Endogenous FGF21 attenuates blood-brain barrier disruption in penumbra after delayed recanalization in MCAO rats through FGFR1/PI3K/Akt pathway / 中南大学学报(医学版)

OBJECTIVES@#Restoration of blood circulation within "time window" is the principal treating goal for treating acute ischemic stroke. Previous studies revealed that delayed recanalization might cause serious ischemia/reperfusion injury. However, plenty of evidences showed delayed recanalization improved neurological outcomes in acute ischemic stroke. This study aims to explore the role of delayed recanalization on blood-brain barrier (BBB) in the penumbra (surrounding ischemic core) and neurological outcomes after middle cerebral artery occlusion (MCAO).@*METHODS@#Recanalization was performed on the 3rd day after MCAO. BBB disruption was tested by Western blotting, Evans blue dye, and immunofluorescence staining. Infarct volume and neurological outcomes were evaluated on the 7th day after MCAO. The expression of fibroblast growth factor 21 (FGF21), fibroblast growth factor receptor 1 (FGFR1), phosphatidylinositol-3-kinase (PI3K), and serine/threonine kinase (Akt) in the penumbra were observed by immunofluorescence staining and/or Western blotting.@*RESULTS@#The extraversion of Evans blue, IgG, and albumin increased surrounding ischemic core after MCAO, but significantly decreased after recanalization. The expression of Claudin-5, Occludin, and zona occludens 1 (ZO-1) decreased surrounding ischemic core after MCAO, but significantly increased after recanalization. Infarct volume reduced and neurological outcomes improved following recanalization (on the 7th day after MCAO). The expressions of Claudin-5, Occludin, and ZO-1 decreased surrounding ischemic core following MCAO, which were up-regulated corresponding to the increases of FGF21, p-FGFR1, PI3K, and p-Akt after recanalization. Intra-cerebroventricular injection of FGFR1 inhibitor SU5402 down-regulated the expression of PI3K, p-Akt, Occludin, Claudin-5, and ZO-1 in the penumbra, which weakened the beneficial effects of recanalization on neurological outcomes after MCAO.@*CONCLUSIONS@#Delayed recanalization on the 3rd day after MCAO increases endogenous FGF21 in the penumbra and activates FGFR1/PI3K/Akt pathway, which attenuates BBB disruption in the penumbra and improves neurobehavior in MCAO rats.

Electroacupuncture Improves Blood-Brain Barrier and Hippocampal Neuroinflammation in SAMP8 Mice by Inhibiting HMGB1/TLR4 and RAGE/NADPH Signaling Pathways / 中国结合医学杂志

OBJECTIVE@#To investigate the molecular mechanisms underlying the beneficial effect of electroacupuncture (EA) in experimental models of Alzheimer's disease (AD) in vivo.@*METHODS@#Senescence-accelerated mouse prone 8 (SAMP8) mice were used as AD models and received EA at Yingxiang (LI 20, bilateral) and Yintang (GV 29) points for 20 days. For certain experiments, SAMP8 mice were injected intravenously with human fibrin (2 mg). The Morris water maze test was used to assess cognitive and memory abilities. The changes of tight junctions of blood-brain barrier (BBB) in mice were observed by transmission electron microscope. The expressions of fibrin, amyloid- β (Aβ), and ionized calcium-binding adapter molecule 1 (IBa-1) in mouse hippocampus (CA1/CA3) were detected by reverse transcription-quantitative polymerase chain reaction (qRT-PCR), Western blot or immunohistochemical staining. The expression of fibrin in mouse plasma was detected by enzyme-linked immunosorbent assay. The expressions of tight junction proteins zonula occludens-1 and claudin-5 in hippocampus were detected by qRT-PCR and immunofluorescence staining. Apoptosis of hippocampal neurons was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining.@*RESULTS@#Fibrin was time-dependently deposited in the hippocampus of SAMP8 mice and this was inhibited by EA treatment (P<0.05 or P<0.01). Furthermore, EA treatment suppressed the accumulation of Aβ in the hippocampus of SAMP8 mice (P<0.01), which was reversed by fibrin injection (P<0.05 or P<0.01). EA improved SAMP8 mice cognitive impairment and BBB permeability (P<0.05 or P<0.01). Moreover, EA decreased reactive oxygen species levels and neuroinflammation in the hippocampus of SAMP8 mice, which was reversed by fibrin injection (P<0.05 or P<0.01). Mechanistically, EA inhibited the promoting effect of fibrin on the high mobility group box protein 1 (HMGB1)/toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE)/nicotinamide adenine dinucleotide phosphate (NADPH) signaling pathways (P<0.01).@*CONCLUSION@#EA may potentially improve cognitive impairment in AD via inhibition of fibrin/A β deposition and deactivation of the HMGB1/TLR4 and RAGE/NADPH signaling pathways.

