatística. A análise dos géis com os spots proteicos demonstrou uma redução na quantidade destes de acordo com o tratamento recebido pelos grupos. O grupo controle mostrou a maior quantidade de spots, ao passo que os grupos que receberam a maior concentração de Pb (400 mg/L) apresentaram as menores quantidade de...

Lead (Pb) is a heavy metal that may yield changes in all body systems, yet the greatest health damages occur when it affects the central nervous system (CNS). Many studies demonstrate the clinical/behavioral changes caused by the action of Pb on the CNS. However, studies are necessary to demonstrate the biochemical changes caused by Pb in this system. Conversely, it has been reported that iron (Fe) seems to play a protective role on the brain toxicity caused by Pb. Therefore, this study analyzed the concentration of Pb in the brain tissue, and conducted proteomic analysis in the brain of rats intoxicated by Pb, submitted or not to Fe supplementation. The study was conducted on 30 weaning rats (Rattus norvegicus, Wistar type) divided in 6 groups (n=5/group), according to the treatment established for 6 weeks, as follows: Control (not exposed to Pb or Fe), Control Fe (exposed to administration of 20 mg/Kg p.c. of FeSO4 at every 2 days, by gastric gavage), Pb 100 exposed to water containing 100 mg/L of Pb), Pb 400 (exposed to water containing 400 mg/L of Pb) Pb100 + Fe (exposed to water containing 100 mg/L of Pb and gavage with FeSO4) and Pb400 + Fe (exposed to water containing 400 mg/L of Pb and gavage with FeSO4). After the experimental period, the animals were killed and the brains of animals were removed, discarding the cerebellum and brainstem. The remaining structure was submitted to analysis of Pb concentration and proteomic analysis. A dose-response relationship was observed in Pb concentration in the brain. The administration of FeSO4 reduced the levels of Pb in the brain, though without statistical significance. The analysis of gels with proteic spots demonstrated reduction in their quantity according to the treatment performed in the groups. The control group exhibited greater concentration of spots, while groups receiving higher Pb concentration (400 mg/L) presented the lowest quantity of spots...

Análise proteômica em cérebro de ratos submetidos a tratamento subcrônico com chumbo: influência da suplementação com ferro / Proteomic analysis of brain in rats submitted to subchronic treatment with lead: influence of iron supplementation

O chumbo (Pb) é um metal pesado que pode ocasionar alterações em todos os sistemas. Porém os maiores danos à saúde ocorrem quando este acomete o sistema nervoso central (SNC). Muitos estudos demonstram as alterações clinicas/comportamentais causadas pela ação do Pb no SNC. Entretanto, ainda são necessários estudos que demonstrem as alterações bioquímicas causadas pelo Pb neste sistema. Por outro lado, tem sido relatado que o ferro (Fe) parece ter um efeito protetor na toxicidade cerebral causada pelo Pb. Assim, o objetivo deste estudo foi analisar a concentração de Pb no tecido cerebral, bem como realizar análise proteômica em cérebro de ratos intoxicados por Pb, submetidos à suplementação com Fe ou não. O experimento foi realizado com 30 ratos recém-desmamados (Rattus norvegicus, variedade Wistar) divididos em 6 grupos (n=5/grupo), de acordo com o tratamento recebido por 6 semanas, a saber: Controle (não exposto ao Pb ou Fe), Controle Fe (exposto à administração de 20 mg/Kg p.c. de FeSO4 a cada 2 dias, por gavagem gástrica), Pb 100 (exposto à água contendo 100 mg/L de Pb), Pb 400 (exposto à água contendo 400 mg/L de Pb) Pb100 + Fe (exposto à água contendo 100 mg/L de Pb e à gavagem com FeSO4) e Pb400 + Fe (exposto à água contendo 400 mg/L de Pb e à gavagem com FeSO4). Decorrido o período experimental, os animais foram eutanasiados e o cérebro dos animais foi removido, sendo descartados o cerebelo e o tronco encefálico. O restante foi submetido à concentração de Pb e à análise proteômica. Foi observada uma dose-resposta em relação à concentração de Pb no cérebro. A administração de FeSO4 reduziu os níveis de Pb no cérebro, embora sem significância estatística. A análise dos géis com os spots proteicos demonstrou uma redução na quantidade destes de acordo com o tratamento recebido pelos grupos. O grupo controle mostrou a maior quantidade de spots, ao passo que os grupos que receberam a maior concentração de Pb (400 mg/L) apresentaram as menores quantidade de...

