RESUMO
Hyperglycemia alters the function of cerebral endothelial cells from the blood-brain barrier, increasing the risk of cerebrovascular complications during diabetes. This study evaluated the protective effect of polyphenols on inflammatory and permeability markers on bEnd3 cerebral endothelial cells exposed to high glucose concentration. Results show that hyperglycemic condition increased nuclear factor kappa B (NFκB) activity, deregulated the expression of interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), interleukin-10 (IL-10) and endothelial-leukocyte adhesion molecule (E-selectin) genes, raised MCP-1 secretion and elevated monocyte adhesion and transendothelial migration. High glucose decreased occludin, claudin-5, zona occludens-1 (ZO-1) and zona occludens-2 (ZO-2) tight junctions production and altered the endothelial permeability. Characterized polyphenolic extracts from the French medicinal plants Antirhea borbonica, Ayapana triplinervis, Dodonaea viscosa and Terminalia bentzoe, and their major polyphenols quercetin, caffeic, chlorogenic and gallic acids limited the pro-inflammatory and permeability alterations caused by high glucose. Peroxisome proliferator-activated receptor gamma (PPARγ) agonist also attenuated these damages while PPARγ antagonist aggravated them, suggesting PPARγ protective action. Interestingly, polyphenols improved PPARγ gene expression lowered by high glucose. Moreover, polyphenols were detected at the intracellular level or membrane-bound to cells, with evidence for breast cancer resistance protein (BCRP) efflux transporter role. Altogether, these findings emphasize the ability of polyphenols to protect cerebral endothelial cells in hyperglycemic condition and their relevance for pharmacological strategies aiming to limit cerebrovascular disorders in diabetes.
Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Transtornos Cerebrovasculares/prevenção & controle , Hiperglicemia/imunologia , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Glicemia/metabolismo , Barreira Hematoencefálica/citologia , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/patologia , Permeabilidade Capilar/efeitos dos fármacos , Permeabilidade Capilar/imunologia , Linhagem Celular , Transtornos Cerebrovasculares/etiologia , Transtornos Cerebrovasculares/imunologia , Transtornos Cerebrovasculares/patologia , Avaliação Pré-Clínica de Medicamentos , Células Endoteliais/imunologia , Células Endoteliais/patologia , Endotélio Vascular/citologia , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Humanos , Hiperglicemia/sangue , Hiperglicemia/complicações , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/imunologia , NF-kappa B/metabolismo , PPAR gama/agonistas , PPAR gama/antagonistas & inibidores , PPAR gama/metabolismo , Extratos Vegetais/uso terapêutico , Polifenóis/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/imunologia , Junções Íntimas/patologiaRESUMO
Neurodegeneration is the pathological condition, in which the nervous system or neuron loses its structure, function, or both, leading to progressive degeneration or the death of neurons, and well-defined associations of tissue system, resulting in clinical manifestations. Neuroinflammation has been shown to precede neurodegeneration in several neurodegenerative diseases (NDs). No drug is yet known to delay or treat neurodegeneration. Although the etiology and potential causes of NDs remain widely indefinable, matrix metalloproteinases (MMPs) evidently have a crucial role in the progression of NDs. MMPs, a protein family of zinc (Zn2+)-containing endopeptidases, are pivotal agents that are involved in various biological and pathological processes in the central nervous system (CNS). The current review delineates the several emerging evidence demonstrating the effects of MMPs in the progression of NDs, wherein they regulate several processes, such as (neuro)inflammation, microglial activation, amyloid peptide degradation, blood brain barrier (BBB) disruption, dopaminergic apoptosis, and α-synuclein modulation, leading to neurotoxicity and neuron death. Published papers to date were searched via PubMed, MEDLINE, etc., while using selective keywords highlighted in our manuscript. We also aim to shed a light on pathophysiological effect of MMPs in the CNS and focus our attention on its detrimental and beneficial effects in NDs, with a special focus on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), multiple sclerosis (MS), and Huntington's disease (HD), and discussed various therapeutic strategies targeting MMPs, which could serve as potential modulators in NDs. Over time, several agents have been developed in order to overcome challenges and open up the possibilities for making selective modulators of MMPs to decipher the multifaceted functions of MMPs in NDs. There is still a greater need to explore them in clinics.
