RESUMO
With increasing attention on the essential roles of the tumour microenvironment in recent years, the nervous system has emerged as a novel and crucial facilitator of cancer growth. In this Review, we describe the foundational, translational, and clinical advances illustrating how nerves contribute to tumour proliferation, stress adaptation, immunomodulation, metastasis, electrical hyperactivity and seizures, and neuropathic pain. Collectively, this expanding knowledge base reveals multiple therapeutic avenues for cancer neuroscience that warrant further exploration in clinical studies. We discuss the available clinical data, including ongoing trials investigating novel agents targeting the tumour-nerve axis, and the therapeutic potential for repurposing existing neuroactive drugs as an anti-cancer approach, particularly in combination with established treatment regimens. Lastly, we discuss the clinical challenges of these treatment strategies and highlight unanswered questions and future directions in the burgeoning field of cancer neuroscience.
Assuntos
Neoplasias/tratamento farmacológico , Neurociências , Dor do Câncer/tratamento farmacológico , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/etiologia , Neoplasias/imunologia , Neoplasias/patologia , Fenômenos Fisiológicos do Sistema Nervoso/efeitos dos fármacos , Microambiente TumoralRESUMO
Cyanobacteria are capable of producing a wide range of bioactive compounds with many considered to be toxins. Although there are a number of toxicological outcomes with respect to cyanobacterial exposure, this review aims to examine those which affect the central nervous system (CNS) or have neurotoxicological properties. Such exposures can be acute or chronic, and we detail issues concerning CNS entry, detection and remediation. Exposure can occur through a variety of media but, increasingly, exposure through air via inhalation may have greater significance and requires further investigation. Even though cyanobacterial toxins have traditionally been classified based on their primary mode of toxicity, increasing evidence suggests that some also possess neurotoxic properties and include known cyanotoxins and unknown compounds. Furthermore, chronic long-term exposure to these compounds is increasingly being identified as adversely affecting human health.
Assuntos
Toxinas de Cianobactérias/toxicidade , Cianobactérias/química , Fenômenos Fisiológicos do Sistema Nervoso/efeitos dos fármacos , HumanosRESUMO
BACKGROUND: We hypothesised that Calabadion 1, an acyclic cucurbit[n]uril molecular container, reverses fentanyl-induced respiratory depression and dysfunction of the CNS. METHODS: Experiments were conducted in male Sprague-Dawley rats. A constant-rate i.v. infusion of fentanyl (12.5 or 25 µg kg-1 over 15 min) was administered followed by an i.v. bolus of Calabadion 1 (0.5-200 mg kg-1) or placebo. The primary outcome was reversal of ventilatory and respiratory depression, assessed by pneumotachography and arterial blood gas analysis, respectively. Key secondary outcomes were effects on fentanyl-induced central nervous dysfunction quantified by righting reflex, balance beam test, and electromyography (EMG). RESULTS: Calabadion 1 reversed fentanyl-induced respiratory depression across the endpoints minute ventilation, pH, and Paco2 (P=0.001). Compared with placebo, Calabadion 1 dose dependently (P for trend <0.001) reversed fentanyl-induced hypoventilation {81.9 [5.1] (mean [standard error of the mean]) vs 45.5 [12.4] ml min-1; P<0.001}, acidosis (pH 7.43 [0.01] vs 7.28 [0.04]; P=0.005), and hypercarbia (Paco2 43.4 [1.6] vs 63.4 [8.1] mm Hg; P=0.018). The effective Calabadion 1 doses required to reverse respiratory depression by 50% and 90% (ED50Res and ED90Res) were 1.7 and 15.6 mg kg-1, respectively. Higher effective doses were needed for recovery of righting reflex (ED50CNS: 9.6 mg kg-1; ED90CNS: 86.1 mg kg-1), which was accelerated by Calabadion 1 (4.6 [0.3] vs 9.0 [0.7] min; P<0.001). Calabadion 1 also significantly accelerated recovery of full functional mobility and reversal of muscle rigidity. CONCLUSIONS: Calabadion 1 selectively and dose dependently reversed the respiratory system and CNS side-effects of fentanyl.
