Antipsychotics for patients with pain

Going back to basics prior to mentioning the use of antipsychotics in patients with pain, the International Association for the Study of Pain (IASP) definition of pain can be summarized as an unpleasant experience, composed of sensory experience caused by actual tissue damage and/or emotional experience caused by potential tissue damage. Less used than antidepressants, antipsychotics have also been used for treating this unpleasant experience as adjuvant analgesics without sufficient evidence from research. Because recently developed atypical antipsychotics reduce the adverse reactions of extrapyramidal symptoms, such as acute dystonia, pseudo-parkinsonism, akathisia, and tardive dyskinesia caused by typical antipsychotics, they are expected to be used more frequently in various painful conditions, while increasing the risk of metabolic syndromes (weight gain, diabetes, and dyslipidemia). Various antipsychotics have different neurotransmitter receptor affinities for dopamine (D), 5-hydroxytryptamine (5-HT), adrenergic (α), histamine (H), and muscarinic (M) receptors. Atypical antipsychotics antagonize transient, weak D₂ receptor bindings with strong binding to the 5-HT(2A) receptor, while typical antipsychotics block long-lasting, tight D₂ receptor binding. On the contrary, antidepressants in the field of pain management also block the reuptake of similar receptors, mainly on the 5-HT and, next, on the norepinephrine, but rarely on the D receptors. Antipsychotics have been used for treating positive symptoms, such as delusion, hallucination, disorganized thought and behavior, perception disturbance, and inappropriate emotion, rather than the negative, cognitive, and affective symptoms of psychosis. Therefore, an antipsychotic may be prescribed in pain patients with positive symptoms of psychosis during or after controlling all sensory components.

Cocaine- and Amphetamine-Regulated Transcript (CART) Peptide Plays Critical Role in Psychostimulant-Induced Depression

Cocaine- and amphetamine-regulated transcript (CART) peptide is a widely distributed neurotransmitter expressed in the central nervous systems. Previously, several reports demonstrated that nucleus accumbal-injected CART peptide positively modulated behavioral sensitization induced by psychostimulants and regulated the mesocorticolimbic dopaminergic pathway. It is confirmed that CART peptide exerted inhibitory effect on psychostimulant-enhanced dopamine receptors signaling, Ca2+/calmodulin-dependent kinase signaling and crucial transcription factors expression. Besides modulation of dopamine receptors-related pathways, CART peptide also exhibited elaborated interactions with other neurotransmitter receptors, such as glutamate receptors and γ-aminobutyric acid receptors, which further account for attribution of CART peptide to inhibition of psychostimulant-potentiated locomotor activity. Recently, CART peptide has been shown to have anxiolytic functions on the aversive mood and uncontrolled drug-seeking behaviors following drug withdrawal. Moreover, microinjection of CART peptide has been shown to have an anti-depressant effect, which suggests its potential utility in the mood regulation and avoidance of depression-like behaviors. In this review, we discuss CART pathways in neural circuits and their interactions with neurotransmitters associated with psychostimulant-induced depression.

Neuropharmacological Targets for Drug Action in Vestibular Sensory Pathways

The use of pharmacological agents is often the preferred approach to the management of vestibular dysfunction. In the vestibular sensory pathways, the sensory neuroepithelia are thought to be influenced by a diverse number of neuroactive substances that may act to enhance or inhibit the effect of the primary neurotransmitters [i.e., glutamate (Glu) and acetylcholine (ACh)] or alter their patterns of release. This review summarizes various efforts to identify drug targets including neurotransmitter and neuromodulator receptors in the vestibular sensory pathways. Identifying these receptor targets provides a strategic basis to use specific pharmacological tools to modify receptor function in the treatment and management of debilitating balance disorders. A review of the literature reveals that most investigations of the neuropharmacology of peripheral vestibular function have been performed using in vitro or ex vivo animal preparations rather than studying drug action on the normal intact vestibular system in situ. Such noninvasive approaches could aid the development of more accurate and effective intervention strategies for the treatment of dizziness and vertigo. The current review explores the major neuropharmacological targets for drug action in the vestibular system.

Neuropharmacological Targets for Drug Action in Vestibular Sensory Pathways

The use of pharmacological agents is often the preferred approach to the management of vestibular dysfunction. In the vestibular sensory pathways, the sensory neuroepithelia are thought to be influenced by a diverse number of neuroactive substances that may act to enhance or inhibit the effect of the primary neurotransmitters [i.e., glutamate (Glu) and acetylcholine (ACh)] or alter their patterns of release. This review summarizes various efforts to identify drug targets including neurotransmitter and neuromodulator receptors in the vestibular sensory pathways. Identifying these receptor targets provides a strategic basis to use specific pharmacological tools to modify receptor function in the treatment and management of debilitating balance disorders. A review of the literature reveals that most investigations of the neuropharmacology of peripheral vestibular function have been performed using in vitro or ex vivo animal preparations rather than studying drug action on the normal intact vestibular system in situ. Such noninvasive approaches could aid the development of more accurate and effective intervention strategies for the treatment of dizziness and vertigo. The current review explores the major neuropharmacological targets for drug action in the vestibular system.