Assuntos
Barreira Hematoencefálica/patologia , Inibidores de Metaloproteinases de Matriz/uso terapêutico , Metaloproteinases da Matriz/metabolismo , Doenças Neurodegenerativas/patologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/enzimologia , Barreira Hematoencefálica/imunologia , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Inibidores de Metaloproteinases de Matriz/farmacologia , Microglia/imunologia , Microglia/metabolismo , Microglia/patologia , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/imunologia , Neurônios/imunologia , Neurônios/patologia , Resultado do TratamentoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: The medicinal properties of grapes (Vitis vinifera L.) are well known since ancient times. Ethnobotanical grape preparations, like the Ayurvedic Darakchasava are used as cardiotonic and for the treatment of cardiovascular diseases. Dried grape products are also applied in Iranian traditional medicine for memory problems, which are linked to the pathology of brain microvessels, a special part of the cardiovascular system. The anti-inflammatory and protective effects of these traditional preparations on the cardiovascular system are related to their bioactive phenolic compounds. AIM OF THE STUDY: The blood-brain barrier (BBB), formed by brain capillaries, is not only involved in inflammatory and other diseases of the central nervous system, but also in many systemic diseases with an inflammatory component. Dietary obesity is a systemic chronic inflammatory condition in which the peripheral and central vascular system is affected. Among the cerebrovascular changes in obesity defective leptin transport across the BBB related to central leptin resistance is observed. Our aim was to study the protective effects of grape phenolic compounds epicatechin (EC), gallic acid (GA) and resveratrol (RSV) and grape-seed proanthocyanidin-rich extract (GSPE) on a cytokine-induced vascular endothelial inflammation model. Using a culture model of the BBB we investigated cytokine-induced endothelial damage and changes in the expression of leptin receptors and leptin transfer. MATERIALS AND METHODS: For the BBB model, primary cultures of rat brain endothelial cells, glial cells and pericytes were used in co-culture. Cells were treated by tumor necrosis factor-α (TNF-α) and interleukin-1 ß (IL-1ß) (10â¯ng/ml each) to induce damage. Cell toxicity was evaluated by the measurement of impedance. The expression of leptin receptors was assessed by RT-qPCR and western blot. The production of reactive oxygen species (ROS) and nitric oxide (NO) were detected by fluorescent probes. RESULTS: GSPE (10⯵g/ml), EC (10⯵M), GA (1⯵M) or RSV (10⯵M) did not change the viability of brain endothelial cells. The gene expression of the short leptin receptor isoform, Ob-Ra, was up-regulated by GSPE, EC and RSV, while the mRNA levels of Lrp2 and clusterin, clu/ApoJ were not affected. The tested compounds did not change the expression of the long leptin receptor isoform, Ob-Rb. RSV protected against the cytokine-induced increase in albumin permeability of the BBB model. GSPE and EC exerted an antioxidant effect and GSPE increased NO both alone and in the presence of cytokines. The cytokine-induced nuclear translocation of transcription factor NF-κB was blocked by GSPE, GA and RSV. Cytokines increased the mRNA expression of Lrp2 which was inhibited by EC. RSV increased Ob-Ra and Clu in the presence of cytokines. Cytokines elevated leptin transfer across the BBB model, which was not modified by GSPE or RSV. CONCLUSION: Our results obtained on cell culture models confirm that natural grape compounds protect vascular endothelial cells against inflammatory damage in accordance with the ethnopharmacological use of grape preparations in cardiovascular diseases. Furthermore, grape compounds and GSPE, by exerting a beneficial effect on the BBB, may also be considered in the treatment of obesity after validation in clinical trials.
Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Extrato de Sementes de Uva/farmacologia , Inflamação/tratamento farmacológico , Proantocianidinas/farmacologia , Vitis/química , Animais , Animais Recém-Nascidos , Astrócitos , Barreira Hematoencefálica/citologia , Barreira Hematoencefálica/imunologia , Catequina/farmacologia , Células Cultivadas , Citocinas/imunologia , Avaliação Pré-Clínica de Medicamentos , Células Endoteliais/imunologia , Células Endoteliais/patologia , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/imunologia , Etnofarmacologia , Ácido Gálico/farmacologia , Extrato de Sementes de Uva/química , Extrato de Sementes de Uva/uso terapêutico , Humanos , Inflamação/imunologia , Inflamação/patologia , Leptina/imunologia , Leptina/metabolismo , Ayurveda/métodos , Cultura Primária de Células , Proantocianidinas/química , Proantocianidinas/uso terapêutico , Ratos , Espécies Reativas de Oxigênio/metabolismo , Receptores para Leptina/metabolismo , Resveratrol/farmacologiaRESUMO
Ischemic stroke is a devastating and debilitating medical condition with limited therapeutic options. However, accumulating evidence indicates a central role of inflammation in all aspects of stroke including its initiation, the progression of injury, and recovery or wound healing. A central target of inflammation is disruption of the blood brain barrier or neurovascular unit. Here we discuss recent developments in identifying potential molecular targets and immunomodulatory approaches to preserve or protect barrier function and limit infarct damage and functional impairment. These include blocking harmful inflammatory signaling in endothelial cells, microglia/macrophages, or Th17/γδ T cells with biologics, third generation epoxyeicosatrienoic acid (EET) analogs with extended half-life, and miRNA antagomirs. Complementary beneficial pathways may be enhanced by miRNA mimetics or hyperbaric oxygenation. These immunomodulatory approaches could be used to greatly expand the therapeutic window for thrombolytic treatment with tissue plasminogen activator (t-PA). Moreover, nanoparticle technology allows for the selective targeting of endothelial cells for delivery of DNA/RNA oligonucleotides and neuroprotective drugs. In addition, although likely detrimental to the progression of ischemic stroke by inducing inflammation, oxidative stress, and neuronal cell death, 20-HETE may also reduce susceptibility of onset of ischemic stroke by maintaining autoregulation of cerebral blood flow. Although the interaction between inflammation and stroke is multifaceted, a better understanding of the mechanisms behind the pro-inflammatory state at all stages will hopefully help in developing novel immunomodulatory approaches to improve mortality and functional outcome of those inflicted with ischemic stroke.