Assuntos
Analgésicos Opioides/efeitos adversos , Fentanila/efeitos adversos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Fenômenos Fisiológicos do Sistema Nervoso/efeitos dos fármacos , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/prevenção & controle , Ácidos Sulfônicos/farmacologia , Animais , Modelos Animais de Doenças , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Japan provides many lessons for the Environmental Neurology's issues. Drama and disasters have paved the recent history of Japan. The Japanese people have been intoxicated by chemical compounds (methylmercury, sulfur dioxide, cadmium, PCBs and other dioxin-related compounds) and were the victims of several dramatic disasters (atomic bombing, nuclear disaster, sarin gas attack). They are still exposed to air pollution. Prion diseases including dura-graft-associated CJD are still an issue. In addition, continuously spreading chronic wasting disease is a worldwide challenge .
Assuntos
Encefalopatias , Encéfalo/fisiologia , Meio Ambiente , Fenômenos Fisiológicos do Sistema Nervoso , Encéfalo/efeitos dos fármacos , Encefalopatias/induzido quimicamente , Encefalopatias/epidemiologia , Poluentes Ambientais/toxicidade , Acidente Nuclear de Fukushima , História do Século XX , História do Século XXI , Humanos , Japão/epidemiologia , Sistema Nervoso/efeitos dos fármacos , Fenômenos Fisiológicos do Sistema Nervoso/efeitos dos fármacos , Sarina/toxicidadeRESUMO
Conventional drug screens and treatments often ignore the underlying complexity of brain network dysfunctions, resulting in suboptimal outcomes. Here we ask whether we can correct abnormal functional connectivity of the entire brain by identifying and combining multiple neuromodulators that perturb connectivity in complementary ways. Our approach avoids the combinatorial complexity of screening all drug combinations. We develop a high-speed platform capable of imaging more than 15000 neurons in 50ms to map the entire brain functional connectivity in large numbers of vertebrates under many conditions. Screening a panel of drugs in a zebrafish model of human Dravet syndrome, we show that even drugs with related mechanisms of action can modulate functional connectivity in significantly different ways. By clustering connectivity fingerprints, we algorithmically select small subsets of complementary drugs and rapidly identify combinations that are significantly more effective at correcting abnormal networks and reducing spontaneous seizures than monotherapies, while minimizing behavioral side effects. Even at low concentrations, our polytherapy performs superior to individual drugs even at highest tolerated concentrations.
Assuntos
Epilepsias Mioclônicas/tratamento farmacológico , Modelos Biológicos , Rede Nervosa/efeitos dos fármacos , Fenômenos Fisiológicos do Sistema Nervoso/efeitos dos fármacos , Neurotransmissores/farmacologia , Algoritmos , Animais , Animais Geneticamente Modificados , Comportamento Animal/efeitos dos fármacos , Encéfalo/citologia , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Mapeamento Encefálico/métodos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Sinergismo Farmacológico , Quimioterapia Combinada/métodos , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/patologia , Ensaios de Triagem em Larga Escala/métodos , Humanos , Microscopia Confocal/métodos , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Neurotransmissores/uso terapêutico , Peixe-ZebraRESUMO
Spinal phrenic nerve activity (PNA) drives the diaphragm but cranial hypoglossal nerve activity (HNA) also expresses synchronous activity during inspiration. Here, we investigated the effects of local disinhibition (bilateral microinjections of bicuculline) of the nucleus tractus solitarius (NTS), the pre-Bötzinger complex and Bötzinger complex core circuit (pre-BötC/BötC) and the Kölliker-Fuse nuclei (KFn) on the synchronization of PNA and HNA in arterially-perfused brainstem preparations of rats. To quantitatively analyze the bicuculline effects on a putatively distributed inspiratory central pattern generator (i-CPG), we quantified the phase synchronization properties between PNA and HNA. The analysis revealed that bicuculline-evoked local disinhibition significantly reduced the strength of phase synchronization between PNA and HNA at any target site. However, the emergence of desynchronized HNA following disinhibition was more prevalent after NTS or pre-BötC/BötC microinjections compared to the KFn. We conclude that the primary i-CPG is located in a distributed medullary circuit whereas pontine contributions are restricted to synaptic gating of synchronous HNA and PNA.