A review on alcohol: from the central action mechanism to chemical dependency / Uma revisão sobre o álcool: do mecanismo de ação central à dependência química

SummaryIntroduction:alcohol is a psychotropic depressant of the central nervous system (CNS) that promotes simultaneous changes in several neuronal pathways, exerting a profound neurological impact that leads to various behavioral and biological alterations.Objectives:to describe the effects of alcohol on the CNS, identifying the signaling pathways that are modified and the biological effects resulting from its consumption.Methods:a literature review was conducted and articles published in different languages over the last 15 years were retrieved.Results:the studies reviewed describe the direct effect of alcohol on several neurotransmitter receptors (gamma-aminobutyric acid [GABA], glutamate, endocannabinoids AEA and 2-AG, among others), the indirect effect of alcohol on the limbic and opioid systems, and the effect on calcium and potassium channels and on proteins regulated by GABA in the hippocampus.Discussion and conclusion:the multiple actions of alcohol on the CNS result in a general effect of psychomotor depression, difficulties in information storage and logical reasoning and motor incoordination, in addition to stimulating the reward system, a fact that may explain the development of addiction. Knowledge on the neuronal signaling pathways that are altered by alcohol allows the identification of effectors which could reduce its central action, thus, offering new therapeutic perspectives for the rehabilitation of alcohol addicts.

ResumoIntrodução:o álcool é uma substância psicotrópica depressora do sistema nervoso central (SNC), que promove alteração simultânea de inúmeras vias neuronais, gerando profundo impacto neurológico e traduzindo-se em diversas alterações biológicas e comportamentais.Objetivos:descrever as ações do álcool sobre o SNC, identificando as vias de sinalização modificadas e os efeitos biológicos gerados pelo seu consumo.Métodos:revisão bibliográfica, priorizando trabalhos multilinguísticos publicados nos últimos 15 anos.Resultados:são descritas ação direta do álcool em inúmeros receptores de neurotransmissores (ácido gama-aminobutírico – GABA, glutamato, endocanabinoides AEA e 2-AG, entre outros), ação indireta do álcool no sistema límbico e opioide, ação sobre canais de cálcio, potássio e proteínas reguladas por GABA no hipocampo, além de ações centrais mediadas pela deficiência de vitamina B1.Conclusão:a ação multifocal do álcool sobre o SNC resulta em efeito geral de depressão psicomotora, dificuldades no armazenamento de informações e no raciocínio lógico, incoordenação motora, além da estimulação do sistema de recompensa, o que pode explicar o desenvolvimento da dependência química. O conhecimento das vias de sinalização neuronais alteradas pelo álcool permite reconhecer a descrição de efetores que possam reduzir sua ação central e, assim, vislumbrar novas perspectivas terapêuticas para a reabilitação de adictos a essa substância.

The effect of Wnt signaling pathway on paraquat induced PC12 cells damage / 中华劳动卫生职业病杂志

<p><b>OBJECTIVE</b>To investigate the role of Wnt signaling pathway on paraquat (PQ)induced PC12 cells damage.</p><p><b>METHODS</b>Using PC12 cells, in this study CCK8 assay was used to detect the effect of cell viability. The cell apoptosis and cell cycle was detected by flow cytometry. The real-time polymerase chain reaction (RT-PCR) was used to measure the mRNA expression of Wnt pathway key genes including Fzd1, Dvl2 and β-catenin and downstream genes including Bax, Bcl2, Survivin, Cyclin D1 and C-myc.</p><p><b>RESULT</b>Compared with the control, PC12 cells viability in 50.00 and 100.00 µmol/L PQ treatment groups were obviously decreased, the cell cycle S phase arrest, and cell apoptosis increased (P<0.05). The 25.00, 50.00 and 100.00 µmol/L PQ treatment groups mRNA expression of Wnt pathway key genes including Fzd1, Dvl2 and β-catenin and downstream genes including apoptosis suppressor genes (Bcl-2 and survivin)and cyclin gene (Cyclin D1) were downregulated (P<0.05). The mRNA expression of pro-apoptosis gene (Bax) and cyclin gene (C-myc) were upregulated (P<0.05).</p><p><b>CONCLUSION</b>It suggested that PQ can activate Wnt pathway to regulate downsteam genes expression, resulting in PC12 cell cycle arrest and apoptosis.</p>

Purificação de células troco de lipoaspirado humano por aptâmeros de DNA, seguida da caracterização dos fenótipos obtidos da diferenciação neuronal / Human adipose mesechymal stem cell separation by DNA aptamers followed by the characterization of the obtained phenotypes from neuronal differentiation