Blood-cerebrospinal fluid (CSF) barrier dysfunction means reduced CSF flow not barrier leakage - conclusions from CSF protein data / Disfunção da barreira hemato-liquórica significa redução do fluxo de líquido cefalorraquidiano, e não quebra de barreira - conclusões a partir de estudos sobre as proteínas do LCR

ABSTRACT Background: Increased concentrations of serum proteins in cerebrospinal fluid (CSF) are interpreted as blood-CSF barrier dysfunction. Frequently used interpretations such as barrier leakage, disruption or breakdown contradict CSF protein data, which suggest a reduced CSF flow rate as the cause. Results: Even the severest barrier dysfunctions do not change the molecular size-dependent selectivity or the interindividual variation of the protein transfer across barriers. Serum protein concentrations in lumbar CSF increase with hyperbolic functions, but the levels of proteins that do not pass the barrier remain constant (brain proteins) or increase linearly (leptomeningal proteins). All CSF protein dynamics above and below a lumbar blockade can also be explained, independent of their barrier passage, by a reduced caudally directed flow. Local accumulation of gadolinium in multiple sclerosis (MS) is now understood as due to reduced bulk flow elimination by interstitial fluid (ISF). Nonlinear change of the steady state in barrier dysfunction and along normal rostro-caudal gradients supports the diffusion/flow model and contradicts obstructions of diffusion pathways. Regardless of the cause of the disease, pathophysiological flow blockages are found in bacterial meningitis, leukemia, meningeal carcinomatosis, Guillain-Barré syndrome, MS and experimental allergic encephalomyelitis. In humans, the fortyfold higher albumin concentrations in early fetal development decrease later with maturation of the arachnoid villi, i.e., with beginning CSF outflow, which contradicts a relevant outflow to the lymphatic system. Respiration- and heartbeat-dependent oscillations do not disturb net direction of CSF flow. Conclusion: Blood-CSF and blood-brain barrier dysfunctions are an expression of reduced CSF or ISF flow rate.

RESUMO Introdução: Concentrações aumentadas de proteínas séricas no líquido cefalorraquidiano são interpretadas como disfunção da barreira (hemato-liquórica) sanguínea do LCR. Interpretações frequentemente usadas, como vazamento de barreira (quebra ou rompimento de barreira), rompimento ou quebra, contradiz os dados de proteína do LCR, que sugerem uma taxa de fluxo reduzida do LCR como a causa. Resultados: Mesmo as disfunções de barreira mais graves não alteram a seletividade dependente do tamanho molecular nem a variação interindividual da transferência de proteína através de barreiras. As concentrações de proteínas séricas no LCR lombar aumentam com as funções hiperbólicas, mas as proteínas que não passam a barreira permanecem constantes (proteínas do cérebro) ou aumentam linearmente (proteínas leptomeningeais). Toda a dinâmica das proteínas do LCR acima e abaixo de um bloqueio lombar também pode ser explicada, independente de sua passagem pela barreira, por um fluxo caudal reduzido. O acúmulo local de gadolínio na esclerose múltipla (EM) é agora entendido como decorrente da redução da eliminação do bulk flow pelo fluido intersticial (FIS). A mudança não linear do estado estacionário na disfunção da barreira e ao longo dos gradientes rostro-caudais normais apoia o modelo de difusão/fluxo e contradiz as obstruções das vias de difusão. Independentemente da causa da doença, os bloqueios fisiopatológicos do fluxo são encontrados na meningite bacteriana, leucemia, carcinomatose meníngea, síndrome de Guillain-Barré, EM e encefalomielite alérgica experimental. Em humanos, as concentrações de albumina quarenta vezes mais altas no desenvolvimento fetal inicial diminuem tarde com a maturação das vilosidades aracnoides, isto é, com o início do fluxo de LCR, o que contradiz um fluxo relevante para o sistema linfático. As oscilações dependentes da respiração e do batimento cardíaco não perturbam a direção do fluxo do LCR. Conclusão: As disfunções das barreiras hemato-liquórica e hemato-encefálica são uma expressão da redução da taxa de fluxo do LCR ou FIS.