Assuntos
Geradores de Padrão Central/fisiologia , Núcleo de Kölliker-Fuse/fisiologia , Bulbo/fisiologia , Rede Nervosa/fisiologia , Fenômenos Fisiológicos do Sistema Nervoso , Nervo Frênico/fisiologia , Respiração , Núcleo Solitário/fisiologia , Animais , Bicuculina/farmacologia , Geradores de Padrão Central/efeitos dos fármacos , Feminino , Antagonistas de Receptores de GABA-A/farmacologia , Núcleo de Kölliker-Fuse/efeitos dos fármacos , Masculino , Bulbo/efeitos dos fármacos , Rede Nervosa/efeitos dos fármacos , Fenômenos Fisiológicos do Sistema Nervoso/efeitos dos fármacos , Nervo Frênico/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Núcleo Solitário/efeitos dos fármacosRESUMO
Although silver nanoparticles (AgNPs) are used in various commercial products, the biological effects of AgNPs on fish embryogenesis and the underlying molecular mechanisms are still poorly understood. In this study, both touch responses and neuron membrane potential were found to be abnormal in AgNPs-stressed embryos. Moreover, neurogenesis genes were unveiled to be down-regulated and were enriched in ligand-gated ion channel activity, dopamine receptor signaling pathway, etc. in AgNPs-stressed embryos by microarray assays. Additionally, the down-regulated expression of otpa/sncgb - gad1b/gad2 dopaminergic neurotransmitter genes, robo2 - vim and glrbb synaptic transmission genes, and motor neuron genes isl1 &isl2a was further identified in both AgNPs- and Ag+-stressed embryos by qPCR, whole-mount in situ hybridization (WISH), and by using specific promoter-derived GFP fluorescence transgenic zebrafish. Moreover, the reduced expression of gad1b, gad2, and isl1 could be recovered by adding Ag+ chelating compound l-cysteine in AgNPs stressed embryos. Our results reveal for the first time that it is through damaging the formation of neural circuits, including dopaminergic neurotransmitter, synaptic transmission, and motor activities, that AgNPs induce abnormal electrical membrane properties, leading to dysfunctional touch responses and locomotor escape responses mostly via their released Ag+ during embryogenesis.
Assuntos
Embrião não Mamífero/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Fenômenos Fisiológicos do Sistema Nervoso/efeitos dos fármacos , Prata/química , Prata/toxicidade , Tato/efeitos dos fármacos , Peixe-Zebra/embriologia , Animais , Embrião não Mamífero/fisiologia , Tato/fisiologia , Peixe-Zebra/metabolismo , Peixe-Zebra/fisiologia , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismoRESUMO
Intraspecies variation is common in both clinical and animal research of various brain disorders. Relatively well-studied in mammals, intraspecies variation in aquatic fish models and its role in their behavioral and pharmacological responses remain poorly understood. Like humans and mammals, fishes show high variance of behavioral and drug-evoked responses, modulated both genetically and environmentally. The zebrafish (Danio rerio) has emerged as a particularly useful model organism tool to access neurobehavioral and drug-evoked responses. Here, we discuss recent findings and the role of the intraspecies variance in neurobehavioral, pharmacological and toxicological studies utilizing zebrafish and other fish models. We also critically evaluate common sources of intraspecies variation and outline potential strategies to improve data reproducibility and translatability.
Assuntos
Comportamento Animal/efeitos dos fármacos , Fenômenos Fisiológicos do Sistema Nervoso/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/fisiologia , Animais , Interação Gene-Ambiente , Humanos , Modelos Biológicos , Fenômenos Fisiológicos do Sistema Nervoso/genética , Fenótipo , Reprodutibilidade dos Testes , Caracteres Sexuais , Especificidade da Espécie , Peixe-Zebra/genéticaRESUMO
A contribution to SBN/ICN special issue. Endocrine-disrupting chemicals (EDCs) are pervasive in the environment. They are found in plastics and plasticizers (bisphenol A (BPA) and phthalates), in industrial chemicals such as polychlorinated biphenyls (PCBs), and include some pesticides and fungicides such as vinclozolin. These chemicals act on hormone receptors and their downstream signaling pathways, and can interfere with hormone synthesis, metabolism, and actions. Because the developing brain is particularly sensitive to endogenous hormones, disruptions by EDCs can change neural circuits that form during periods of brain organization. Here, we review the evidence that EDCs affect developing hypothalamic neuroendocrine systems, and change behavioral outcomes in juvenile, adolescent, and adult life in exposed individuals, and even in their descendants. Our focus is on social, communicative and sociosexual behaviors, as how an individual behaves with a same- or opposite-sex conspecific determines that individual's ability to exist in a community, be selected as a mate, and reproduce successfully.