Assuntos
Isquemia Encefálica/terapia , Imunomodulação , Inflamação/terapia , Fármacos Neuroprotetores/farmacologia , Acidente Vascular Cerebral/terapia , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/patologia , Encéfalo/irrigação sanguínea , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Isquemia Encefálica/imunologia , Isquemia Encefálica/patologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/imunologia , Células Endoteliais/patologia , Terapia Genética/métodos , Humanos , Ácidos Hidroxieicosatetraenoicos/imunologia , Ácidos Hidroxieicosatetraenoicos/metabolismo , Oxigenoterapia Hiperbárica , Inflamação/imunologia , Inflamação/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Microglia/efeitos dos fármacos , Microglia/imunologia , Microglia/patologia , Fármacos Neuroprotetores/uso terapêutico , Oligonucleotídeos/administração & dosagem , Oligonucleotídeos/genética , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/patologiaRESUMO
Salvianolic acid A (SAA) is a water-soluble component from the root of Salvia Miltiorrhiza Bge, a traditional Chinese medicine, which has been used for the treatment of cerebrovascular diseases for centuries. The present study aimed to determine the brain protective effects of SAA against cerebral ischemia reperfusion injury in rats, and to figure out whether SAA could protect the blood brain barrier (BBB) through matrix metallopeptidase 9 (MMP-9) inhibition. A focal cerebral ischemia reperfusion model was induced by middle cerebral artery occlusion (MCAO) for 1.5-h followed by 24-h reperfusion. SAA was administered intravenously at doses of 5, 10, and 20 mg·kg-1. SAA significantly reduced the infarct volumes and neurological deficit scores. Immunohistochemical analyses showed that SAA treatments could also improve the morphology of neurons in hippocampus CA1 and CA3 regions and increase the number of neurons. Western blotting analyses showed that SAA downregulated the levels of MMP-9 and upregulated the levels of tissue inhibitor of metalloproteinase 1 (TIMP-1) to attenuate BBB injury. SAA treatment significantly prevented MMP-9-induced degradation of ZO-1, claudin-5 and occludin proteins. SAA also prevented cerebral NF-κB p65 activation and reduced inflammation response. Our results suggested that SAA could be a promising agent to attenuate cerebral ischemia reperfusion injury through MMP-9 inhibition and anti-inflammation activities.
Assuntos
Anti-Inflamatórios/administração & dosagem , Barreira Hematoencefálica/enzimologia , Isquemia Encefálica/tratamento farmacológico , Ácidos Cafeicos/administração & dosagem , Medicamentos de Ervas Chinesas/administração & dosagem , Lactatos/administração & dosagem , Metaloproteinase 9 da Matriz/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Salvia miltiorrhiza/química , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/imunologia , Encéfalo , Isquemia Encefálica/enzimologia , Isquemia Encefálica/genética , Humanos , Masculino , Metaloproteinase 9 da Matriz/genética , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/imunologia , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/imunologiaRESUMO
The incidence of neurological disorders is growing in developed countries together with increased lifespan. Nowadays, there are still no effective treatments for neurodegenerative pathologies, which make necessary to search for new therapeutic agents. Natural products, most of them used in traditional medicine, are considered promising alternatives for the treatment of neurodegenerative diseases. Honokiol is a natural bioactive phenylpropanoid compound, belonging to the class of neolignan, found in notable amounts in the bark of Magnolia tree, and has been reported to exert diverse pharmacological properties including neuroprotective activities. Honokiol can permeate the blood brain barrier and the blood-cerebrospinal fluid to increase its bioavailability in neurological tissues. Diverse studies have provided evidence on the neuroprotective effect of honokiol in the central nervous system, due to its potent antioxidant activity, and amelioration of the excitotoxicity mainly related to the blockade of glutamate receptors and reduction in neuroinflammation. In addition, recent studies suggest that honokiol can attenuate neurotoxicity exerted by abnormally aggregated Aß in Alzheimer's disease. The present work summarizes what is currently known concerning the neuroprotective effects of honokiol and its potential molecular mechanisms of action, which make it considered as a promising agent in the treatment and management of neurodegenerative diseases. © 2017 BioFactors, 43(6):760-769, 2017.