Effects of on behavior and blood-brain barrier in Alzheimer's disease mice / 浙江大学学报·医学版

To investigate the effects of on behavior and blood brain barrier (BBB) in Alzheimer's disease mice. Thirty-eight 4-month-old APP/PS1 double transgenic mice were randomly divided into three groups: model group, low-dose group and high-dose group. Saline, and 12 g·kg·d were given to each group by continuous gavage once a day for respectively. The changes in activities of daily live and fear conditioning memory behavior of mice were examined by nesting behavior test and fear conditioning test, respectively. The β-amyloid protein (Aβ) depositions in cortex and hippocampal CA1 area of mice were detected by thioflavin T staining. The CD34 and activities fibrinogen (Fib) immunofluorescence double staining were used to determine the vascular endothelial integrity and BBB exudation. Compared with model mice, activities of daily live were significantly improved in low-dose and high-dose groups (both <0.01), the fear memory ability was significantly increased in high-dose group (<0.01). The amount of Aβ deposition in cortex and hippocampal CA1 decreased significantly in high-dose group, the area ratio decreased significantly; the area ratio of Aβ deposition in hippocampal CA1 region in low-dose group also decreased (all <0.05). The proportions of CD34 positive area of cortex in low and high dose groups increased, the percentage of fibrinogen positive area decreased (all <0.05). The proportion of CD34 positive area in hippocampal CA1 region in high-dose group was significantly increased, the percentage of fibrinogen positive area decreased significantly (both <0.05). especially high-dose can improve the activities of daily live and fear conditioning memory function of APP/PS1 mice, reduce the deposition of Aβ in brain. The mechanism may be related to the reduction of BBB permeability and the protection of the integrity of BBB.

Comparison among ACR1997, SLICC and the new EULAR/ACR classification criteria in childhood-onset systemic lupus erythematosus

Abstract Background: To date there are no specific classification criteria for childhood-onset systemic lupus erythematosus (cSLE). This study aims to compare the performance among the American College of Rheumatology (ACR) 1997, the Systemic Lupus International Collaborating Clinics criteria (SLICC) and the new European League Against Rheumatism (EULAR)/ACR criteria, in a cSLE cohort. Methods: We conducted a medical chart review study of cSLE cases and controls with defined rheumatic diseases, both ANA positive, to establish each ACR1997, SLICC and EULAR/ACR criterion fulfilled, at first visit and 1-year-follow-up. Results: Study population included 122 cSLE cases and 89 controls. At first visit, SLICC criteria had higher sensitivity than ACR 1997 (89.3% versus 70.5%, p < 0.001), but similar specificity (80.9% versus 83.2%, p = 0.791), however performance was not statistically different at 1-year-follow-up. SLICC better scored in specificity compared to EULAR/ACR score ≥ 10 at first visit (80.9% versus 67.4%, p = 0.008) and at 1-year (76.4% versus 58.4%, p = 0.001), although sensitivities were similar. EULAR/ACR criteria score ≥ 10 exhibited higher sensitivity than ACR 1997 (87.7% versus 70.5%, p < 0.001) at first visit, but comparable at 1-year, whereas specificity was lower at first visit (67.4% versus 83.2%, p = 0.004) and 1-year (58.4% versus 76.4%, p = 0.002). A EULAR/ACR score ≥ 13 against a score ≥ 10, resulted in higher specificity, positive predictive value, and cut-off point accuracy. Compared to SLICC, a EULAR/ACR score ≥ 13 resulted in lower sensitivity at first visit (76.2% versus 89.3%, p < 0.001) and 1-year (91% versus 97.5%, p = 0.008), but similar specificities at both assessments. When compared to ACR 1997, a EULAR/ACR total score ≥ 13, resulted in no differences in sensitivity and specificity at both observation periods. Conclusions: In this cSLE population, SLICC criteria better scored at first visit and 1-year-follow-up. The adoption of a EULAR/ACR total score ≥ 13 in this study, against the initially proposed ≥10 score, was most appropriate to classify cSLE. Further studies are necessary to address if SLICC criteria might allow fulfillment of cSLE classification earlier in disease course and may be more inclusive of cSLE subjects for clinical studies.