Lead (Pb) is a heavy metal that may yield changes in all body systems, yet the greatest health damages occur when it affects the central nervous system (CNS). Many studies demonstrate the clinical/behavioral changes caused by the action of Pb on the CNS. However, studies are necessary to demonstrate the biochemical changes caused by Pb in this system. Conversely, it has been reported that iron (Fe) seems to play a protective role on the brain toxicity caused by Pb. Therefore, this study analyzed the concentration of Pb in the brain tissue, and conducted proteomic analysis in the brain of rats intoxicated by Pb, submitted or not to Fe supplementation. The study was conducted on 30 weaning rats (Rattus norvegicus, Wistar type) divided in 6 groups (n=5/group), according to the treatment established for 6 weeks, as follows: Control (not exposed to Pb or Fe), Control Fe (exposed to administration of 20 mg/Kg p.c. of FeSO4 at every 2 days, by gastric gavage), Pb 100 exposed to water containing 100 mg/L of Pb), Pb 400 (exposed to water containing 400 mg/L of Pb) Pb100 + Fe (exposed to water containing 100 mg/L of Pb and gavage with FeSO4) and Pb400 + Fe (exposed to water containing 400 mg/L of Pb and gavage with FeSO4). After the experimental period, the animals were killed and the brains of animals were removed, discarding the cerebellum and brainstem. The remaining structure was submitted to analysis of Pb concentration and proteomic analysis. A dose-response relationship was observed in Pb concentration in the brain. The administration of FeSO4 reduced the levels of Pb in the brain, though without statistical significance. The analysis of gels with proteic spots demonstrated reduction in their quantity according to the treatment performed in the groups. The control group exhibited greater concentration of spots, while groups receiving higher Pb concentration (400 mg/L) presented the lowest quantity of spots...

Envejecimiento cerebral normal y patológico: continuum fisiopatológico o dualidad de procesos involutivos / Normal and pathological brain aging: a physiopathological continuum or an involutive duality

Desde hace años existe una controversia sobre si existe una doble vía (dualidad involutiva) de involución senil del cerebro, que podemos denominar, respectivamente, hacia la senilidad fisiológica o «normal» sin signos de demencia, o bien hacia la senilidad "patológica" o Enfermedad de Alzheimer, que se manifiesta por la aparición de una demencia progresiva, o, por el contrario, una sola vía (continuum) que conduce desde los primeros signos de involución morfológica o funcional senil hasta la fase final de la demencia EA en todos los individuos. Además, en estos últimos años, se está produciendo una profunda revisión de los conceptos sobre la senilidad patológica / EA de manera que ya no se considera que dicho proceso de envejecimiento sólo existe tras efectuar un diagnóstico de demencia, sino que se inicia en el momento en que se produce una alteración de los circuitos cognitivos cerebrales y/o cambio neuropatológico. Con estos nuevos criterios se supone que la senilidad patológica / EA comprende diversas fases sin demencia (asintomáticas o prodrómicas) y otras con demencia de distinto grado. En esta revisión se analizan las razones que se aducen en defensa de una u otra teoría y las características morfofuncionales de los cerebros seniles normales y los patológicos. La mayoría de los estudios realizados apuntan que existen características diferenciales muy marcadas entre los cerebros seniles normales sin demencia y los patológicos con demencia, pero en otros existen grandes discrepancias entre la presencia o no demencia y la de signos de neuropatológicos. La existencia o no del continuum tiene también una muy importante repercusión práctica pues tanto la prevención como la asistencia de las personas mayores dependerán del posible número de individuos afectados: bien solamente los individuos de riesgo o bien toda la población. Existen algunos terrenos donde la investigación podría hacer avanzar nuestros conocimientos en el envejecimiento cerebral, especialmente en el estudio pormenorizado de los individuos controles sanos de entre 30 y 60 años, en el de los "centenarios" con y sin demencia y en grupos con características diferenciales neuropsicológicas (posibles estadíos intermedios de EA según el nuevo "lexicón"). También sería de gran interés estudiar comparativamente el envejecimiento cerebral humano con el de otras especies de mamíferos que no presentaran patología amiloide o tau y con los primates que pueden presentar patología amiloidea. En este último sentido, los animales transgénicos con patología inducida amiloide o/y tau también serían importantes fuentes de información

For years, there is a controversy whether there is a two-way (involutive duality) of senile involution of the brain, which may be called, respectively, pathway to the physiological or "normal" senility, without signs of dementia but with neuronal adaptative responses, and pathway to "pathological" senility or Alzheimer's Disease (AD), which is characterized by the appearance of a progressive dementia, or, conversely, a single way (continuum) leading from the first morphological or functional signs of senile involution until the final stage of AD dementia in all individuals. Moreover, in recent years, a thorough review of the concepts of the pathological senility / EA is producing, so that is not now considered necessary to have dementia to diagnose a pathological aging process because it is considered that the pathological aging / EA is started at the time that a disturbance in cognitive brain circuits and / or neuropathological changes occurs. With these new criteria different clinic-pathological stages are supposed from normal senility to terminal pathological senility / EA, without dementia (prodromal or asymptomatic) and with varying degrees of dementia. In this review the reasons given in defense of one or another theory are analyzed, as well as the morphofunctional features of normal and pathological senile brains. Most studies indicate that there are very marked differential characteristics between normal brains without dementia and senile pathological brains with dementia, but in other, large discrepancies exist between the presence or absence of dementia and the existence or not of neuropathological signs. The existence or not of the continuum also has a very important practical implication for both prevention and care of the elderly, because the possible number of individuals affected: the entire population or only at-risk individuals in the pathological brain senility pathway. There are some areas where research could improve our knowledge on brain aging, especially in the detailed study of healthy control subjects between 30 and 60, «centenarians» with and without dementia and individuals with neuropsychological characteristics different to AD (possible intermediate stages of AD according to the new «lexicon»). It would also be of great interest a comparative study of human brain aging with that of other mammalian species that showed no amyloid or tau pathology and primates that may have amyloid pathology. Transgenic animals with induced amyloid and /or tau pathology, are also important sources of information on pathological aging