Assuntos
Antioxidantes/farmacologia , Compostos de Bifenilo/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Lignanas/farmacologia , Magnolia/química , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/imunologia , Antioxidantes/isolamento & purificação , Antioxidantes/farmacocinética , Produtos Biológicos/química , Transporte Biológico , Compostos de Bifenilo/isolamento & purificação , Compostos de Bifenilo/farmacocinética , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/metabolismo , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/patologia , Citocinas/antagonistas & inibidores , Citocinas/genética , Citocinas/imunologia , Regulação da Expressão Gênica , Humanos , Lignanas/isolamento & purificação , Lignanas/farmacocinética , Fatores de Crescimento Neural/antagonistas & inibidores , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/imunologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/patologia , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacocinética , Casca de Planta/química , Receptores de Glutamato/genética , Receptores de Glutamato/imunologiaRESUMO
The preventive and therapeutic mechanisms in multiple sclerosis are not clearly understood. We investigated whether Hyungbangpaedok-san (HBPDS), a traditional herbal medicine, has a beneficial effect in experimental autoimmune encephalomyelitis (EAE) mice immunized with myelin oligodendrocyte glycoprotein peptide (MOG 35-55). Onset-treatment with 4 types of HBPDS (extracted using distilled water and 30%/70%/100% ethanol as the solvent) alleviated neurological signs, and HBPDS extracted within 30% ethanol (henceforth called HBPDS) was more effective. Onset-treatment with HBPDS reduced demyelination and the recruitment/infiltration and activation of microglia/macrophages in the spinal cord of EAE mice, which corresponded to the reduced mRNA expression of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß), iNOS, and chemokines (MCP-1, MIP-1α, and RANTES) in the spinal cord. Onset-treatment with HBPDS inhibited changes in the components of the blood-brain barrier such as astrocytes, adhesion molecules (ICAM-1 and VCAM-1), and junctional molecules (claudin-3, claudin-5, and zona occludens-1) in the spinal cord of EAE mice. Onset-treatment with HBPDS reduced the elevated population of CD4+, CD4+/IFN-γ+, and CD4+/IL-17+ T cells in the spinal cord of EAE mice but it further increased the elevated population of CD4+/CD25+/Foxp3+ and CD4+/Foxp3+/Helios+ T cells. Pre-, onset-, post-, but not peak-treatment, with HBPDS had a beneficial effect on behavioral impairment in EAE mice. Taken together, HBPDS could alleviate the development/progression of EAE by regulating the recruitment/infiltration and activation of microglia and peripheral immune cells (macrophages, Th1, Th17, and Treg cells) in the spinal cord. These findings could help to develop protective strategies using HBPDS in the treatment of autoimmune disorders including multiple sclerosis.
Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologia , Paralisia/tratamento farmacológico , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/imunologia , Linfócitos T CD4-Positivos/imunologia , Citocinas/imunologia , Encefalomielite Autoimune Experimental/imunologia , Feminino , Fatores de Transcrição Forkhead/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Medicina Tradicional do Leste Asiático/métodos , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/imunologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Paralisia/imunologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologiaRESUMO
The blood-brain barrier (BBB) is an integral part of the neurovascular unit (NVU). The NVU is comprised of endothelial cells that are interconnected by tight junctions resting on a parenchymal basement membrane ensheathed by pericytes, smooth muscle cells and a layer of astrocyte end feet. Circulating blood cells, such as leukocytes, complete the NVU. BBB disruption is common in several neurological diseases, but the molecular mechanisms involved remain largely unknown. We analyzed the role of TWIK-related potassium channel-1 (TREK1, encoded by KCNK2) in human and mouse endothelial cells and the BBB. TREK1 was downregulated in endothelial cells by treatment with interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). Blocking TREK1 increased leukocyte transmigration, whereas TREK1 activation had the opposite effect. We identified altered mitogen-activated protein (MAP) kinase signaling, actin remodeling and upregulation of cellular adhesion molecules as potential mechanisms of increased migration in TREK1-deficient (Kcnk2(-/-)) cells. In Kcnk2(-/-) mice, brain endothelial cells showed an upregulation of the cellular adhesion molecules ICAM1, VCAM1 and PECAM1 and facilitated leukocyte trafficking into the CNS. Following the induction of experimental autoimmune encephalomyelitis (EAE) by immunization with a myelin oligodendrocyte protein (MOG)35-55 peptide, Kcnk2(-/-) mice showed higher EAE severity scores that were accompanied by increased cellular infiltrates in the central nervous system (CNS). The severity of EAE was attenuated in mice given the amyotrophic lateral sclerosis drug riluzole or fed a diet enriched with linseed oil (which contains the TREK-1 activating omega-3 fatty acid α-linolenic acid). These beneficial effects were reduced in Kcnk2(-/-) mice, suggesting TREK-1 activating compounds may be used therapeutically to treat diseases related to BBB dysfunction.