Identificação de um novo motivo peptídico específico para a vasculatura cerebral e que diferencia as barreiras hematoenfálica e hematoretiniana / Identification of a new specific peptide motif to the brain vasculature that differentiates between the blood brain barrier and the bloodretinal barrier

O conceito de heterogeneidade vascular é bem aceito pela comunidade cientifica, desempenhando papel essencial em processos fisiológicos e patológicos. Uma vez que os vasos sanguíneos são importantes na organogênese, diferenciação e morfogênese de tecidos e órgãos, torna-se interessante desvendar a diversidade vascular cerebral, identificando novos marcadores moleculares para este órgão tão importante. Utilizando tecnologia combinatorial de phage display in vivo, identificamos um novo motivo peptídico, na qual os aminoácidos FenilalaninaArginina-Triptofano (Phe-Arg-Trp; FRW) predominam. Este motivo peptídico é um ligante seletivo para vasos sanguíneos cerebrais e não se acumula em outros órgãos, incluíndo tecidos como intestinos e gônadas, que também apresentam barreiras endoteliais especificas. No entanto, mais surpreendente foi a observação de que o motivo FRW não se liga aos vasos sanguíneos da retina, o que implica em uma diferença até então desconhecida entre duas barreiras: a barreira hematoencefálica e a barreira hematoretiniana. Combinando phage display in vivo e microscopia eletrônica de transmissão, observamos a presença de partículas de fago ligadas à vasculatura cerebral em um nível supramolecular: aglomerados de fagos filamentosos expressando o motivo FRW foram visualizados ligados às regiões de contato entre as células endoteliais. Por fim, a utilização do peptídeo CFFWKFRWMC permite imageamento in vivo, demonstrando que novas ferramentas para estudar e visualizar o cérebro podem surgir deste motivo

The concept of vascular heterogeneity is well accepted by the scientific community, playing an essential role in physiological and pathological processes. Since blood vessels are important in organogenesis, differentiation, and morphogenesis of tissues and organs, it becomes interesting to unveil the cerebral vascular diversity, identifying new molecular markers for such important organ. Using in vivo phage display, we show that a new peptide motif that emerged from our combinatorial screening of the vasculature binds selectively to blood vessels in the brain in vivo but not to vessels in other organs. Peptides containing a conserved motif in which amino acids Phenylalanine-Arginine-Tryptophan (Phe-Arg-Trp; FRW) predominate could be visualized by transmission electron microscopy bound to the junctions between endothelial in all areas of the brain, including the optic nerve but not in other barrier containing tissues, such as intestines and testis. Remarkably, peptides containing the motif do not bind to vessels in the retina, implying an important molecular difference between these two vascular barriers. Furthermore, the peptide allows for in vivo imaging, demonstrating that new tools for studying and imaging the brain are likely to emerge from this motif

Expression of Aquaporin 4 in Diffuse Brain Injury of Rats / 法医学杂志

OBJECTIVE@#To observe the expression of aquaporin 4 (AQP4) in diffuse brain injury (DBI) of rats and to explore the corresponding effect of AQP4 for brain edema.@*METHODS@#The rat model of DBI was established using Marmarou's impact-compression trauma model. Brain water content was measured by dry-wet weight method. Blood-brain barrier permeability was evaluated by Evans blue (EB) staining. Immunohistochemical method was used to observe the expression of AQP4.@*RESULTS@#Brain water content increased after 3 h and peaked at 24 h after DBI. Brain EB content significantly increased and peaked at 12 h after DBI. The expression of AQP4 significantly increased after 3 h and peaked at 24 h after DBI, and the number of AQP4 positive astrocytes increased.@*CONCLUSION@#The increment of the permeability of blood-brain barrier and the expression of AQP4 may contribute to the development of brain edema in rat DBI. The change of AQP4 expression in astrocytes may also contribute to determine DBI.