Assuntos
Disruptores Endócrinos/farmacologia , Sistema Nervoso/efeitos dos fármacos , Sistemas Neurossecretores/efeitos dos fármacos , Comportamento Social , Adolescente , Adulto , Animais , Criança , Poluentes Ambientais/farmacologia , Humanos , Fenômenos Fisiológicos do Sistema Nervoso/efeitos dos fármacos , Reprodução/efeitos dos fármacosRESUMO
The majority of the currently available insecticides target the nervous system and genetic mutations of invertebrate neural proteins oftentimes yield deleterious consequences, yet the current methods for recording nervous system activity of an individual animal is costly and laborious. This suction electrode preparation of the third-instar larval central nervous system of Drosophila melanogaster, is a tractable system for testing the physiological effects of neuroactive agents, determining the physiological role of various neural pathways to CNS activity, as well as the influence of genetic mutations to neural function. This ex vivo preparation requires only moderate dissecting skill and electrophysiological expertise to generate reproducible recordings of insect neuronal activity. A wide variety of chemical modulators, including peptides, can then be applied directly to the nervous system in solution with the physiological saline to measure the influence on the CNS activity. Further, genetic technologies, such as the GAL4/UAS system, can be applied independently or in tandem with pharmacological agents to determine the role of specific ion channels, transporters, or receptors to arthropod CNS function. In this context, the assays described herein are of significant interest to insecticide toxicologists, insect physiologists, and developmental biologists for which D. melanogaster is an established model organism. The goal of this protocol is to describe an electrophysiological method to enable the measurement of electrogenesis of the central nervous system in the model insect, Drosophila melanogaster, which is useful for testing a diversity of scientific hypotheses.
Assuntos
Sistema Nervoso Central/fisiologia , Drosophila melanogaster/fisiologia , Larva/fisiologia , Animais , Sistema Nervoso Central/efeitos dos fármacos , Dissecação/métodos , Relação Dose-Resposta a Droga , Drosophila melanogaster/efeitos dos fármacos , Líquido Extracelular/efeitos dos fármacos , Líquido Extracelular/fisiologia , Inseticidas/farmacologia , Larva/efeitos dos fármacos , Microscopia/métodos , Modelos Animais , Fenômenos Fisiológicos do Sistema Nervoso/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/fisiologiaRESUMO
BACKGROUND: Oxidative stress and inflammation are considered to be important pathways leading to particulate matter (PM)-associated disease. In this exploratory study, we examined the effects of metals and oxidative potential (OP) in urban PM on biomarkers of systemic inflammation, oxidative stress and neural function. METHODS: Fifty-three healthy non-smoking volunteers (mean age 28â¯years, twenty-eight females) were exposed to coarse (2.5-10⯵m, mean 213⯵g/m3), fine (0.15-2.5⯵m, 238⯵g/m3), and/or ultrafine concentrated ambient PM (<0.3⯵m, 136⯵g/m3). Exposures lasted 130â¯min, separated by ≥2â¯weeks. Metal concentrations and OP (measured by ascorbate and glutathione depletion in synthetic airway fluid) in PM were analyzed. Blood and urine samples were collected pre-exposure, and 1-h and 21-h post exposure for assessment of biomarkers. We used mixed-regression models to analyze associations adjusting for PM size and mass concentration. RESULTS: Results for metals were expressed as change (%) from daily pre-exposure biomarker levels after exposure to a metal at a level equivalent to the mean concentration. Exposure to various metals (silver, aluminum, barium, copper, iron, potassium, lithium, nickel, tin, and/or vanadium) was significantly associated with increased levels of various blood or urinary biomarkers. For example, the blood inflammatory marker vascular endothelia growth factor (VEGF) increased 