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1.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33809224

RESUMO

The myelin sheath wraps around axons, allowing saltatory currents to be transmitted along neurons. Several genetic, viral, or environmental factors can damage the central nervous system (CNS) myelin sheath during life. Unless the myelin sheath is repaired, these insults will lead to neurodegeneration. Remyelination occurs spontaneously upon myelin injury in healthy individuals but can fail in several demyelination pathologies or as a consequence of aging. Thus, pharmacological intervention that promotes CNS remyelination could have a major impact on patient's lives by delaying or even preventing neurodegeneration. Drugs promoting CNS remyelination in animal models have been identified recently, mostly as a result of repurposing phenotypical screening campaigns that used novel oligodendrocyte cellular models. Although none of these have as yet arrived in the clinic, promising candidates are on the way. Many questions remain. Among the most relevant is the question if there is a time window when remyelination drugs should be administrated and why adult remyelination fails in many neurodegenerative pathologies. Moreover, a significant challenge in the field is how to reconstitute the oligodendrocyte/axon interaction environment representative of healthy as well as disease microenvironments in drug screening campaigns, so that drugs can be screened in the most appropriate disease-relevant conditions. Here we will provide an overview of how the field of in vitro models developed over recent years and recent biological findings about how oligodendrocytes mature after reactivation of their staminal niche. These data have posed novel questions and opened new views about how the adult brain is repaired after myelin injury and we will discuss how these new findings might change future drug screening campaigns for CNS regenerative drugs.


Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Doenças Desmielinizantes/tratamento farmacológico , Descoberta de Drogas , Remielinização/efeitos dos fármacos , Animais , Axônios/efeitos dos fármacos , Axônios/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Sistema Nervoso Central/patologia , Doenças Desmielinizantes/patologia , Humanos , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/patologia , Regeneração Nervosa/efeitos dos fármacos , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/patologia
2.
Int J Mol Sci ; 22(8)2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33920904

RESUMO

COVID-19 is a severe respiratory disease caused by the newly identified human coronavirus (HCoV) Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). The virus was discovered in December 2019, and in March 2020, the disease was declared a global pandemic by the World Health Organization (WHO) due to a high number of cases. Although SARS-CoV-2 primarily affects the respiratory system, several studies have reported neurological complications in COVID-19 patients. Headache, dizziness, loss of taste and smell, encephalitis, encephalopathy, and cerebrovascular diseases are the most common neurological complications that are associated with COVID-19. In addition, seizures, neuromuscular junctions' disorders, and Guillain-Barré syndrome were reported as complications of COVID-19, as well as neurodegenerative and demyelinating disorders. However, the management of these conditions remains a challenge. In this review, we discuss the prevalence, pathogenesis, and mechanisms of these neurological sequelae that are secondary to SARS-CoV-2 infection. We aim to update neurologists and healthcare workers on the possible neurological complications associated with COVID-19 and the management of these disease conditions.


Assuntos
/complicações , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/etiologia , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/virologia , Transtornos Cerebrovasculares/tratamento farmacológico , Transtornos Cerebrovasculares/etiologia , Transtornos Cerebrovasculares/virologia , Humanos , Doenças do Sistema Nervoso/epidemiologia , Doenças do Sistema Nervoso/virologia , Prevalência , /metabolismo
3.
Nutrients ; 13(5)2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33921980

RESUMO

Iron-fortified formulas and iron drops (both usually ferrous sulfate, FS) prevent early life iron deficiency, but may delay growth and adversely affect neurodevelopment by providing excess iron. We used a rat pup model to investigate iron status, growth, and development outcomes following daily iron supplementation (10 mg iron/kg body weight, representative of iron-fortified formula levels) with FS or an alternative, bioavailable form of iron, ferrous bis-glycinate chelate (FC). On postnatal day (PD) 2, sex-matched rat litters (n = 3 litters, 10 pups each) were randomly assigned to receive FS, FC, or vehicle control until PD 14. On PD 15, we evaluated systemic iron regulation and CNS mineral interactions and we interrogated iron loading outcomes in the hippocampus, in search of mechanisms by which iron may influence neurodevelopment. Body iron stores were elevated substantially in iron-supplemented pups. All pups gained weight normally, but brain size on PD 15 was dependent on iron source. This may have been associated with reduced hippocampal oxidative stress but was not associated with CNS mineral interactions, iron regulation, or myelination, as these were unchanged with iron supplementation. Additional studies are warranted to investigate iron form effects on neurodevelopment so that iron recommendations can be optimized for all infants.