Assuntos
Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Células Endoteliais/metabolismo , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Actinas/metabolismo , Animais , Anticonvulsivantes/farmacologia , Barreira Hematoencefálica/imunologia , Encéfalo/imunologia , Moléculas de Adesão Celular/biossíntese , Moléculas de Adesão Celular/imunologia , Movimento Celular , Células Cultivadas , Técnicas de Cocultura , Células Dendríticas , Regulação para Baixo , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/metabolismo , Feminino , Células HEK293 , Humanos , Molécula 1 de Adesão Intercelular/imunologia , Molécula 1 de Adesão Intercelular/metabolismo , Interferon-alfa/farmacologia , Leucócitos/metabolismo , Óleo de Semente do Linho/administração & dosagem , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos , Canais de Potássio de Domínios Poros em Tandem/genética , Riluzol/farmacologia , Migração Transendotelial e TransepitelialRESUMO
Disruption of the blood-brain barrier (BBB) contributes to the inflammatory response and edema formation in the brain, exacerbating brain damage. The present study evaluated the effects of Scutellaria baicalensis (SR) water extracts on BBB disruption after intracerebral hemorrhage (ICH) in rats. ICH was induced by stereotaxic intrastriatal injection of bacterial type VII collagenase, and SR was administrated orally three times (50 mg/ml/kg) during the 48 h after ICH onset. SR treatment significantly reduced the degree of (1) hemorrhage volume and edema percentage of the ipsilateral hemisphere, (2) brain water content, (3) MPO-positive neutrophil infiltration in the peri-hematoma, and (4) BBB permeability measured by Evans blue leakage. In addition, expression of matrix metalloproteinase (MMP)-9, MMP-12, and tissue inhibitor of MMPs (TIMP)-1 were investigated with immunohistochemistry. SR treatment reduced MMP-9 and MMP-12 expression in the peri-hematoma after ICH. These results indicate that SR attenuates the BBB disruption through anti-inflammatory effects and suppression of MMP expression. These findings provide a pharmacological basis for the use of SR in the treatment of the BBB disruption following stroke and trauma.
Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Edema Encefálico/prevenção & controle , Hemorragia Cerebral/tratamento farmacológico , Inflamação/prevenção & controle , Fitoterapia , Extratos Vegetais/uso terapêutico , Scutellaria baicalensis , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/metabolismo , Água Corporal/metabolismo , Lesões Encefálicas/prevenção & controle , Hemorragia Cerebral/imunologia , Hemorragia Cerebral/metabolismo , Colagenases , Hematoma/tratamento farmacológico , Hematoma/metabolismo , Masculino , Metaloproteinase 12 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Infiltração de Neutrófilos/efeitos dos fármacos , Permeabilidade , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-Dawley , Inibidor Tecidual de Metaloproteinase-1/metabolismoRESUMO
The term ''psychoneuroimmunology'' connotes separate compartments that interact. The blood-brain barrier (BBB) is both the dividing line, physical and physiologic, between the immune system and the central nervous system (CNS) and the locale for interaction. The BBB restricts unregulated mixing of immune substances in the blood with those in the CNS, directly transports neuroimmune-active substances between the blood and CNS, and itself secretes neuroimmune substances. These normal functions of the BBB can be altered by neuroimmune events. As such, the BBB is an important conduit in the communication between the immune system and the CNS.
Assuntos
Barreira Hematoencefálica/imunologia , Sistema Imunitário , Psiconeuroimunologia , HumanosRESUMO
Mast cells accessing the brain parenchyma through the blood-brain barrier in healthy animals are limited to pre-cortical sensory relays - the olfactory bulb and the thalamus. We have demonstrated that unilateral repetitive stimulation of the abdominal wall generates asymmetry in midline thalamic mast cell (TMC) distribution in cyclophosphamide-injected rats, consisting of contralateral side-prevalence with respect to the abdominal wall stimulation. TMC asymmetry 1) was generated in strict relation with cystitis, and was absent in disease-free and mesna-treated animals, 2) was restricted to the anterior portion of the paraventricular pars anterior and reuniens nuclei subregion, i.e., the rostralmost part of the paraventricular thalamic nucleus, the only thalamic area associated with viscero-vagal and somatic inputs, via the nucleus of the solitary tract, and via the medial contingent of the spinothalamic tract, respectively, and 3) originated from somatic tissues, i.e., the abdominal wall where bladder inflammation generates secondary somatic hyperesthesia leading to referred pain in humans. Present data suggest that TMCs may be involved in thalamic sensory processes, including some aspects of visceral pain and abnormal visceral/somatic interactions.