5.3% (95% confidence interval: 0.3%, 10.2%) 1-h post exposure to nickel; the traumatic brain injury marker ubiquitin C-terminal hydrolase L1 (UCHL1) increased 11% (1.2%, 21%) and 14% (0.3%, 29%) 1-h and 21-h post exposure to barium, respectively; and the systemic stress marker cortisol increased 1.5% (0%, 2.9%) and 1.5% (0.5%, 2.8%) 1-h and 21-h post exposure to silver, respectively. Urinary DNA oxidation marker 8hydroxydeoxyguanosine increased 14% (6.4%, 21%) 1-h post exposure to copper; urinary neural marker vanillylmandelic acid increased 29% (3%, 54%) 1-h post exposure to aluminum; and urinary cortisol increased 88% (0.9%, 176%) 1-h post exposure to vanadium. Results for OP were expressed as change (%) from daily pre-exposure biomarker levels after exposure to ascorbate-related OP at a level equivalent to the mean concentration, or for exposure to glutathione-related OP at a level above the limit of detection. Exposure to ascorbate- or glutathione-related OP was significantly associated with increased inflammatory and neural biomarkers including interleukin-6, VEGF, UCHL1, and S100 calcium-binding protein B in blood, and malondialdehyde and 8-hydroxy-deoxy-guanosine in urine. For example, UCHL1 increased 9.4% (1.8%, 17%) in blood 21-h post exposure to ascorbate-related OP, while urinary malondialdehyde increased 19% (3.6%, 35%) and 8-hydroxy-deoxy-guanosine increased 24% (2.9%, 48%) 21-h post exposure to ascorbate- and glutathione-related OP, respectively. CONCLUSION: Our results from this exploratory study suggest that metal constituents and OP in ambient PM may influence biomarker levels associated with systemic inflammation, oxidative stress, perturbations of neural function, and systemic physiological stress.
Assuntos
Poluentes Atmosféricos , Inflamação/induzido quimicamente , Exposição por Inalação/efeitos adversos , Metais , Oxidantes , Material Particulado/efeitos adversos , Adulto , Poluentes Atmosféricos/sangue , Poluentes Atmosféricos/urina , Biomarcadores/sangue , Biomarcadores/urina , Feminino , Humanos , Masculino , Metais/sangue , Metais/urina , Pessoa de Meia-Idade , Fenômenos Fisiológicos do Sistema Nervoso/efeitos dos fármacos , Ontário , Oxidantes/sangue , Oxidantes/urina , Estresse Oxidativo , Adulto JovemRESUMO
BACKGROUND: Transitions into and out of the anaesthetised state exhibit resistance to state transitions known as neural inertia. As a consequence, emergence from anaesthesia occurs at a consistently lower anaesthetic concentration than induction. Motivated by stochastic switching between discrete activity patterns observed at constant anaesthetic concentration, we investigated the consequences of such switching for neural inertia. METHODS: We simulated stochastic switching in MATLAB as Brownian motion on an energy landscape or equivalently as a discrete Markov process. Effects of anaesthetics were modelled as changing stability of the awake and the anaesthetised states. Simulation results were compared with re-analysed neural inertia data from mice and Drosophila. RESULTS: Diffusion on a two-well energy landscape gives rise to hysteresis. With additive noise, hysteresis collapses. This collapse occurs over a mixing time that is independent from pharmacokinetics. The two-well potential gives rise to the leftward shift for the emergence dose-response curve. Yet, from in vivo data, ΔEC50 and Δ Hill slope are strongly negatively correlated (R2=0.45, P<1.7×10-15). This correlation is not explained by a two-well potential. The extension of the diffusion model to a Markov process with 10 states (three awake, seven unconscious) reproduces both the left shift and the shallower Hill slope for emergence. CONCLUSIONS: Stochastic state switching accounts for all known features of neural inertia. More than two states are required to explain the consistent increase observed in variability of recovery from general anaesthesia. This model predicts that hysteresis should collapse with a time scale independent of anaesthetic drug pharmacokinetics.