Células tronco mesenquimais de tecido adiposo, são uma promissora ferramenta para aplicações clínicas em terapias celular e regenerativa, em vista da facilidade de sua extração e da maior quantidade de células por unidade de massa de tecido quando comparado a outras fontes clássicas de células mesenquimais como medula óssea. O protocolo clássico de extração e purificação dessas células, depende de sua adesão em plástico e xeno-materiais demandando muito tempo para ser utilizado por médicos para auxiliar pacientes em procedimentos de emergência. Estas células são capazes se diferenciar em diversos tipos celulares, o que as torna boas candidatas para terapia celular, embora sua capacidade de transdiferenciação para fenótipos neuronais seja ainda discutida. Neste trabalho demonstramos um novo processo para isolar essas células na base de epitopos específicos expressos (assinatura molecular de superfície) utilizando aptâmeros como ligantes de alta afinidade para estes sitios. Aptâmeros, moléculas de DNA simples fita identificadas a partir de uma biblioteca combinatória de sequencias de DNA simples-fita foram identificados por ciclos reiterativos de seleção in vitro (SELEX) utilizando células tronco do lipoaspirado como alvo. Dois aptâmeros isolados, denominados APT9 e APT11, foram capazes de identificar subpopulações (15,8 e 23,7% respectivamente) dentre as células tronco mesenquimais (classicamente CD29+/CD90+/CD45-) e separá-las usando nano-partículas magnéticas acopladas aos aptâmeros. Além disso, seguindo uma indução para diferenciação neuronal, as células tronco mesenquimais passam a apresentar morfologia neuronal e apresentam expressão e atividade de diversos receptores de neurotransmissores, avaliados por PCR real-time e imageamento de variações da concentração de cálcio intracelular ápos stimulação com vários agonistas de receptores metatrópicos e ionotrópicos. Ao longo da diferenciação, os níveis transcricionais de mRNA de receptores de cininas (B1 e B2), nicotínicos (alfa 7), muscarínicos (M1, M3 e M4), glutamatérgicos (AMPA2 e mGluR2), purinérgicos (P2Y1 e P2Y4) e GABAergicos (GABA-A, subunidade 3) e da óxido nítrico sintase neural aumentaram quando comparados aos níveis das células não diferenciadas, enquanto que os níveis de expressão de outros receptores incluindo purinérgicos P2X1, P3X4, P2X7 e P2Y6 e muscarínico M5 diminuíram. Os níveis de atividade das classes dos receptores estudados, por imageamento de variações da concentração de cálcio intrac, aumentaram para a maioria dos agonistas analisados durante a diferenciação neuronal com exceção para respostas induzidas por glutamato e NMDA. Células diferenciadas expressavam altos níveis de antígenos específicos de neurônios como ß3-tubulina, NF-H, NeuN e MAP-2 indicando uma diferenciação em fenótipo neuronal bem sucedida. Desta maneira, esta tese, ao identificar aptâmeros, prove uma inovadora solução para médicos usarem as células tronco mesenquimais dentro de uma sala de cirurgia, através de um método que é capaz de purificar essas células em um tempo clínico viável, com pureza e sem contato com contaminantes. Além disso, nós mostramos aqui que com um protocolo como o proposto para diferenciação neuronal, nós poderíamos induzir essas células para se diferenciar em neurônios, através da ativação de fatores de transcrição específicos, levando às células tronco mesenquimais a serem possivelmente utilizadas em terapias celulares de reparo neuronal

Adipose mesenchymal stem cells are promising tools for clinical applications in cellular and regeneration therapies, in view of easiness of extraction and higher amount of isolated stem cells per mass of tissue when compared to other classical mesenchymal stem cell sources including bone marrow. The classical protocol to extract and purify these cells, depending on plastic adherence and xeno-materials, is too time consuming to be used by physicians to help patients at emergency procedures. These cells are able to differentiate into various cell types, making them good candidates for cell therapy, however their capability for transdifferentiation into neural phenotypes is yet discussed. Here we show a novel process to isolate these cells using their surface molecular signature and aptamers, ssDNA molecules identified through the SELEX technique, denominated APT9 and APT11 that are able to identify subpopulations (15,8 and 23,7% respectively) within the mesenchymal stem cells (classically CD29+/CD90+/CD45-) and separate them using magnetic nano-particles attached to the aptamers. Moreover, following induction to neural differentiation, mesenchymal cells presents neuronal morphology and present expression and activity of several neurotransmitter receptors, as evaluated by real-time PCR and calcium imaging. During this process, mRNA transcription levels of bradykinin (B1 and B2), cholinergic (alpha 7), muscarinic (M1, M3 and M4), glutamatergic (AMPA2 and mGlu2), purinergic (P2Y1 and P2Y4) and GABAergic (GABA-A, subunit 3) receptors and neuronal nitric oxide synthase were augmented when compared to levels of undifferentiated cells, while the expression levels of other receptors including purinergic P2X1, P2X4, P2X7 and P2Y6 and muscarinic M5 receptors were down-regulated. Activity levels of the studied receptor classes, as studied by calcium imaging, increased for most of the agonists analyzed during the neuronal differentiation with the exception for glutamate- and NMDA-induced receptor responses. Differentiated cells expressed high levels of neuron-specific antigens such as ß3-tubulin, NF-H, NeuN and MAP-2, indicating a successful differentiation into neuronal phenotypes. This thesis, by identifying aptamers, provides a novel solution for physicians to use mesenchymal stem cells inside a surgery room, by using a method that are able to purify the cells in a clinical viable time, with purity and no contact with contaminats. Furthermore, we show here that with a protocol as provided for neuronal differentiation, we could induce these cells to differentiate into neurons, by activating specific transcription factors,making mesenchymal stem cells to possibly be used in neuronal repair cell therapies