Assuntos
Quimiotaxia de Leucócito/imunologia , Cistite/imunologia , Mastócitos/imunologia , Dor/imunologia , Tálamo/imunologia , Fibras Aferentes Viscerais/imunologia , Vias Aferentes/anatomia & histologia , Vias Aferentes/imunologia , Vias Aferentes/fisiopatologia , Animais , Vias Autônomas/anatomia & histologia , Vias Autônomas/imunologia , Vias Autônomas/fisiopatologia , Barreira Hematoencefálica/imunologia , Encéfalo/anatomia & histologia , Encéfalo/imunologia , Encéfalo/fisiopatologia , Ciclofosfamida/efeitos adversos , Cistite/fisiopatologia , Modelos Animais de Doenças , Lateralidade Funcional/fisiologia , Imunossupressores/efeitos adversos , Masculino , Mastócitos/citologia , Mesna/farmacologia , Nociceptores/efeitos dos fármacos , Nociceptores/imunologia , Nociceptores/fisiopatologia , Dor/fisiopatologia , Substâncias Protetoras/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Tálamo/citologia , Tálamo/fisiopatologia , Fibras Aferentes Viscerais/anatomia & histologia , Fibras Aferentes Viscerais/fisiopatologiaRESUMO
Communication between the central nervous and immune systems lies at the heart of the neuroimmune axis. We trace here some of the major conceptual hurdles which were raised, first against the acceptance of a neuroimmune axis and later in understanding it. We review the major concepts formulated and established during the last two decades and focus on four pathways that have been proposed as important in communication: the neural route, circumventricular organs, blood-brain barrier transport of cytokines, and secretions from BBB cells. These and other pathways have established the existence of a neuroimmune axis, but raise new questions on how they act and interact with one another.
Assuntos
Barreira Hematoencefálica/imunologia , Sistema Nervoso Central/fisiologia , Ventrículos Cerebrais/fisiologia , Neuroimunomodulação/fisiologia , Psiconeuroimunologia/história , Animais , Barreira Hematoencefálica/metabolismo , Comunicação Celular/imunologia , Comunicação Celular/fisiologia , Ventrículos Cerebrais/imunologia , Citocinas/metabolismo , História do Século XX , História do Século XXI , Humanos , Vias Neurais/fisiologiaRESUMO
The very term "psychoneuroimmunology" connotes separate compartments that interact. The BBB is the physical and physiologic dividing line between the immune system and the CNS and is the locale for interaction. Interactions between the immune system and the CNS are mediated at the BBB through a variety of mechanisms. The BBB restricts unregulated mixing of the immune substances in the blood with those in the CNS, directly transports neuroimmune active substances between the blood and the CNS, and secretes neuroimmune substances. All these normal functions of the BBB can be altered in an adaptive or pathologic manner by neuroimmune events. As such, the BBB is an important conduit in the communication of the immune and the central nervous systems.
Assuntos
Barreira Hematoencefálica/imunologia , Psiconeuroimunologia , Encéfalo/irrigação sanguínea , Permeabilidade Capilar/fisiologia , Citocinas/sangue , Endotélio Vascular/imunologia , Humanos , Junções Intercelulares/imunologia , Lipopolissacarídeos/imunologia , Comunicação Parácrina/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Sufficient evidence is now available to accept the concept that the brain recognizes cytokines as molecular signals of sickness. Clarifying the way the brain processes information generated by the innate immune system is accompanied by a progressive elucidation of the cellular and molecular components of the intricate system that mediates cytokine-induced sickness behavior. We are still far, however, from understanding the whole. Among the hundreds of genes that proinflammatory cytokines can induce in their cellular targets, only a handful has been examined functionally. In addition, a dynamic view of the cellular interactions that occur at the brain sites of cytokine production and action is missing, together with a clarification of the mechanisms that favor the transition toward pathology.
Assuntos
Encéfalo/imunologia , Citocinas/sangue , Transtorno Depressivo/imunologia , Papel do Doente , Animais , Barreira Hematoencefálica/imunologia , Transtorno Depressivo/psicologia , Humanos , Inflamação/imunologia , Camundongos , Psiconeuroimunologia , Ratos , Transdução de Sinais/fisiologia , Estresse Psicológico/complicações , Estresse Psicológico/imunologiaRESUMO
The idea that type 2 diabetes is associated with augmented innate immune function characterized by increased circulating levels of acute phase reactants and altered macrophage biology is fairly well established, even though the mechanisms involved in this complex interaction still are not entirely clear. To date, the majority of studies investigating innate immune function in type 2 diabetes are limited to the context of wound healing, atherosclerosis, stroke, and other commonly identified comorbidities. Several important recurring themes come out of these data. First, type 2 diabetes is associated with a state of chronic, subclinical inflammation. Second, in macrophages, type 2 diabetic conditions enhance proinflammatory reactions and impair anti-inflammatory responses. Third, after acute activation of the innate immune system in type 2 diabetes, recovery or resolution of inflammation is impaired. The consequences of type 2 diabetes-associated inflammatory alterations on PNI processes have been recognized only recently. Given the impact of diminished emotional well-being on the quality of life in patients who have type 2 diabetes, diabetes-induced exacerbation of PNI responses should be considered a serious complication of type 2 diabetes that warrants further clinical attention.