Assuntos
Sistema Nervoso Central/crescimento & desenvolvimento , Suplementos Nutricionais , Compostos Ferrosos/farmacologia , Glicina/farmacologia , Quelantes de Ferro/farmacologia , Ferro/metabolismo , Ferro/farmacologia , Animais , Animais Recém-Nascidos , Sistema Nervoso Central/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Homeostase/efeitos dos fármacos , Ferro/sangue , Bainha de Mielina/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Oligoelementos/análise , Ganho de Peso/efeitos dos fármacos
4.
Eur J Pharmacol ; 900: 174065, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33775646

RESUMO

Akt (protein kinase B) signaling is frequently activated in diverse cancers. Akt inhibitors such as perifosine and MK-2206 have been evaluated as potential cancer chemotherapeutics. Although both drugs are generally well tolerated, among their most common side-effects vomiting is a major concern. Here we investigated whether these Akt inhibitors evoke emesis in the least shrew model of vomiting. Indeed, both perifosine and MK-2206 induced vomiting with maximal efficacies of 90% at 50 mg/kg (i.p.) and 100% at 10 mg/kg (i.p.), respectively. MK-2206 (10 mg/kg, i.p.) increased c-Fos immunoreactivity both centrally in the shrew brainstem dorsal vagal complex (DVC) emetic nuclei, and peripherally in the jejunum. MK-2206 also evoked phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in both the DVC emetic nuclei and the enteric nervous system in the jejunum. The ERK1/2 inhibitor U0126 suppressed MK-2206-induced emesis dose-dependently. We then evaluated the suppressive efficacy of diverse antiemetics against MK-2206-evoked vomiting including antagonists/inhibitors of the: L-type Ca2+ channel (nifedipine at 2.5 mg/kg, subcutaneously (s.c.)); glycogen synthase kinase 3 (GSK-3) (AR-A014418 at 10 mg/kg and SB216763 at 0.25 mg/kg, i.p.); 5-hydroxytryptamine 5-HT3 receptor (palonosetron at 0.5 mg/kg, s.c.); substance P neurokinin NK1 receptor (netupitant at 10 mg/kg, i.p.) and dopamine D2/3 receptor (sulpride at 8 mg/kg, s.c.). All tested antagonists/blockers attenuated emetic parameters to varying degrees. In sum, this is the first study to demonstrate how pharmacological inhibition of Akt evokes vomiting via both central and peripheral mechanisms, a process which involves multiple emetic receptors.


Assuntos
Antieméticos/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis , Proteína Oncogênica v-akt/antagonistas & inibidores , Sistema Nervoso Periférico/efeitos dos fármacos , Musaranhos/fisiologia , Vômito/induzido quimicamente , Vômito/fisiopatologia , Animais , Antieméticos/uso terapêutico , Tronco Encefálico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Eméticos/farmacologia , Sistema Nervoso Entérico/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/antagonistas & inibidores , Jejuno/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fosforilação , Proteínas Proto-Oncogênicas c-fos/metabolismo , Vômito/tratamento farmacológico
5.
Molecules ; 26(4)2021 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-33668452

RESUMO

Based on the broad spectrum of biological activity of hydrazide-hydrazones, trifluoromethyl compounds, and clinical usage of cholinesterase inhibitors, we investigated hydrazones obtained from 4-(trifluoromethyl)benzohydrazide and various benzaldehydes or aliphatic ketones as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). They were evaluated using Ellman's spectrophotometric method. The hydrazide-hydrazones produced a dual inhibition of both cholinesterase enzymes with IC50 values of 46.8-137.7 µM and 19.1-881.1 µM for AChE and BuChE, respectively. The majority of the compounds were stronger inhibitors of AChE; four of them (2-bromobenzaldehyde, 3-(trifluoromethyl)benzaldehyde, cyclohexanone, and camphor-based 2o, 2p, 3c, and 3d, respectively) produced a balanced inhibition of the enzymes and only 2-chloro/trifluoromethyl benzylidene derivatives 2d and 2q were found to be more potent inhibitors of BuChE. 4-(Trifluoromethyl)-N'-[4-(trifluoromethyl)benzylidene]benzohydrazide 2l produced the strongest inhibition of AChE via mixed-type inhibition determined experimentally. Structure-activity relationships were identified. The compounds fit physicochemical space for targeting central nervous systems with no apparent cytotoxicity for eukaryotic cell line together. The study provides new insights into this CF3-hydrazide-hydrazone scaffold.