Assuntos
Período de Recuperação da Anestesia , Anestesia Geral , Fenômenos Fisiológicos do Sistema Nervoso/efeitos dos fármacos , Processos Estocásticos , Algoritmos , Anestésicos/farmacocinética , Anestésicos/farmacologia , Simulação por Computador , Eletroencefalografia , Humanos , Cadeias de Markov , Modelos TeóricosRESUMO
Amitriptyline is a commonly used tricyclic antidepressant (TCA) inhibiting serotonin and norepinephrine reuptake. The exact CNS action of TCAs remains poorly understood, necessitating new screening approaches and novel model organisms. Zebrafish (Danio rerio) are rapidly emerging as a promising tool for pharmacological research of antidepressants, including amitriptyline. Here, we examine the effects of chronic 2-week exposure to 10 and 50 µg/L amitriptyline on zebrafish behavior and monoamine neurotransmitters. Overall, the drug at 50 µg/L evoked pronounced anxiolytic-like effects in the novel tank test (assessed by more time in top, fewer transition and shorter latency to enter the top). Like other TCAs, amitriptyline reduced serotonin turnover, but also significantly elevated whole-brain norepinephrine and dopamine levels. The latter effect was not reported in this model previously, and accompanied higher brain expression of tyrosine hydroxylase (a rate-limiting enzyme of catecholamine biosynthesis), but unaltered expression of dopamine-ß-hydroxylase and monoamine oxidase (the enzymes of dopamine metabolism). This response may underlie chronic amitriptyline action on dopamine and norepinephrine neurotransmission, and contribute to the complex CNS profile of this drug observed both clinically and in animal models. Collectively, these findings also confirm the important role of monoamine modulation in the regulation of anxiety-related behavior in zebrafish, and support the utility of this organism as a promising in-vivo model for CNS drug screening.
Assuntos
Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Animais , Ansiolíticos/farmacologia , Antidepressivos Tricíclicos/farmacologia , Encéfalo/metabolismo , Fenômenos Fisiológicos do Sistema Nervoso/efeitos dos fármacos , Neuroquímica/métodos , Norepinefrina/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Peixe-ZebraRESUMO
The current paradigms of prevention and treatment are unable to curb obesity rates, which indicates the need to explore alternative therapeutic approaches. Obesity leads to several damages to the body and is an important risk factor for a number of other chronic diseases. Furthermore, despite the first alterations in obesity being observed and reported in peripheral tissues, studies indicate that obesity can also cause brain damage. Obesity leads to a chronic low-grade inflammatory state, and the therapeutic manipulation of inflammation can be explored. In this context, the use of n-3 PUFA (especially in the form of fish oil, rich in EPA and DHA) may be an interesting strategy, as this substance is known by its anti-inflammatory effect and numerous benefits to the body, such as reduction of TAG, cardiac arrhythmias, blood pressure and platelet aggregation, and has shown potential to help treat obesity. Thereby, the aim of this narrative review was to summarise the literature related to n-3 PUFA use in obesity treatment. First, the review provides a brief description of the obesity pathophysiology, including alterations that occur in peripheral tissues and at the central nervous system. In the sequence, we describe what are n-3 PUFA, their sources and their general effects. Finally, we explore the main topic linking obesity and n-3 PUFA. Animal and human studies were included and alterations on the whole organism were described (peripheral tissues and brain).
Assuntos
Ácidos Graxos Ômega-3/administração & dosagem , Fenômenos Fisiológicos do Sistema Nervoso/efeitos dos fármacos , Obesidade/prevenção & controle , Humanos , Fatores de RiscoRESUMO
Caffeine is a widely consumed psychoactive substance, but little is known about the effects of caffeine stimulation on global gene expression changes in neurons. Here, we conducted gene expression profiling of human neuroepithelial stem cell-derived neurons, stimulated with normal consumption levels of caffeine (3 µM and 10 µM), over a period of 9 h. We found dosage-dependent activation of immediate early genes after 1 h. Neuronal projection development processes were up-regulated and negative regulation of axon extension processes were down-regulated at 3 h. In addition, genes involved in extracellular matrix organization, response for wound healing, and regulation of immune system processes were down-regulated by caffeine at 3 h. This study identified novel genes within the neuronal projection guidance pathways that respond to acute caffeine stimulation and suggests potential mechanisms for the effects of caffeine on neuronal cells.