Roles of Matrix Metalloproteinases and Their Targets in Epileptogenesis and Seizures

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) remodel the pericellular environment by regulating the cleavage of extracellular matrix proteins, cell surface components, neurotransmitter receptors, and growth factors, which together regulate cell adhesion, synaptogenesis, synaptic plasticity, and long-term potentiation. Increased MMP activity and dysregulation of the balance between MMPs and TIMPs have also been implicated in various pathological conditions. Recent studies have suggested that prolonged seizures are associated with high MMP levels in serum and neural tissues, and certain extracellular macromolecule targets may influence the pathogenesis of epilepsy and seizure. In this review, we discuss the roles of MMP activation in animal models of epilepsy.

Regulação autonômica das propriedades mecânicas em bioprótese valvar porcina / Autonomic regulation of mechanical properties in porcine mitral valve cusps / Regulación autonómica de las propiedades mecánicas en bioprótesis valvular porcina

FUNDAMENTO: A presença de nervos nas válvulas cardíacas foi demonstrada pela primeira vez há décadas e identificadas em subpopulações: simpáticas e parassimpáticas, e, portanto, é esperado que as válvulas sejam grandemente afetadas pelos nervos autônomos. Entretanto, poucos estudos têm se concentrado na regulação de válvulas cardíacas pelo sistema nervoso autônomo. OBJETIVO: Buscamos identificar o papel do sistema nervoso autônomo na regulação das propriedades mecânicas dos tecidos de válvulas mitrais porcinas. MÉTODOS: As propriedades mecânicas dos folhetos de válvulas mitrais porcinas foram avaliados em resposta à norepinefrina (NE) e acetilcolina (ACH), os principais neurotransmissores. Ao mesmo tempo, fentolamina (FENT), metoprolol (Metop), atropina (Atrop) e desnudamento endotelial foram adicionados ao sistema reativo. RESULTADOS: Sob condições fisiológicas, a rigidez não foi afetada pelo desnudamento endotelial (p > 0,05). A NE significantemente aumentou a rigidez valvar por aumento de 10 vezes na concentração (10-6 vs 10-7, p < 0,05; 10-5 vs 10-6, p < 0,05). Essa resposta foi amenizada por FENT, Metop ou desnudamento endotelial (p < 0,05); entretanto, manteve-se aumentada de maneira significante quando comparada aos Controles (p < 0,05). A ACH causou uma diminuição na rigidez acompanhada por um aumento em sua concentração (alteração significante na rigidez por aumento de 10 vezes na concentração de ACH, 10-6 vs Controle, p < 0,05; 10-5 vs 10-6, p < 0,05), que foi revertida pelo desnudamento endotelial e Atrop (p > 0,05 vs Controle). CONCLUSÃO: Esses achados ressaltam o papel do sistema nervoso autônomo na regulação das propriedades mecânicas das cúspides de válvula mitral porcina, o que reforça a importância do estado nervoso autônomo no funcionamento ideal da válvula.

BACKGROUND: The presence of nerves in heart valves was first depicted decades ago and identified into subpopulations: sympathetic, parasympathetic. So valves are expected to be greatly affected by the autonomic nerves. However, few studies have focused on the regulation of heart valves by the autonomic nervous system. OBJECTIVE: We sought to identify the role of the autonomic nervous system in the regulation of the mechanical properties of porcine mitral valve tissues. METHODS: Mechanical properties of porcine mitral valve leaflets were evaluated in response to norepinephrine (NE) and acetylcholine (ACH), the main neurotransmitters. At the same time, phentolamine (Phent), metoprolol (Metop), atropine (Atrop) and endothelial denudation were added to the reactive system. RESULTS: Under physiological conditions, the stiffness was not affected by endothelial denudation (p > 0.05). NE elevated the valve stiffness significantly per 10-fold increase in concentration (10-6 vs 10-7, p < 0.05; 10-5 vs 10-6, p < 0.05). This response was mitigated by Phent, Metop or endothelial denudation (p < 0.05), however, it was still increased significantly when compared to Controls (p < 0.05). ACH caused a decrease in stiffness accompanied by an increase in its concentration (significant change in stiffness per 10-fold increase in ACH concentration, 10-6 vs Control, p < 0.05; 10-5 vs 10-6, p < 0.05), which were reversed by endothelial denudation and Atrop (p > 0.05 vs Control). CONCLUSION: These findings highlight the role of the autonomic nervous system in the regulation of the mechanical properties of porcine mitral valve cusps, which underline the importance of autonomic nervous status for optimal valve function.