Blood-brain barrier breakdown and repair following gliotoxic drug injection in the brainstem of streptozotocin-diabetic rats / Ruptura e reparo da barreira hematoencefálica pós-injeção de droga gliotóxica no tronco encefálico ratos diabéticos

Ethidium bromide (EB) causes local astrocytic disappearance, with glia limitans disruption and blood-brain barrier (BBB) breakdown. The aim of this study was to evaluate the BBB integrity after the injection of 0.1 percent EB or 0.9 percent saline solution into the cisterna pontis of Wistar rats submitted or not to the streptozotocin diabetogenic model. Brainstem sections were collected from 24 hours to 31 days post-injection for ultrastructural analysis and glial fibrillary acidic protein immunohistochemical staining. Some animals received colloidal carbon ink by intravenous route at the same periods. In rats injected with EB, results revealed astrocyte disappearance and leakage of carbon particles beginning at 48 hours and persisting for 7 days in non-diabetic rats and for 15 days in the diabetic ones, although, in both groups, several areas remained devoid of astrocytic processes up to 31 days. In rats injected with saline, there was no sign of astrocytic loss or carbon particles leakage.

O brometo de etídio (BE) determina o desaparecimento local de astrócitos, com ruptura da glia limitans e dano na barreira hematoencefálica (BHE). Este estudo visou avaliar a integridade da BHE após injeção de solução de BE a 0,1 por cento ou de salina a 0,9 por cento na cisterna pontis de ratos Wistar submetidos ou não ao modelo diabetogênico da estreptozotocina. Fragmentos do tronco encefálico foram coletados das 24 horas aos 31 dias pós-injeção para estudo ultraestrutural e marcação imuno-histoquímica para proteína glial fibrilar ácida. Alguns animais receberam carvão coloidal por via intravenosa nos mesmos períodos. Nos grupos injetados com BE, os resultados mostraram desaparecimento astrocitário e extravasamento de partículas de carvão nas lesões a partir das 48 horas, persistindo por até sete dias nos animais não diabéticos e 15 dias nos diabéticos, embora, em ambos os grupos, diversas áreas permanecessem destituídas de astrócitos até 31 dias após. Nos ratos injetados com salina, diabéticos ou não, não houve sinal de perda astrocitária nem de extravasamento vascular de carvão.

Human Exposure and Health Effects of Inorganic and Elemental Mercury / 예방의학회지

Mercury is a toxic and non-essential metal in the human body. Mercury is ubiquitously distributed in the environment, present in natural products, and exists extensively in items encountered in daily life. There are three forms of mercury, i.e., elemental (or metallic) mercury, inorganic mercury compounds, and organic mercury compounds. This review examines the toxicity of elemental mercury and inorganic mercury compounds. Inorganic mercury compounds are water soluble with a bioavailability of 7% to 15% after ingestion; they are also irritants and cause gastrointestinal symptoms. Upon entering the body, inorganic mercury compounds are accumulated mainly in the kidneys and produce kidney damage. In contrast, human exposure to elemental mercury is mainly by inhalation, followed by rapid absorption and distribution in all major organs. Elemental mercury from ingestion is poorly absorbed with a bioavailability of less than 0.01%. The primary target organs of elemental mercury are the brain and kidney. Elemental mercury is lipid soluble and can cross the blood-brain barrier, while inorganic mercury compounds are not lipid soluble, rendering them unable to cross the blood-brain barrier. Elemental mercury may also enter the brain from the nasal cavity through the olfactory pathway. The blood mercury is a useful biomarker after short-term and high-level exposure, whereas the urine mercury is the ideal biomarker for long-term exposure to both elemental and inorganic mercury, and also as a good indicator of body burden. This review discusses the common sources of mercury exposure, skin lightening products containing mercury and mercury release from dental amalgam filling, two issues that happen in daily life, bear significant public health importance, and yet undergo extensive debate on their safety.