Assuntos
Cafeína/administração & dosagem , Estimulantes do Sistema Nervoso Central/administração & dosagem , Fenômenos Fisiológicos do Sistema Nervoso/efeitos dos fármacos , Fenômenos Fisiológicos do Sistema Nervoso/genética , Neuritos/efeitos dos fármacos , Neuritos/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Transcriptoma , Biomarcadores , Diferenciação Celular , Células Cultivadas , Biologia Computacional/métodos , Relação Dose-Resposta a Droga , Imunofluorescência , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Anotação de Sequência Molecular , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Neurogênese/efeitos dos fármacos , Neurogênese/genética , Neurônios/citologia , FenótipoRESUMO
Connexins are ubiquitous channel forming proteins that assemble as plasma membrane hemichannels and as intercellular gap junction channels that directly connect cells. In the heart, gap junction channels electrically connect myocytes and specialized conductive tissues to coordinate the atrial and ventricular contraction/relaxation cycles and pump function. In blood vessels, these channels facilitate long-distance endothelial cell communication, synchronize smooth muscle cell contraction, and support endothelial-smooth muscle cell communication. In the central nervous system they form cellular syncytia and coordinate neural function. Gap junction channels are normally open and hemichannels are normally closed, but pathologic conditions may restrict gap junction communication and promote hemichannel opening, thereby disturbing a delicate cellular communication balance. Until recently, most connexin-targeting agents exhibited little specificity and several off-target effects. Recent work with peptide-based approaches has demonstrated improved specificity and opened avenues for a more rational approach toward independently modulating the function of gap junctions and hemichannels. We here review the role of connexins and their channels in cardiovascular and neurovascular health and disease, focusing on crucial regulatory aspects and identification of potential targets to modify their function. We conclude that peptide-based investigations have raised several new opportunities for interfering with connexins and their channels that may soon allow preservation of gap junction communication, inhibition of hemichannel opening, and mitigation of inflammatory signaling.
Assuntos
Doenças Cardiovasculares/fisiopatologia , Conexinas/antagonistas & inibidores , Conexinas/fisiologia , Doenças do Sistema Nervoso/fisiopatologia , Animais , Doenças Cardiovasculares/tratamento farmacológico , Fenômenos Fisiológicos Cardiovasculares/efeitos dos fármacos , Humanos , Doenças do Sistema Nervoso/tratamento farmacológico , Fenômenos Fisiológicos do Sistema Nervoso/efeitos dos fármacosRESUMO
We examined whether hydrocortisone exposure≤1week in very low birth weight infants (VLBWI) was associated with poor neurodevelopmental outcomes at corrected 18months. Further, the clinical factors associated with worse long term outcome were also evaluated. Of a total of 191 VLBWI, the clinical data for these infants relating were retrospectively collected for analysis. Among the 191 VLBWI, 115 (60.2%) infants were exposed to early postnatal hydrocortisone≤1week of life in our NICU of Seoul St. Mary's Hospital, The Catholic University of Korea between December 2012 and December 2014. The morbidities were significantly higher in the group with early hydrocortisone exposure group. At corrected age of 18months, 109/183 (59.6%) infants in the early hydrocortisone exposure group had significantly lower scores in all three (cognitive, language and motor) composites of Bayley Scales of Infant and Toddler Development III. The multivariable logistic regression analysis showed that only periventricular leukomalacia (PVL) is consistently associated with poor long-term outcomes. Our results suggest that early hydrocortisone exposure≤1week in VLBWI may not increase the risk for poor long-term outcomes compared to those not exposed. Only PVL is considered as a risk factor for poor long-term neurodevelopmental outcomes.