Assuntos
Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Hidrazinas/química , Hidrazonas/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Sistema Nervoso Central/efeitos dos fármacos , Humanos , Hidrazonas/química , Cinética
6.
Sci Rep ; 11(1): 5402, 2021 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-33686135

RESUMO

Most multiple sclerosis (MS) patients given currently available disease-modifying drugs (DMDs) experience progressive disability. Accordingly, there is a need for new treatments that can limit the generation of new waves T cell autoreactivity that drive disease progression. Notably, immune cells express GABAA-receptors (GABAA-Rs) whose activation has anti-inflammatory effects such that GABA administration can ameliorate disease in models of type 1 diabetes, rheumatoid arthritis, and COVID-19. Here, we show that oral GABA, which cannot cross the blood-brain barrier (BBB), does not affect the course of murine experimental autoimmune encephalomyelitis (EAE). In contrast, oral administration of the BBB-permeable GABAA-R-specific agonist homotaurine ameliorates monophasic EAE, as well as advanced-stage relapsing-remitting EAE (RR-EAE). Homotaurine treatment beginning after the first peak of paralysis reduced the spreading of Th17 and Th1 responses from the priming immunogen to a new myelin T cell epitope within the CNS. Antigen-presenting cells (APC) isolated from homotaurine-treated mice displayed an attenuated ability to promote autoantigen-specific T cell proliferation. The ability of homotaurine treatment to limit epitope spreading within the CNS, along with its safety record, makes it an excellent candidate to help treat MS and other inflammatory disorders of the CNS.


Assuntos
Sistema Nervoso Central/patologia , Esclerose Múltipla/imunologia , Linfócitos T/imunologia , Taurina/análogos & derivados , Animais , Apresentação do Antígeno/efeitos dos fármacos , Células Apresentadoras de Antígenos/efeitos dos fármacos , Células Apresentadoras de Antígenos/imunologia , Proliferação de Células/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/imunologia , Modelos Animais de Doenças , Progressão da Doença , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Camundongos Endogâmicos C57BL , Esclerose Múltipla/patologia , Proteína Proteolipídica de Mielina/imunologia , Fragmentos de Peptídeos/imunologia , Recidiva , Baço/patologia , Linfócitos T/efeitos dos fármacos , Taurina/farmacologia , Ácido gama-Aminobutírico/farmacologia
7.
Int J Mol Sci ; 22(5)2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33668791

RESUMO

Interactions between phospholipid membranes and selected drugs affecting the central nervous system (CNS) were investigated. Small, unilamellar liposomes were used as biomimetic cell membrane models. Microelectrophoretic experiments on two-component liposomes were performed using the electrophoretic light scattering technique (ELS). The effect of both positively (perphenazine, PF) and negatively (barbituric acid, BA) charged drugs on zwitterionic L-α-phosphatidylcholine (PC) membranes were analyzed. Experimental membrane surface charge density (δ) data were determined as a function of pH. Quantitative descriptions of the adsorption equilibria formed due to the binding of solution ions to analyzed two-component membranes are presented. Binding constants of the solution ions with perphenazine and barbituric acid-modified membranes were determined. The results of our research show that both charged drugs change surface charge density values of phosphatidylcholine membranes. It can be concluded that perphenazine and barbituric acid are located near the membrane surface, interacting electrostatically with phosphatidylcholine polar heads.


Assuntos
Barbitúricos/farmacologia , Sistema Nervoso Central/fisiologia , Eletricidade , Perfenazina/farmacologia , Fosfatidilcolinas/metabolismo , Animais , Ânions , Cátions , Sistema Nervoso Central/efeitos dos fármacos , Galinhas , Ponto Isoelétrico , Lipossomos , Membranas Artificiais , Modelos Biológicos , Espalhamento de Radiação , Soluções , Eletricidade Estática
8.
Neurosci Lett ; 748: 135691, 2021 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-33524474

RESUMO

Aggressive use of antiretroviral therapy has led to excellent viral suppression within the systemic circulation. However, despite these advances, HIV reservoirs still persist. The persistence of HIV within the brain can lead to the development of HIV-associated neurocognitive disorders (HAND). Although the causes of the development of neurocognitive disorders is likely multifactorial, the inability of antiretroviral therapy to achieve adequate concentrations within the brain is likely a major contributing factor. Information about antiretroviral drug exposure within the brain is limited. Clinically, drug concentrations within the cerebrospinal fluid (CSF) are used as markers for central nervous system (CNS) drug exposure. However, significant differences exist; CSF concentration is often a poor predictor of drug exposure within the brain. This article reviews the current information regarding antiretroviral exposure within the brain in humans as well as preclinical animals and discusses the impact of co-morbidities on antiretroviral efficacy within the brain. A more thorough understanding of antiretroviral penetration into the brain is an essential component to the development of better therapeutic strategies for neuroAIDS.