Protective effects of transduced Tat-DJ-1 protein against oxidative stress and ischemic brain injury

Reactive oxygen species (ROS) contribute to the development of a number of neuronal diseases including ischemia. DJ-1, also known to PARK7, plays an important role in transcriptional regulation, acting as molecular chaperone and antioxidant. In the present study, we investigated whether DJ-1 protein shows a protective effect against oxidative stress-induced neuronal cell death in vitro and in ischemic animal models in vivo. To explore DJ-1 protein's potential role in protecting against ischemic cell death, we constructed cell permeable Tat-DJ-1 fusion proteins. Tat-DJ-1 protein efficiently transduced into neuronal cells in a dose- and time-dependent manner. Transduced Tat-DJ-1 protein increased cell survival against hydrogen peroxide (H2O2) toxicity and also reduced intracellular ROS. In addition, Tat-DJ-1 protein inhibited DNA fragmentation induced by H2O2. Furthermore, in animal models, immunohistochemical analysis revealed that Tat-DJ-1 protein prevented neuronal cell death induced by transient forebrain ischemia in the CA1 region of the hippocampus. These results demonstrate that transduced Tat-DJ-1 protein protects against cell death in vitro and in vivo, suggesting that the transduction of Tat-DJ-1 may be useful as a therapeutic agent for ischemic injuries related to oxidative stress.

Iron mediates endothelial cell damage and blood-brain barrier opening in the hippocampus after transient forebrain ischemia in rats

Blood cells are transported into the brain and are thought to participate in neurodegenerative processes following hypoxic ischemic injury. We examined the possibility that transient forebrain ischemia (TFI) causes the blood-brain barrier (BBB) to become permeable to blood cells, possibly via dysfunction and degeneration of endothelial cells in rats. Extravasation of Evans blue and immunoglobulin G (IgG) was observed in the hippocampal CA1-2 areas within 8 h after TFI, and peaked at 48 h. This extravasation was accompanied by loss of tight junction proteins, occludin, and zonula occludens-1, and degeneration of endothelial cells in the CA1-2 areas. Iron overload and mitochondrial free radical production were evident in the microvessel endothelium of the hippocampus before endothelial cell damage occurred. Administration of deferoxamine (DFO), an iron chelator, or Neu2000, an antioxidant, blocked free radical production and endothelial cell degeneration. Our findings suggest that iron overload and iron-mediated free radical production cause loss of tight junction proteins and degeneration of endothelial cells, opening of the BBB after TFI.

Enhanced expression of aquaporin-9 in rat brain edema induced by bacterial lipopolysaccharides / 华中科技大学学报（医学）（英德文版）

To investigate the role of AQP9 in brain edema, the expression of AQP9 in an infectious rat brain edema model induced by the injection of lipopolysaccharide (LPS) was examined. Immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) analysis demonstrated that the expressions of AQP9 mRNA and protein at all observed intervals were significantly increased in LPS-treated animals in comparison with the control animals. Time-course analysis showed that the first signs of blood-brain barrier disruption and the increase of brain water content in LPS-treated animals were evident 6 h after LPS injection, with maximum value appearing at 12 h, which coincided with the expression profiles of AQP9 mRNA and protein in LPS-treated animals. The further correlation analysis revealed strong positive correlations among the brain water content, the disruption of the blood-brain barrier and the enhanced expressions of AQP9 mRNA and protein in LPS-treated animals. These results suggested that the regulation of AQP9 expression may play important roles in water movement and in brain metabolic homeostasis associated with the pathophysiology of brain edema induced by LPS injection.

Understanding safety of glutamate in food and brain.