Assuntos
Recém-Nascido de muito Baixo Peso/fisiologia , Fenômenos Fisiológicos do Sistema Nervoso/efeitos dos fármacos , Esteroides/efeitos adversos , Feminino , Humanos , Recém-Nascido , Recém-Nascido de muito Baixo Peso/crescimento & desenvolvimento , Masculino , Fatores de TempoRESUMO
BACKGROUND: Previous studies have demonstrated inconsistent neurophysiologic effects of ketamine, although discrepant findings might relate to differences in doses studied, brain regions analyzed, coadministration of other anesthetic medications, and resolution of the electroencephalograph. The objective of this study was to characterize the dose-dependent effects of ketamine on cortical oscillations and functional connectivity. METHODS: Ten healthy human volunteers were recruited for study participation. The data were recorded using a 128-channel electroencephalograph during baseline consciousness, subanesthetic dosing (0.5 mg/kg over 40 min), anesthetic dosing (1.5 mg/kg bolus), and recovery. No other sedative or anesthetic medications were administered. Spectrograms, topomaps, and functional connectivity (weighted and directed phase lag index) were computed and analyzed. RESULTS: Frontal theta bandwidth power increased most dramatically during ketamine anesthesia (mean power ± SD, 4.25 ± 1.90 dB) compared to the baseline (0.64 ± 0.28 dB), subanesthetic (0.60 ± 0.30 dB), and recovery (0.68 ± 0.41 dB) states; P < 0.001. Gamma power also increased during ketamine anesthesia. Weighted phase lag index demonstrated theta phase locking within anterior regions (0.2349 ± 0.1170, P < 0.001) and between anterior and posterior regions (0.2159 ± 0.1538, P < 0.01) during ketamine anesthesia. Alpha power gradually decreased with subanesthetic ketamine, and anterior-to-posterior directed connectivity was maximally reduced (0.0282 ± 0.0772) during ketamine anesthesia compared to all other states (P < 0.05). CONCLUSIONS: Ketamine anesthesia correlates most clearly with distinct changes in the theta bandwidth, including increased power and functional connectivity. Anterior-to-posterior connectivity in the alpha bandwidth becomes maximally depressed with anesthetic ketamine administration, suggesting a dose-dependent effect.
Assuntos
Analgésicos/farmacologia , Encéfalo/efeitos dos fármacos , Eletroencefalografia/efeitos dos fármacos , Ketamina/farmacologia , Fenômenos Fisiológicos do Sistema Nervoso/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Valores de ReferênciaRESUMO
BACKGROUND: Functional neuroimaging studies have examined the neural substrates of treatments for major depressive disorder (MDD). Low sample size and methodological heterogeneity, however, undermine the generalizability of findings from individual studies. We conducted a meta-analysis to identify reliable neural changes resulting from different modes of treatment for MDD and compared them with each other and with reliable neural functional abnormalities observed in depressed versus control samples. METHODS: We conducted a meta-analysis of studies reporting changes in brain activity (e.g., as indexed by positron emission tomography) following treatments with selective serotonin reuptake inhibitors (SSRIs), electroconvulsive therapy (ECT), or transcranial magnetic stimulation. Additionally, we examined the statistical reliability of overlap among thresholded meta-analytic SSRI, ECT, and transcranial magnetic stimulation maps as well as a map of abnormal neural function in MDD. RESULTS: Our meta-analysis revealed that 1) SSRIs decrease activity in the anterior insula, 2) ECT decreases activity in central nodes of the default mode network, 3) transcranial magnetic stimulation does not result in reliable neural changes, and 4) regional effects of these modes of treatment do not significantly overlap with each other or with regions showing reliable functional abnormality in MDD. CONCLUSIONS: SSRIs and ECT produce neurally distinct effects relative to each other and to the functional abnormalities implicated in depression. These treatments therefore may exert antidepressant effects by diminishing neural functions not implicated in depression but that nonetheless impact mood. We discuss how the distinct neural changes resulting from SSRIs and ECT can account for both treatment effects and side effects from these therapies as well as how to individualize these treatments.
Assuntos
Antidepressivos/uso terapêutico , Encéfalo/cirurgia , Transtorno Depressivo Maior/terapia , Eletroconvulsoterapia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Eletroconvulsoterapia/métodos , Feminino , Humanos , Masculino , Fenômenos Fisiológicos do Sistema Nervoso/efeitos dos fármacos , Reprodutibilidade dos Testes , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Estimulação Magnética Transcraniana/métodos , Resultado do TratamentoRESUMO
Honey bees demonstrate astonishing learning abilities and advanced social behavior and communication. In addition, their brain is small, easy to visualize and to study. Therefore, bees have long been a favored model amongst neurobiologists and neuroethologists for studying the neural basis of social and natural behavior. It is important, however, that the experimental techniques used to study bees do not interfere with the behaviors being studied. Because of this, it has been necessary to develop a range of techniques for pharmacological manipulation of honey bees. In this paper we demonstrate methods for treating restrained or free-flying honey bees with a wide range of pharmacological agents. These include both noninvasive methods such as oral and topical treatments, as well as more invasive methods that allow for precise drug delivery in either systemic or localized fashion. Finally, we discuss the advantages and disadvantages of each method and describe common hurdles and how to best overcome them. We conclude with a discussion on the importance of adapting the experimental method to the biological questions rather than the other way around.