Assuntos
Antirretrovirais/farmacologia , Encéfalo/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Infecções por HIV/tratamento farmacológico , Animais , Sistema Nervoso Central/efeitos dos fármacos , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Humanos
9.
Chem Biol Interact ; 339: 109268, 2021 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-33617801

RESUMO

Salidroside has been identified as one of the most potent compounds isolated from various Rhodiola plants, which have been used for a long time as adaptogens in traditional Chinese medicine. However, due to the severe growing environment of herbal medicine and large-scale excavation, the content of natural salidroside is extremely small. Most of the previous studies focused on herbal medicine, and there were few reviews on the synthesis of its main active ingredient salidroside. This paper presents different synthetic routes of salidroside to resolve the contradiction between supply and demand and lays the foundation for new drug research and development. Furthermore, emerging evidence indicates that salidroside, a promising environmentally-adapted drug with low toxicity and few side effects, possesses a wide spectrum of pharmacological properties, including activities on the cardiovascular system and central nervous system, anti-hypoxia, anti-fatigue and anti-aging activities, anticancer activity, anti-inflammatory activity, antioxidant activity, antivirus and immune stimulation activities, antidiabetic activity, anti-osteoporotic activity, and so on. Although the former researches have summarized the pharmacological effects of salidroside, focusing on the central nervous system, diabetes, and cancer, the overall pharmacological aspects of it have not been analyzed. This review highlights biological characteristics and mechanisms of action from 2009 to now as well as toxicological and pharmacokinetic data of the analyzed compound reported so far, with a view to providing a reference for further development and utilization of salidroside.


Assuntos
Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Fenóis/farmacologia , Fenóis/uso terapêutico , Animais , Sistema Nervoso Central/efeitos dos fármacos , Diabetes Mellitus/tratamento farmacológico , Humanos , Neoplasias/tratamento farmacológico , Rhodiola/química
10.
Toxicol Appl Pharmacol ; 415: 115429, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33524447

RESUMO

The zebrafish is extensively used as a model organism for studying several disorders of the central nervous system (CNS), including epilepsy. Some antiseizure drugs (ASDs) have been shown to produce discrepant results in larvae and adults zebrafish, therefore, their anticonvulsant efficacy in subsequent stages of the pentylenetetrazole (PTZ)-induced seizures should be more precisely characterized. The purpose of this study was to investigate behavioral effects of five classic ASDs: valproate (VPA), phenytoin (PHT), carbamazepine (CBZ), diazepam (DZP), and phenobarbital (PB) administered intraperitoneally (i.p.) in the PTZ-induced seizure test in adult zebrafish. We determined the time of maximal effect and the dose-response relationship of the studied ASDs. Furthermore, we assessed changes in the locomotor activity and the anxiety-like behavior in the color preference test. Moreover, drug concentrations in zebrafish homogenates were examined. VPA, DZP, and PB significantly increased the seizure latency at three subsequent stages of seizures (SI-SIII). PHT produced the anticonvulsant-like effect at SI and SII, while CBZ was effective at SII and SIII. Only DZP decreased zebrafish locomotor activity. A strong anxiolytic-like effect was observed after administration of PHT and PB. A weak anxiolytic-like effect occurred after treatment with VPA and DZP. The HPLC analysis showed the average concentrations of the studied ASDs in the fish body during the maximum anticonvulsant activity of each drug. Our results confirm the advantages of using zebrafish with the mature CNS over larval models and its utility to investigate some neuropharmacological properties of the tested drugs.


Assuntos
Ansiolíticos/farmacologia , Anticonvulsivantes/farmacologia , Ansiedade/prevenção & controle , Comportamento Animal/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Convulsões/prevenção & controle , Fatores Etários , Animais , Ansiolíticos/metabolismo , Anticonvulsivantes/metabolismo , Ansiedade/fisiopatologia , Ansiedade/psicologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiopatologia , Percepção de Cores/efeitos dos fármacos , Visão de Cores/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Locomoção/efeitos dos fármacos , Masculino , Pentilenotetrazol , Convulsões/induzido quimicamente , Convulsões/fisiopatologia , Fatores de Tempo , Peixe-Zebra/metabolismo
11.
Yakugaku Zasshi ; 141(1): 93-110, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33390452

RESUMO

There has been little information about the role of histamine on the central nervous system (CNS), different from dopamine and serotonin. In the present study, therefore, the effects of histamine and related compounds on the CNS were studied using rats. Intracerebroventricular (i.c.v.) injection of histamine and 2-methylhistamine ameliorated memory deficit after long interrution of learning in active avoidance response. First generation H1-antagonists inhibited active avoidance response, whereas newly develpoed H1-antagonists showed little effect. α-Fluoromethylhistidine, an histidine decarboxylase inhibitor, also inhibited active avoidance response. In radial maze performance, almost the same findings were obtained. I.c.v. injection of histamine and H1-agonists inhibited amygdaloid kindled seizures. First generation H1-antagonists attenuated histamine-induced inhibition of amygdaloid kindled seizures. Both i.c.v. and intraperitoneal injections of H3-antagonist, thioperamide, resulted in a dose-related inhibition of amygdaloid kindled seizures. The effect of thioperamide was inhibited by an H3-agonists and H1-antagonists. Similar to nitrazepam, diphenhydramine and chlorpheniramine caused a shortening of sleep latency. On the other hand, no significant effects were observed with second generation H1-antagonists. These findings suggest that histamine plays an important role in learning and memory via H1-receptors, an inhibition of amygdaloid kindled seizures induced by histamine occurred through not only H1-receptors but also H3-receptors, and that classic H1-antagonists can be useful as a effective hypnotic for difficulty in falling asleep.


Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H1/farmacologia , Histamina/farmacologia , Metilistaminas/farmacologia , Metilistidinas/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Histamina/administração & dosagem , Histamina/metabolismo , Histamina/fisiologia , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Humanos , Hipnóticos e Sedativos , Injeções Intraventriculares , Excitação Neurológica/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Metilistaminas/administração & dosagem , Metilistidinas/administração & dosagem , Camundongos , Ratos , Receptores Histamínicos H3/metabolismo , Receptores Histamínicos H3/fisiologia , Convulsões/tratamento farmacológico , Sono/efeitos dos fármacos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico
12.
Eur J Pharmacol ; 893: 173837, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33359647

RESUMO

Neuropsychiatric disorders are diseases of the central nervous system (CNS) which are characterised by complex pathomechanisms that including homeostatic failure, malfunction, atrophy, pathology remodelling and reactivity anomaly of the neuronal system where treatment options remain challenging. ß-Carboline (ßC) alkaloids are scaffolds of structurally diverse tricyclic pyrido[3,4-b]indole alkaloid with vast occurrence in nature. Their unique structural features which favour interactions with enzymes and protein receptor targets account for their potent neuropharmacological properties. However, our current understanding of their biological mechanisms for these beneficial effects, especially for neuropsychiatric disorders is sparse. Therefore, we present a comprehensive review of the scientific progress in the last two decades on the prospective pharmacology and physiology of the ßC alkaloids in the treatment of some neuropsychiatric conditions such as depression, anxiety, Alzheimer's disease, Parkinson's disease, brain tumour, essential tremor, epilepsy and seizure, licking behaviour, dystonia, agnosia, spasm, positive ingestive response as demonstrated in non-clinical models. The current evidence supports that ßC alkaloids offer potential therapeutic agents against most of these disorders and amenable for further drug design.


Assuntos
Carbolinas/uso terapêutico , Fármacos do Sistema Nervoso Central/uso terapêutico , Doenças do Sistema Nervoso Central/tratamento farmacológico , Sistema Nervoso Central/efeitos dos fármacos , Carbolinas/efeitos adversos , Carbolinas/química , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Sistema Nervoso Central/fisiopatologia , Fármacos do Sistema Nervoso Central/efeitos adversos , Fármacos do Sistema Nervoso Central/química , Doenças do Sistema Nervoso Central/metabolismo , Doenças do Sistema Nervoso Central/fisiopatologia , Doenças do Sistema Nervoso Central/psicologia , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
13.
Toxicol Lett ; 339: 39-50, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33373663

RESUMO

Traffic-generated air pollutants have been correlated with alterations in blood-brain barrier (BBB) integrity, which is associated with pathologies in the central nervous system (CNS). Much of the existing literature investigating the effects of air pollution in the CNS has predominately been reported in males, with little known regarding the effects in females. As such, this study characterized the effects of inhalation exposure to mixed vehicle emissions (MVE), as well as the presence of female sex hormones, in the CNS of female ApoE-/- mice, which included cohorts of both ovariectomized (ov-) and ovary-intact (ov+) mice. Ov + and ov- were placed on a high-fat diet and randomly grouped to be exposed to either filtered-air (FA) or MVE (200 PM/m3: 50 µg PM/m3 gasoline engine + 150 µg PM/m3 from diesel engine emissions) for 6 h/d, 7d/wk, for 30d. MVE-exposure resulted in altered cerebral microvascular integrity and permeability, as determined by the decreased immunofluorescent expression of tight junction (TJ) proteins, occludin, and claudin-5, and increased IgG extravasation into the cerebral parenchyma, compared to FA controls, regardless of ovary status. Associated with the altered cerebral microvascular integrity, we also observed an increase in matrix metalloproteinases (MMPs) -2/9 activity in the MVE ov+, MVE ov-, and FA ov- groups, compared to FA ov+. There was also elevated expression of intracellular adhesion molecule (ICAM)-1, inflammatory interleukins (IL-1, IL-1ß), and tumor necrosis factor (TNF-α) mRNA in the cerebrum of MVE ov + and MVE ov- animals. IκB kinase (IKK) subunits IKKα and IKKß mRNA expressions were upregulated in the cerebrum of MVE ov- and FA ov- mice. Our findings indicate that MVE exposure mediates altered integrity of the cerebral microvasculature correlated with increased MMP-2/9 activity and inflammatory signaling, regardless of female hormones present.