Assuntos
Encéfalo/imunologia , Complicações do Diabetes/imunologia , Diabetes Mellitus Tipo 2/imunologia , Imunidade Inata/imunologia , Proteínas de Fase Aguda/metabolismo , Animais , Barreira Hematoencefálica/imunologia , Citocinas/sangue , Complicações do Diabetes/psicologia , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 2/psicologia , Glucocorticoides/fisiologia , Humanos , Imunidade Celular/imunologia , Inflamação/imunologia , Inflamação/psicologia , Resistência à Insulina/imunologia , Lipopolissacarídeos/imunologia , Camundongos , Psiconeuroimunologia , Ratos , Papel do DoenteRESUMO
Brain infections as well as peripheral challenges to the immune system lead to an increased production of interleukin-1beta (IL-1beta), a cytokine involved in leukocyte-mediated breakdown of the blood-brain barrier. The effects of IL-1beta have been reported to depend on whether the route of administration is systemic or intracerebral. Using 50-day-old male rats, we compared the effects of IL-1beta on brain gamma-glutamyl transpeptidase (GGT; an enzymatic marker of brain capillary endothelium) at 2, 24 and 96 h after either an intravenous (i.v.) injection of 5 microg IL-1beta or an intracerebroventricular (i.c.v. - lateral ventricle) infusion of 50 ng IL-1beta. When the i.v. route was used, the GGT activity underwent small but significant changes; decreasing in the hippocampus 2 h after the i.v. injection, increasing 24 h later and returning to control levels at 96 h. No significant changes in the hippocampal GGT activity were observed at 2 and 24 h following the i.c.v. infusion. The GGT activity in the hypothalamus remained unchanged regardless of the route of IL-1beta administrations. Similar changes in GGT activity were revealed histochemically. The labeling was found mainly in the capillary bed, the changes being most evident in the hippocampal stratum radiatum and stratum lacunosum-moleculare. A transient increase in GGT activity at 24 h, together with a less sharp delineation of GGT-stained vessels, may reflect IL-1beta induced increased turnover of glutathione and/or oxidative stress, that may in turn, be related to altered permeability of the blood-brain barrier in some neurological and mental disorders, including schizophrenia.
Assuntos
Hipocampo/enzimologia , Hipocampo/imunologia , Interleucina-1/metabolismo , gama-Glutamiltransferase/metabolismo , Animais , Biomarcadores/metabolismo , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/metabolismo , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/imunologia , Radicais Livres/metabolismo , Hipocampo/irrigação sanguínea , Hipotálamo/irrigação sanguínea , Hipotálamo/enzimologia , Hipotálamo/imunologia , Interleucina-1/imunologia , Interleucina-1/farmacologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/imunologia , Ratos , Ratos WistarRESUMO
A reliable way to visualise the state of microglial activation is to monitor the microglial gene expression profile. Microglia are the only CNS resident cells that synthesise C1q, the recognition sub-component of the classical complement pathway, in vivo. C1q biosynthesis in resting ramified microglia is often low, but it increases dramatically in activated microglia. In this study, the expression of C1q was used to monitor microglial activation at all stages of 3-chloropropanediol-induced neurotoxicity, a new model of blood-brain barrier (BBB) breakdown. In rats, 3-chloropropanediol produces very focused lesions in the brain, characterised by early astrocyte swelling and loss, followed by neuronal death and barrier dysfunction. Using in situ hybridisation, immunohistochemistry, and real-time RT-PCR, we found that increased C1q biosynthesis and microglial activation precede BBB dysfunction by at least 18 and peak 48 h after injection of 3-chloropropanediol, which coincides with the onset of active haemorrhage. Microglial activation is biphasic; an early phase of global activation is followed by a later phase in which microglial activation becomes increasingly focused in the lesions. During the early phase, expression of the pro-inflammatory mediators interleukin-1beta (IL1beta), tumour necrosis factor alpha (TNFalpha) and early growth response-1 (Egr-1) increased in parallel with C1q, but was restricted to the lesions. Expression of C1q (but not IL1beta, TNFalpha or Egr-1) remains high after BBB function is restored, and is accompanied by late up-regulation of the C1q-associated serine proteases, C1r and C1s, suggesting that microglial biosynthesis of the activation complex of the classical pathway may support the removal of cell debris by activation of complement.