FUNDAMENTO: La presencia de nervios en las válvulas cardíacas quedó demostrada por primera vez hace algunas décadas e identificadas en sub-poblaciones: simpáticas y parasimpáticas y por lo tanto, lo que se espera es que las válvulas reciban una gran afectación de los nervios autónomos. Sin embargo, pocos estudios se han concentrado en la regulación de válvulas cardíacas a través del sistema nervioso autónomo. OBJETIVO: Buscamos identificar el papel del sistema nervioso autónomo en la regulación de las propiedades mecánicas de los tejidos de las válvulas mitrales porcinas. MÉTODOS: Las propiedades mecánicas de las capas de válvulas mitrales porcinas fueron evaluadas en respuesta a la norepinefrina (NE) y a la acetilcolina (ACH), los principales neurotransmisores. Igualmente, la fentolamina (FENT), el metoprolol (Metop), la atropina (Atrop) y la denudación endotelial también se añadieron al sistema reactivo. RESULTADOS: Bajo condiciones fisiológicas, la rigidez no se afectó por el denudación endotelial (p > 0,05). La NE aumentó significativamente la rigidez valvular con un aumento de 10 veces en la concentración (10-6 vs 10-7, p < 0,05; 10-5 vs 10-6, p < 0,05). Esa respuesta fue amenizada por FENT, Metop o denudación endotelial (p < 0,05); pero se mantuvo aumentada de manera significativa cuando se le comparó con los Controles (p < 0,05). La ACH causó una disminución en la rigidez acompañada por un aumento en su concentración (alteración significativa en la rigidez por el aumento en 10 veces de la concentración de ACH, 10-6 vs Control, p < 0,05; 10-5 vs 10-6, p < 0,05), que fue revertida por la denudación endotelial y Atrop (p > 0,05 vs Control). CONCLUSIÓN: Esos hallazgos destacan el rol del sistema nervioso autónomo en la regulación de las propiedades mecánicas de las cúspides de la válvula mitral porcina, lo que refuerza la importancia del estado nervioso autónomo en el funcionamiento ideal de la válvula.

Association between a Missense Polymorphism (rs3924999, Arg253Gln) of Neuregulin 1 and Schizophrenia in Korean Population

Neuregulin 1 (NRG1) is associated with the pathogenesis of schizophrenia through controlling activation and signaling of neurotransmitter receptors. Influence to schizophrenia development by the NRG1 gene may differ in individuals, and genetic polymorphism is one of the factors affecting their differences. Association between three single nucleotide polymorphisms (SNPs) (rs7014762, -1174 A/T; rs11998176, -788 A/T; rs3924999, Arg253Gln) of NRG1 and the development of schizophrenia was analyzed in 221 schizophrneia and 359 control subjects. Polymerase chain reaction and direct sequencing were performed to obtain genotype data of NRG1 SNPs of the subjects. In analysis of genetic data, multiple logistic regression models (codominant1, codominant2, dominant, recessive, and log-additive model) were applied. SNPStats and SPSS 18.0 were used to calculate odds ratio (OR), 95% confidence interval (CI), and p-value of each model. The genotype distributions of rs3924999 were associated with schizophrenia development (OR=0.67, 95% CI=0.47-0.95, p=0.022 in the dominant model and OR=0.69, 95% CI=0.51-0.93, p=0.013 in the log-addtive model) and allelic distributions also showed significant association (OR=0.70, 95% CI=0.52-0.93, p=0.014). The results suggest that rs3924999 of the NRG1 gene may be associated with schizophrenia susceptibility.

Activating effect of citrus flavonoids on neuromedin U2 receptor and analysis on siRNA interference / 中国中药杂志

<p><b>OBJECTIVE</b>To screen out active substances on Neuromedin U2 receptor (NMU2R) by using stable NMU2R cell lines and negative cell lines and analyzing siRNA interference.</p><p><b>METHOD</b>NMU2R cells were used to observe the activating effect of nine nine citrus flavonoids on NMU2R cell. Afterwards, false-positive interference of citrus flavonoids that showed higher activating effect was eliminated by using negative cells and analyzing the efficiency of siRNA interference.</p><p><b>RESULT</b>Hesperidin and nobiletin contained in citrus flavonoids were found to effectively activate NMU2R. The efficacy, EC50 and potency values of hesperidin were 4.688, 318.970 micromol x L(-1) and 200.933 micromol x L(-1), while the efficacy, EC50 and potency values of nobiletin were 4.758, 5.832 micromol x L(-1) and 3.124 micromol x L(-).</p><p><b>CONCLUSION</b>Hesperidin and nobiletin contained in citrus flavonoids can activate NMU2R. Nobiletin shows such a low EC50 that it has medicinal value.</p>

O ciclo da vesícula sináptica, espinhos dendríticos e a transdução de sinal / Synaptic vesicle cycle, dendritic spines and signal transduction