Assuntos
Poluentes Atmosféricos/toxicidade , Encéfalo/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Inflamação/induzido quimicamente , Camundongos/genética , Microvasos/efeitos dos fármacos , Emissões de Veículos/toxicidade , Animais , Apolipoproteínas E/efeitos dos fármacos , Feminino , Humanos , Modelos Animais , Fragmentos de Peptídeos/efeitos dos fármacos
14.
Am J Physiol Endocrinol Metab ; 320(2): E234-E239, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33308015

RESUMO

Blood glucose and insulin homeostasis is disrupted during the progression of type 2 diabetes. Insulin levels and action are regulated by both peripheral and central responses that involve the intestine and microbiome. The intestine and its microbiota process nutrients and generate molecules that influence blood glucose and insulin. Peripheral insulin regulation is regulated by gut-segment-dependent nutrient sensing and microbial factors such as short-chain fatty acids and bile acids that engage G-protein-coupled receptors. Innate immune sensing of gut-derived bacterial cell wall components and lipopolysaccharides also alter insulin homeostasis. These bacterial metabolites and postbiotics influence insulin secretion and insulin clearance in part by altering endocrine responses such as glucagon-like peptide-1. Gut-derived bacterial factors can promote inflammation and insulin resistance, but other postbiotics can be insulin sensitizers. In parallel, activation of small intestinal sirtuin 1 increases insulin sensitivity by reversing high fat-induced hypothalamic insulin resistance through a gut-brain neuronal axis, whereas high fat-feeding alters small intestinal microbiome and increases taurochenodeoxycholic acid in the plasma and the dorsal vagal complex to induce insulin resistance. In summary, emerging evidence indicates that intestinal molecular signaling involving nutrient sensing and the host-microbe symbiosis alters insulin homeostasis and action. Gut-derived host endocrine and paracrine factors as well as microbial metabolites act on the liver, pancreas, and the brain, and in parallel on the gut-brain neuronal axis. Understanding common nodes of peripheral and central insulin homeostasis and action may reveal new ways to target the intestinal host-microbe relationship in obesity, metabolic disease, and type 2 diabetes.


Assuntos
Sistema Nervoso Central/fisiologia , Insulina/metabolismo , Intestinos/fisiologia , Microbiota/fisiologia , Administração Intranasal , Animais , Sistema Nervoso Central/efeitos dos fármacos , Endocrinologia/história , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Glucose/metabolismo , História do Século XX , História do Século XXI , Homeostase/fisiologia , Humanos , Insulina/administração & dosagem , Insulina/farmacologia , Resistência à Insulina/fisiologia , Intestinos/efeitos dos fármacos , Leptina/administração & dosagem , Leptina/farmacologia , Microbiota/efeitos dos fármacos
15.
Sci Rep ; 10(1): 22347, 2020 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-33339892

RESUMO

Recent evidence suggests that the central nervous system (CNS) regulates plasma glucose levels, but the underlying mechanism is unclear. The present study investigated the role of dopaminergic function in the CNS in regulation of plasma glucose levels in mice. I.c.v. injection of neither the dopamine D1 receptor agonist SKF 38393 nor the antagonist SCH 23390 influenced plasma glucose levels. In contrast, i.c.v. injection of both the dopamine D2 receptor agonist quinpirole and the antagonist l-sulpiride increased plasma glucose levels. Hyperglycemia induced by quinpirole and l-sulpiride was absent in dopamine D2 receptor knockout mice. I.c.v. injection of quinpirole and l-sulpiride each increased mRNA levels of hepatic glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, which are the key enzymes for hepatic gluconeogenesis. Systemic injection of the ß2 adrenoceptor antagonist ICI 118,551 inhibited hyperglycemia induced by l-sulpiride, but not by quinpirole. In contrast, hyperglycemia induced by quinpirole, but not by l-sulpiride, was inhibited by hepatic vagotomy. These results suggest that stimulation of central dopamine D2 receptors increases plasma glucose level by increasing hepatic glucose production through parasympathetic nerves, whereas inhibition of central dopamine D2 receptors increases plasma glucose level by increasing hepatic glucose production through sympathetic nerves.