Assuntos
Barreira Hematoencefálica/imunologia , Complemento C1q/biossíntese , Proteínas Imediatamente Precoces , Microglia/imunologia , Animais , Sequência de Bases , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Encéfalo/metabolismo , Complemento C1q/genética , DNA Complementar/genética , Proteínas de Ligação a DNA/genética , Proteína 1 de Resposta de Crescimento Precoce , Hibridização In Situ , Interleucina-1/genética , Masculino , Microglia/efeitos dos fármacos , Microglia/fisiologia , Modelos Neurológicos , Neurotoxinas/toxicidade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos F344 , Fatores de Transcrição/genética , Fator de Necrose Tumoral alfa/genética , alfa-Cloridrina/toxicidadeRESUMO
Much research is now focused on a potential vaccine for Alzheimer's disease (AD). Current studies involve administering the amyloid beta peptide (Abeta) in Freund's complete adjuvant, which cannot be used in humans. Our studies show that the immune complex of Abeta is taken up by a receptor-mediated process at the blood-brain barrier (BBB). The success of immunization for AD, therefore, may be critically dependent on circulating Abeta levels which are lower in AD patients compared to AD transgenic mice. Moreover, we have found that modifying the antibody with polyamine increases its BBB permeability and may provide a better approach to passive immunization for Alzheimer's disease.
Assuntos
Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/farmacocinética , Barreira Hematoencefálica/efeitos dos fármacos , Proteínas de Transporte/efeitos dos fármacos , Imunização/métodos , Fragmentos de Peptídeos/farmacocinética , Receptores de Peptídeos/efeitos dos fármacos , Vacinas/farmacocinética , Doença de Alzheimer/imunologia , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/imunologia , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacocinética , Complexo Antígeno-Anticorpo/química , Complexo Antígeno-Anticorpo/imunologia , Complexo Antígeno-Anticorpo/farmacologia , Barreira Hematoencefálica/imunologia , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Encéfalo/metabolismo , Proteínas de Transporte/imunologia , Relação Dose-Resposta a Droga , Humanos , Radioisótopos do Iodo/farmacocinética , Camundongos , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/imunologia , Poliaminas/química , Poliaminas/farmacocinética , Receptores de Peptídeos/imunologia , Vacinas/síntese químicaRESUMO
In a split-litter, cross-fostered design, the numbers of mast cells per 10 micrometer sections within the thalamic boundaries in rats that had been reared by 8 natural or 8 foster mothers were counted 5 days and 10 days after the transfer had occurred on postnatal Day 10. The rats from 4 litters with the highest numbers of thalamic mast cells exhibited marked reductions in these numbers when fostered by mothers of the 4 litters with the fewest numbers of thalamic mast cells. The reverse influence was not observed. These results suggest that adaptation to changing maternal environments for rats with congenitally elevated numbers of mast cells may increase the risk of degranulation and transient anomalies within cerebral vasculature or the blood-brain barrier.
Assuntos
Animais Recém-Nascidos/imunologia , Mastócitos/imunologia , Privação Materna , Meio Social , Tálamo/imunologia , Adaptação Psicológica/fisiologia , Animais , Barreira Hematoencefálica/imunologia , Contagem de Células , Feminino , Masculino , RatosRESUMO
There is a strong interrelationship between the immune system, the central nervous system and psychological processes that are suggested to play a pivotal role in the pathogenesis of psychiatric disorders. In schizophrenia and depression, activation of the immune system has been observed repeatedly. Cytokines play a key role in immune activation. They are actively transported into the CNS, but also released from activated glia cells. Cytokines activate glia cells in the CNS to produce other cytokines, and a cascade of cytokine effects may be initiated by this mechanisms. During the past few years, the influence of the cytokines on dopaminergic, noradrenergic and serotonergic neurotransmission and also on the hormones of the hypothalamus-pituitary-adrenal axis has been elucidated. It suggests a pivotal role in psychological processes and psychiatric disorders. For example, in schizophrenia the IL-2 cerebrospinal fluid concentration shows a stronger relationship to the relapse probability than catecholamine metabolites. Although the hypersecretion of IL-2 in schizophrenia and of IL-6 in depression are suggested to play key roles for these disorders, a specificity of certain cytokines for certain psychiatric disorders seems unlikely. Psychomotor, sleep and sickness behavior are influenced by IL-1, disturbances of memory and attention by IL-2, but also by TNF-alpha. From the distribution of cytokine receptors in the CNS conclusions can be drawn regarding the influence of cytokines on psychological processes. The finding that norepinephrine stimulates activated astrocytes to produce IL-6 implies that the cytokine cascade may be activated by neuronal processes under certain conditions. This can lead to a molecular biological explanation of the influences of stress on the immune system. Lastly, influences of the cytokines on blood-brain barrier disturbances and further consequences resulting from the role of the cytokine network in the CNS are discussed.