No sistema nervoso, a sinapse é a estrutura que permite a um neurônio passar um sinal elétrico ou químico a outro neurônio ou outra célula (muscular ou glandular). A palavra sinapse vem de "synaptein", palavra que Sir Charles Scott Sherrington e seus colegas acunharam do grego "syn" (junto) e "haptein"(afivelar). As sinapses podem ser separadas entre elétricas e químicas, porém a maior parte da transmissão sináptica é realizada através das sinapses químicas. Apesar das sinapses químicas terem uma resposta mais lenta que as elétricas, elas possuem a vantagem da amplificação do sinal gerada através de uma cascata de segundos mensageiros. As sinapses químicas podem ser excitatórias ou inibitórias e são caracterizadas por um terminal pré-sináptico (onde estão presentes as vesículas que contêm os neurotransmissores) em contato com um terminal pós-sináptico (onde estão presentes os receptores ionotrópicos e metabotrópicos para esses neurotransmissores) separados pela fenda sináptica. As sinapses típicas acontecem sobre axônios (axo-axônicas), sobre dendritos (axo-dendríticas), sobre o soma de outro neurônio (axo-somáticas) e sobre os espinhos dendríticos...

In the nervous system, the synapse is the structure that allows a neuron pass an electrical or chemical signal to another neuron or another cell (muscle or glandular). The word synapse comes from "synaptein" that Sir Charles Scott Sherrington and his colleagues minted from the Greek "syn" (together) and "haptein"(buckling). Most part of the synaptic transmission is performed through chemical synapses. Chemical synapses have a slower response than the electric ones; they have the advantage of amplifying the signal generated through a cascade of second messengers. Chemical synapses can be excitatory or inhibitory and are characterized by a presynaptic terminal (where there are vesicles that contain the neurotransmitters) in contact with a postsynaptic terminal (where there are the ionotropic and metabotropic receptors) separated by the synaptic cleft. Synapses can occur on axons (axo-axonal), on dendrites (axodendritic), on soma (axo-somatic) and on dendritic spines...

Modulation by the GABAB receptor siRNA of ethanol-mediated PKA-alpha, CaMKII, and p-CREB intracellular signaling in prenatal rat hippocampal neurons / 대한해부학회지

Fetal alcohol syndrome (FAS) is a developmental neuropathology resulting from in utero exposure to ethanol; many of ethanol's effects are likely to be mediated by the neurotransmitter gamma-aminobutyric acid (GABA). We studied modulation of the neurotransmitter receptor GABABR and its capacity for intracellular signal transduction under conditions of ethanol treatment (ET) and RNA interference to investigate a potential role for GABA signaling in FAS. ET increased GABAB1R protein levels, but decreased protein kinase A-alpha (PKA-alpha), calcium/calmodulin-dependent protein kinase II (CaMKII) and phosphorylation of cAMP-response element binding protein (p-CREB), in cultured hippocampal neurons harvested at gestation day 17.5. To elucidate GABAB1R response to ethanol, we observed the effects of a GABABR agonist and antagonist in pharmacotherapy for ethanol abuse. Baclofen increased GABABR, CaMKII and p-CREB levels, whereas phaclofen decreased GABABR, CaMKII and p-CREB levels except PKA-alpha. Furthermore, when GABAB1R was knocked down by siRNA treatment, CaMKII and p-CREB levels were reduced upon ET. We speculate that stimulation of GABAB1R activity by ET can modulate CaMKII and p-CREB signaling to detrimental effect on fetal brain development.

An examination of synaptic proteins following chronic haloperidol in a rat model of tardive dyskinesia

Tardive dyskinesia (TD) is a late-onset side effect mainly affecting the orofacial region of patients treated chronically with classic antipsychotic drugs such as haloperidol (HAL). The causes of TD remain unknown. We hypothesized that faulty synaptic re-organization might be related to TD-like syndromes and used the vacuous chewing movements (VCM) model in rats to investigate the expression of four synaptic proteins, synaptophysin, syntaxin, spinophilin and PSD-95, in brains of HAL-treated rats. Male Sprague-Dawley rats were treated for 14 weeks with either haloperidol decanoate (21 mg/kg once every 3 weeks, I.M) or vehicle and VCMs were monitored on a weekly basis. As expected, VCMs developed reliably and were consistently more pronounced in some rats than in others. Using immunohistochemistry in anatomically preserved brain sections as well as Western Blot analyses of whole cells or synaptosomal fractions in striatal tissue, we found no significant effect of chronic HAL on levels of these proteins. Neither did we find significant differences in the levels of the four synaptic markers when comparing rats showing High vs. Low levels of VCMs. These results suggest that structural synaptic alterations (e.g. involving increased number of synapses) may not be the underlying mechanism of oral dyskinesias induced by chronic antipsychotic drug treatment. The possibility that functional neuroplastic changes occur remains to be investigated