Assuntos
Glicemia/genética , Quimpirol/farmacologia , Receptores de Dopamina D2/genética , Sulpirida/farmacologia , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Animais , Vias Autônomas/efeitos dos fármacos , Vias Autônomas/metabolismo , Benzazepinas/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Antagonistas dos Receptores de Dopamina D2/farmacologia , Humanos , Camundongos , Camundongos Knockout , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D2/agonistas
16.
Int J Nanomedicine ; 15: 9939-9960, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33376320

RESUMO

Background: Non-spherical titanium dioxide (TiO2) nanoparticles have been increasingly applied in various biomedical and technological fields. Their toxicological characterization is, however, less complete than that of roundish nanoparticles. Materials and Methods: Anatase form TiO2 nanorods, ca. 15x65 nm in size, were applied to cultured astrocytes in vitro and to the airways of young adult Wistar rats in vivo in 5, 10, and 8 mg/kg BW dose for altogether 28 days. Presence of nanorods and cellular damage was investigated in the astrocytes and in rat lungs and kidneys. Functional damage of the nervous system was studied by electrophysiological methods. Results: The treated astrocytes showed loss of viability without detectable apoptosis. In rats, TiO2 nanorods applied to the airways reached the blood and various organs including the lungs, kidneys, and the central nervous system. In lung and kidney samples, nanorods were observed within (partly damaged) phagolysosomes and attached to organelles, and apoptotic cell death was also detected. In cortical and peripheral electrophysiological activity, alterations corresponding to energy shortage (resulting possibly from mitochondrial damage) and astrocytic dysfunction were detected. Local titanium levels and relative weight of the investigated organs, apoptotic cell death in the lungs and kidneys, and changes in the central and peripheral nervous activity were mostly proportional to the applied doses, and viability loss of the cultured astrocytes was also dose-dependent, suggesting causal relationship of treatments and effects. Conclusion: Based on localization of the visualized nanorods, on neuro-functional changes, and on literature data, the toxic mechanism involved mitochondrial damage, oxidative stress, and apoptotic cell death. These indicate potential human toxicity and occupational risk in case of exposure to rod-shaped TiO2 nanoparticles.


Assuntos
Astrócitos/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Rim/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Nanotubos/química , Titânio/química , Titânio/toxicidade , Animais , Apoptose/efeitos dos fármacos , Astrócitos/citologia , Astrócitos/metabolismo , Células Cultivadas , Sistema Nervoso Central/metabolismo , Humanos , Rim/metabolismo , Pulmão/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
17.
Proc Natl Acad Sci U S A ; 117(35): 21527-21535, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32817520

RESUMO

Given the known neuroreparative actions of IL-33 in experimental models of central nervous system (CNS) injury, we predicted that compounds which induce IL-33 are likely to promote remyelination. We found anacardic acid as a candidate molecule to serve as a therapeutic agent to promote remyelination. Addition of anacardic acid to cultured oligodendrocyte precursor cells (OPCs) rapidly increased expression of myelin genes and myelin proteins, suggesting a direct induction of genes involved in myelination by anacardic acid. Also, when added to OPCs, anacardic acid resulted in the induction of IL-33. In vivo, treatment of with anacardic acid in doses which ranged from 0.025 mg/kg to 2.5 mg/kg, improved pathologic scores in experimental allergic encephalitis (EAE) and in the cuprizone model of demyelination/remyelination. Electron microscopic studies performed in mice fed with cuprizone and treated with anacardic acid showed lower g-ratio scores when compared to controls, suggesting increased remyelination of axons. In EAE, improvement in paralytic scores was seen when the drug was given prior to or following the onset of paralytic signs. In EAE and in the cuprizone model, areas of myelin loss, which are likely to remyelinate, was associated with a greater recruitment of IL-33-expressing OPCs in mice which received anacardic acid when compared to controls.


Assuntos
Ácidos Anacárdicos/farmacologia , Interleucina-33/biossíntese , Remielinização/efeitos dos fármacos , Animais , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Doenças Desmielinizantes/tratamento farmacológico , Doenças Desmielinizantes/metabolismo , Feminino , Interleucina-33/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Básica da Mielina/metabolismo , Proteínas da Mielina/metabolismo , Bainha de Mielina/metabolismo , Células Precursoras de Oligodendrócitos/efeitos dos fármacos , Células Precursoras de Oligodendrócitos/metabolismo , Oligodendroglia/metabolismo , Remielinização/fisiologia , Células-Tronco/metabolismo
18.
Arch Insect Biochem Physiol ; 105(2): e21731, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32761928