Glutamate is ubiquitous in nature and is present in all living organisms. It is the principal excitatory neurotransmitter in central nervous system. Glutamate is being used as food additive for enhancing flavour for over last 1200 years imparting a unique taste known as "umami" in Japanese. It is being marketed for about last 100 years. The taste of umami is now recognized as the fifth basic taste. Many of the foods used in cooking for enhancing flavour contain high amount of glutamate. Breast milk has the highest concentration of glutamate amongst all amino acids. Glutamate in high doses as gavage or parenteral injection have been reported to produce neurodegeneration in infant rodents. The neurodegeneration was not produced when gluamate was given with food. The Joint FAO/WHO Expert Committee on Food Additives, based on enumerable scientific evidence, has declared that, "glutamate as an additive in food" is not an health hazard to human being. Glutamate is used as signaling molecule not only in neuronal but also in non-neuronal tissues. Excessive accumulation of glutamate in the synaptic cleft has been associated with excitotoxicty and glutamate is implicated in number of neurological disorders. Excessive accumulation could be attributed to increase release, failure of transport system for uptake mechanism, neuronal injury due to hypoxia-ischemia, trauma and associated metabolic failures. The role blood brain barrier, vesicular glutamate and sodium dependent excitatory amino acid transporters in glutamate homeostasis are emphasized in the review.

Behavioral and neuropharmacological evidence that serotonin crosses the blood-brain barrier in Coturnix japonica (Galliformes; Aves)

This study was carried out aiming to reach behavioral and neuropharmacological evidence of the permeability of the blood-brain barrier (BBB) to serotonin systemically administered in quails. Serotonin injected by a parenteral route (250-1000 æg.kg-1, sc) elicited a sequence of behavioral events concerned with a sleeping-like state. Sleeping-like behaviors began with feather bristling, rapid oral movements, blinking and finally crouching and closure of the eyes. Previous administration of 5-HT2C antagonist, LY53857 (3 mg.kg-1, sc) reduced the episodes of feather bristling and rapid oral movements significantly but without altering the frequency of blinking and closure of the eyes. Treatment with the 5-HT2A/2C antagonist, ketanserin (3 mg.kg-1, sc) did not affect any of the responses evoked by the serotonin. Quipazine (5 mg.kg-1, sc) a 5-HT2A/2C/3 agonist induced intense hypomotility, long periods of yawning-like and sleeping-like states. Previous ketanserin suppressed gaping responses and reduced hypomotility, rapid oral movements and bristling but was ineffective for remaining responses induced by quipazine. Results showed that unlike mammals, serotonin permeates the BBB and activates hypnogenic mechanisms in quails. Studies using serotoninergic agonist and antagonists have disclosed that among the actions of the serotonin, feather bristling, rapid oral movements and yawning-like state originated from activation of 5-HT2 receptors while blinking and closure of the eyes possibly require other subtypes of receptors.

Este estudo foi desenvolvido objetivando ampliar as evidências comportamentais e neurofarmacológicas da permeabilidade da barreira hematoencefálica (BHE) à serotonina administrada sistemicamente em codornas. A serotonina injetada por via parenteral (250-1000 æg.kg-1, sc) produziu uma seqüência de eventos relacionados com um estado semelhante ao sono. Comportamentos semelhantes ao sono começaram com o eriçamento das penas, movimentos orais rápidos, piscadelas e finalmente agachamento e fechamento dos olhos. A administração prévia do antagonista do receptor 5-HT2C, LY53857 (3 mg.kg-1, sc) reduziu significativamente os episódios de eriçamento das penas e movimentos orais rápidos, mas não alterou a freqüência de piscadelas e fechamento dos olhos. Tratamento com o antagonista do receptor 5-HT2A/2C, quetanserina (3 mg.kg-1, sc) não afetou nenhuma das respostas evocadas pela serotonina. A quipazina (5 mg.kg-1, sc), um agonista dos receptores 5-HT2A/2C/3, induziu intensa hipomotilidade e longos períodos de comportamentos semelhantes ao bocejo e ao sono. O tratamento prévio com quetanserina suprimiu as reações de bocejo e reduziu a hipomotilidade, os movimentos orais rápidos e as piscadelas, mas foi sem efeito para as demais respostas induzidas pela quipazina. Os resultados mostraram que, diferentemente dos mamíferos, a serotonina atravessa a BHE e ativa mecanismos hipnogênicos em codornas. Estudos com agonistas serotoninérgicos e antagonistas revelaram que, entre as ações da serotonina, o eriçamento das penas, os movimentos orais rápidos e o comportamento semelhante ao bocejo foram originados pela ativação de receptores 5-HT2, enquanto o piscar e o fechamento dos olhos possivelmente requereu outros subtipos de receptores.