Pharmacological treatment of psychiatric disorders of the elderly

Psychiatric disturbances in the elderly are complicated. Dementia and depression are serious causes of global impairment in the elderly. Aging is characterized by a progressive functional impairment of multiple organs, a reduction of homeostatic mechanisms, and a changed sensitivity or capacity of neurotransmitter receptors. Understanding the influence of age-dependent changes in the composition and function of the body on the pharmacokinetics and pharmacodynamics of drugs is important before prescribing drugs to elderly patients. However, there is little clinical pharmacological information available to guide pharmacotherapy for late-life psychiatric disorders. Treatment of dementia is based on the cognitive decline and behavioral symptoms that accompany dementia. Currently prescribed antidepressants have similar efficacies but the side effect profiles vary. Comprehension of the normal aging process and understanding the characteristics of each of the psychotropics are essential in geriatric psychopharmacology. Up to the present, most studies are confirmations or reproductions of previous results on efficacy or safety. Future directions for psychopharmacological research should include discovering newer drugs, treatment of resistance or nonresponders, and combination or adjunctive therapies. This review focused on the geriatric pharmacokinetic/pharmacodynamic changes and clinical information regarding currently prescribed psychotropic medications.

Aspectos neurobiológicos implicados en el miedo animal / Neurobiological aspects involved in animal fear

El miedo es una emoción que sirve para la expresión de comportamientos defensivos en situaciones de peligro. Posee un sustrato biológico, con base en el funcionamiento coordinado de los diferentes sistemas orgánicos. Particularmente, el sistema nervioso en su actividad intrínseca genera la vivencia y la acción motriz derivada. En efecto, se ha hallado la intervención de varias estructuras neuroanatómicas como la amígdala e hipotálamo, así como un gran conjunto de moléculas distintas como neurotransmisores y sus receptores. La interacción anatomofuncional causa la emoción. Al igual que se cuenta con la capacidad de producir el miedo, también se puede regular su generación. Para este mecanismo se encuentran determinadas estructuras neuroanatómicas como la corteza prefrontal y orbitofrontal, y sustancias como el GABA y los opiáceos, que inhiben o reducen la actividad en las zonas activas que actúan en el miedo. El equilibrio entre la activación y la inhibición posibilita la ocurrencia del miedo en las circunstancias requeridas y no de una manera descontextualizada o generalizada. En esta revisión se presenta una descripción de diferentes aspectos relevantes en la generación y regulación de la emoción.

Fear is an emotion that is useful for expressing defensive behaviors in dangerous situations. It has a biological support based on the coordinating functionality of different organic systems. Particularity, the nervous system in its intrinsic activity generates the experience and the derived motor action. In fact, researchers have discovered the participation of several neuroanatomical structures such as the amygdala and hypothalamus, as well as a wide range of molecules such as neurotransmitters and their receptors. The anatomical and physiological interactions cause emotion. Since the ability to produce fear exists, the nervous system may regulate it, too. Certain anatomical structures are found for this mechanism such as the prefrontal and orbitofrontal cortex and molecules like GABA and opiates, which inhibited or reduced the activity in the active zones that act upon fear. The balance between activation and inhibition enables the event of fear in the circumstances required and not in an out-of-context or generalized manner. This review presents a description of different relevant aspects in thegeneration and regulation of the emotion.

Neurotransmitters - a biochemical view

The neurotransmission at most if not all synapses is chemical and is of great biochemical, physiological and pharmacological importance. Neurons communicate with each other at synapses by a process called synaptic transmission which is the release of small quantities of chemical messengers, called neurotransmitters that alter the electrical activity of neurons after they interact with receptors on post-synaptic cell surfaces. This review gives a biochemical view on the nature of neurotransmitters and presents the biochemical chart and the medical relevance of the most important neurotransmitters

Acción e influencia del bruxismo sobre el sistema masticatorio: revisión de literatura / Action and influences of bruxism on the masticatory system: literature review

El bruxismo afecta un gran porcentaje de la población. A pesar de las investigaciones realizadas con el objetivo de conocer su curso, no es bien conocido y por tanto no es bien tratado debido a su etiología multifactorial. Las alteraciones patológicas, como hábitos orales, maloclusiones, malas condiciones sistémicas y trastornos en las etapas del sueño, hacen que aumente el tono muscular por estímulo de estructuras cerebrales y diferentes neurotransmisores que se relacionan con el bruxismo nocturno. La actividad rítmica de los músculos masticatorios, son interpretadas por los sistemas de controles superiores generando cambios en las funciones normales. Como consecuencias de estas alteraciones se pueden presentar mialgias, desgaste o destrucción de los dientes, daños periodontales y articulares. Esta revisión analiza signos, síntomas y la etiopatogenia, desde el punto de vista histológico, estructural y funcional, la relación con los sistemas de control superior y sus manifestaciones a nivel dental, muscular, la ATM y el periodonto. El conocimiento de estos factores, permitirá al clínico guiarse en el diagnóstico y tratamiento considerando las condiciones de cada individuo. Podemos concluir que la cavidad oral actúa según el estado general del paciente, depende de las afecciones físicas y /o psicológicas y cada una tiene representaciones orales. El estrés, la liberación de algunos neurotransmisores específicos, y hasta el consumo de algunos fármacos pueden generar o inhibir las actividades parafuncionales que son perjudiciales para el sistema estomatognaáico manifestado a través del bruxismo.