RESUMO

Jaburetox is a recombinant peptide derived from one of the Canavalia ensiformis urease isoforms. This peptide induces several toxic effects on insects of different orders, including interference on muscle contractility in cockroaches, modulation of UDP-N-acetylglucosamine pyrophosphorylase (UAP) and nitric oxide synthase (NOS) activities in the central nervous system of triatomines, as well as activation of the immune system in Rhodnius prolixus. When injected, the peptide is lethal for R. prolixus and Triatoma infestans. Here, we evaluated Jaburetox toxicity to Nauphoeta cinerea cockroaches, exploring the effects on the central nervous system through the activities of UAP, NOS, acid phosphatases (ACP), and acetylcholinesterase (AChE). The results indicated that N. cinerea is not susceptible to the lethal effect of the peptide. Moreover, both in vivo and in vitro treatments with Jaburetox inhibited NOS activity, without modifying the protein levels. No alterations on ACP activity were observed. In addition, the enzyme activity of UAP only had its activity affected at 18 hr after injection. The peptide increased the AChE activity, suggesting a mechanism involved in overcoming the toxic effects. In conclusion, our findings indicate that Jaburetox affects the nitrinergic signaling as well as the AChE and UAP activities and establishes N. cinerea as a Jaburetox-resistant model for future comparative studies.


Assuntos
Baratas/efeitos dos fármacos , Baratas/enzimologia , Proteínas de Plantas/toxicidade , Urease/toxicidade , Acetilcolinesterase/efeitos dos fármacos , Fosfatase Ácida/efeitos dos fármacos , Animais , Sistema Nervoso Central/efeitos dos fármacos , Feminino , Masculino , Óxido Nítrico Sintase/efeitos dos fármacos , Nucleotidiltransferases/efeitos dos fármacos , Proteínas Recombinantes/toxicidade
19.
Sci Rep ; 10(1): 9483, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32528183

RESUMO

Chronic kidney disease (CKD) is deemed to be a worldwide health concern connected with neurological manifestations. The etiology of central nervous system (CNS) disorders in CKD is still not fully understood, however particular attention is currently being paid to the impact of accumulated toxins. Indoxyl sulfate (IS) is one of the most potent uremic toxins. The purpose of the present study was to assess IS concentrations in the cerebellum, brainstem, cortex, hypothalamus, and striatum with hippocampus of rats chronically exposed to IS. To evaluate IS impact on neurochemical and behavioral alterations, we examined its influence on brain levels of norepinephrine, epinephrine, dopamine, serotonin and their metabolites, as well as changes in behavioral tests (open field test, elevated plus maze test, chimney test, T maze test, and splash test). Our results show the highest IS accumulation in the brainstem. IS leads to behavioral alterations involving apathetic behavior, increased stress sensitivity, and reduced locomotor and exploratory activity. Besides, IS contributes to the impairment of spatial memory and motor coordination. Furthermore, we observed reduced levels of norepinephrine, dopamine or serotonin, mainly in the brainstem. Our findings indicate that IS can be one of the crucial uremic factors responsible for altered mental status in CKD.


Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Indicã/farmacologia , Toxinas Biológicas/toxicidade , Uremia/induzido quimicamente , Animais , Sistema Nervoso Central/metabolismo , Dopamina/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Modelos Animais , Doenças do Sistema Nervoso/induzido quimicamente , Doenças do Sistema Nervoso/metabolismo , Norepinefrina/metabolismo , Ratos , Ratos Wistar , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/metabolismo , Serotonina/metabolismo , Memória Espacial/efeitos dos fármacos , Uremia/metabolismo
20.
Nat Commun ; 11(1): 3033, 2020 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-32561830

RESUMO

Endogenous opioid peptides and prescription opioid drugs modulate pain, anxiety and stress by activating opioid receptors, currently classified into four subtypes. Here we demonstrate that ACKR3/CXCR7, hitherto known as an atypical scavenger receptor for chemokines, is a broad-spectrum scavenger of opioid peptides. Phylogenetically, ACKR3 is intermediate between chemokine and opioid receptors and is present in various brain regions together with classical opioid receptors. Functionally, ACKR3 is a scavenger receptor for a wide variety of opioid peptides, especially enkephalins and dynorphins, reducing their availability for the classical opioid receptors. ACKR3 is not modulated by prescription opioids, but we show that an ACKR3-selective subnanomolar competitor peptide, LIH383, can restrain ACKR3's negative regulatory function on opioid peptides in rat brain and potentiate their activity towards classical receptors, which may open alternative therapeutic avenues for opioid-related disorders. Altogether, our results reveal that ACKR3 is an atypical opioid receptor with cross-family ligand selectivity.


Assuntos
Peptídeos Opioides/química , Receptores CXCR/metabolismo , Analgésicos Opioides/química , Animais , Encéfalo/metabolismo , Linhagem Celular Tumoral , Sistema Nervoso Central/efeitos dos fármacos , Quimiocinas/metabolismo , Humanos , Ligantes , Sistema de Sinalização das MAP Quinases , Masculino , Fosforilação , Ratos , Ratos Wistar , Transdução de Sinais , Relação Estrutura-Atividade , beta-Arrestina 1/metabolismo
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