Bruxism affects a large percentage of the population. Despite the investigations carried out in order to know their course, is not well known and therefore is not well treated. It is difficult to understand since its etiology is multifactorial. The stomatognathic system has cerebral representations, mediated by chemical and physical systems manifest itself through changes in the functioning of its structures and morphology. Pathological alterations, such as oral habits, malocclusions, poor systemic conditions and disorders in the stages of sleep, are associated with the rhythmic activity of masticatory muscles, where there is increased muscle tone. The stimuli of brain structures and various neurotransmitters related to sleep bruxism and interpreted by higher control systems generate changes in the normal functions. As a result of these alterations, myalgia, destruction of teeth, periodontal and articular damage could be present. This review analyzes signs, symptoms and its etiophatology, from the histological, structural and functional relationship point of view, the relationship with the higher control system and their manifestation at dental, muscular, TMJ, and periodontal level. The understanding of these factors will guide the clinician in the individual diagnosis and treatment of each subject. We can conclude that the oral cavity acts and reflects the general condition of the patient, depending on the physical characteristsics and / or psychological and oral representations. Stress, the release of some specific neurotransmitters, and the use of certain drugs can generate parafunctional activities that are harmful to the stomatognatic system expressed through bruxism.

Expressão de neuromediadores e sua correlação com o padrão fenotípico e funcional do infiltrado inflamatório de lesões de leishmaniose tegumentar americana causadas por Leishmania (Viannia) braziliensis / Expression of neuromediators and its correlation with the phenotypic and functional standard of the inflammatory infiltrated one of injuries of american tegumentary leishmaniasis caused for Leishmania (Viannia) braziliensis

A Leishmaniose Tegumentar Americana (LTA) é uma importante doença na América Latina e, no Brasil, representa um sério problema de saúde pública. A leishmaniose cutânea (LCL) causada por Leishmania (Viannia) braziliensis tende a ser, ao contrário das formas mucosas (LM), susceptível à terapia específica e evolui para a cura espontânea em um período de seis a doze meses. Porém um pequeno grupo de pacientes não alcança a resolução completa da lesão cutânea, evoluindo em alguns casos com metástases, apesar do tratamento adequado. Muitos dados sugerem que a infecção por Leishmania no homem, ao induzir uma resposta umune celular com um padrão local de produção de citocinas e mediadores inflamatórios, poderia contribuir não só para a resolução da infecção mas também para o dano tecidual. Ao mesmo tempo a supressão dessa resposta efetora poderia resultar em persistência parasitária ou até mesmo na cronificação da doença. Em nosso estudo temos como objetivo principal avaliar o infiltrado inflamatório de lesões cutâneas de LTA por L. (V.) braziliensis de acordo com subpopulações celulares, citocinas e neuropeptídeos, estes últimos ainda não bem caracterizados na infecção humana. Para isso utilizamos a técnica de imunohistoquímica indireta e PCR em tempo real após classificarmos os pacientes de acordo com a forma clínica, resposta ao tratamento com antimonial pentavalente e tempo de evolução da doença. Nossos resultados mostraram que os pacientes com má resposta à terapia apresentam uma freqüência mais elevada de linfócitos T CD8, associada a uma produção exacerbada de citocinas do tipo 1, tais como IL-12 e IFN(gama), além de TGF(beta) e IL-10, quando comparados com os pacientes com boa resposta. Além disso, foi observado que pacientes com lesões recentes apresentavam níveis mais altos de células produtoras de IL-4, quando comparados aos pacientes com lesões tardias. Observamos ainda uma freqüência semelhante de linfócitos T regulatórios (Foxp3) em todos os...tecidual.

Expression of quail vascular endothelial growth factor receptor quek-1 extracellular domain 2-4 loop cDNA in Pichia pastoris / 生物医学工程学杂志

The extracellular domain 2-4 loop cDNA of quail vascular endothelial growth factor receptor quek1 (qVEGFR2) was obtained from plasmid carrying qVEGFR2 by PCR. Then it was cloned into expression vector pPICZalphaA of Pichia pastoris. To construct recombinant expression plasmid pPICZalphaA-qVEGFR2, linearized pPICZalphaA-qVEGFR2 with SacI was transformed to electroporated Pichia pastoris GS115. Subsequently, positive clone was selected by PCR and its phenotype was determined. SDSPAGE and Western blot assays of culture medium from a methanol-induced expression strain demonstrated that recombinant qVEGFR2 proteins were expressed and secreted into the culture medium. These results could provide a basis for further researches on tumor protein vaccine as well as for the preparation of tumor protein vaccine with Pichia pastoris.