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1.
Nat Commun ; 12(1): 960, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33574252

RESUMO

Nitric oxide (NO) is an important signaling molecule overexpressed in many diseases, thus the development of NO-activatable probes is of vital significance for monitoring related diseases. However, sensitive photoacoustic (PA) probes for detecting NO-associated complicated diseases (e.g., encephalitis), have yet to be developed. Herein, we report a NO-activated PA probe for in vivo detection of encephalitis by tuning the molecular geometry and energy transformation processes. A strong donor-acceptor structure with increased conjugation can be obtained after NO treatment, along with the active intramolecular motion, significantly boosting "turn-on" near-infrared PA property. The molecular probe exhibits high specificity and sensitivity towards NO over interfering reactive species. The probe is capable of detecting and differentiating encephalitis in different severities with high spatiotemporal resolution. This work will inspire more insights into the development of high-performing activatable PA probes for advanced diagnosis by making full use of intramolecular motion and energy transformation processes.


Assuntos
Técnicas Biossensoriais/métodos , Encefalite/diagnóstico , Encefalite/metabolismo , Óxido Nítrico/isolamento & purificação , Técnicas Fotoacústicas/métodos , Animais , Técnicas Biossensoriais/instrumentação , Modelos Animais de Doenças , Encefalite/patologia , Masculino , Camundongos , Imagem Molecular/métodos , Sondas Moleculares/química , Técnicas Fotoacústicas/instrumentação
3.
Int J Mol Sci ; 21(24)2020 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-33352646

RESUMO

Chronic neuroinflammation is a common pathogenetic link in the development of various neurological and neurodegenerative diseases. Thus, a detailed study of neuroinflammation and the development of drugs that reduce or eliminate the negative effect of neuroinflammation on cognitive processes are among the top priorities of modern neurobiology. N-docosahexanoylethanolamine (DHEA, synaptamide) is an endogenous metabolite and structural analog of anandamide, an essential endocannabinoid produced from arachidonic acid. Our study aims to elucidate the pharmacological activity of synaptamide in lipopolysaccharide (LPS)-induced neuroinflammation. Memory deficits in animals were determined using behavioral tests. To study the effects of LPS (750 µg/kg/day, 7 days) and synaptamide (10 mg/kg/day, 7 days) on synaptic plasticity, long-term potentiation was examined in the CA1 area of acute hippocampal slices. The Golgi-Cox method allowed us to assess neuronal morphology. The production of inflammatory factors and receptors was assessed using ELISA and immunohistochemistry. During the study, functional, structural, and plastic changes within the hippocampus were identified. We found a beneficial effect of synaptamide on hippocampal synaptic plasticity and morphological characteristics of neurons. Synaptamide treatment recovered hippocampal neurogenesis, suppressed microglial activation, and significantly improved hippocampus-dependent memory. The basis of the phenomena described above is probably the powerful anti-inflammatory activity of synaptamide, as shown in our study and several previous works.


Assuntos
Modelos Animais de Doenças , Encefalite/tratamento farmacológico , Etanolaminas/farmacologia , Hipocampo/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Microglia/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Animais , Ácidos Docosa-Hexaenoicos/química , Encefalite/metabolismo , Encefalite/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Potenciação de Longa Duração , Masculino , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Microglia/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia
5.
Nat Commun ; 11(1): 4571, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917871

RESUMO

Early therapeutic interventions are essential to prevent Alzheimer Disease (AD). The association of several inflammation-related genetic markers with AD and the early activation of pro-inflammatory pathways in AD suggest inflammation as a plausible therapeutic target. Inflammatory Caspase-1 has a significant impact on AD-like pathophysiology and Caspase-1 inhibitor, VX-765, reverses cognitive deficits in AD mouse models. Here, a one-month pre-symptomatic treatment of Swedish/Indiana mutant amyloid precursor protein (APPSw/Ind) J20 and wild-type mice with VX-765 delays both APPSw/Ind- and age-induced episodic and spatial memory deficits. VX-765 delays inflammation without considerably affecting soluble and aggregated amyloid beta peptide (Aß) levels. Episodic memory scores correlate negatively with microglial activation. These results suggest that Caspase-1-mediated inflammation occurs early in the disease and raise hope that VX-765, a previously Food and Drug Administration-approved drug for human CNS clinical trials, may be a useful drug to prevent the onset of cognitive deficits and brain inflammation in AD.


Assuntos
Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Disfunção Cognitiva/metabolismo , Serpinas/metabolismo , Proteínas Virais/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Animais , Comportamento Animal , Disfunção Cognitiva/tratamento farmacológico , Citocinas/metabolismo , Dipeptídeos/sangue , Dipeptídeos/farmacologia , Modelos Animais de Doenças , Encefalite/metabolismo , Encefalite/patologia , Feminino , Humanos , Inflamação/metabolismo , Masculino , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Serpinas/sangue , Serpinas/farmacologia , Memória Espacial/fisiologia , Proteínas Virais/sangue , Proteínas Virais/farmacologia , para-Aminobenzoatos/sangue , para-Aminobenzoatos/farmacologia
6.
Int J Mol Sci ; 21(15)2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32751841

RESUMO

Increasing evidence suggests that Severe Acute Respiratory Syndrome-coronavirus-2 (SARS-CoV-2) can also invade the central nervous system (CNS). However, findings available on its neurological manifestations and their pathogenic mechanisms have not yet been systematically addressed. A literature search on neurological complications reported in patients with COVID-19 until June 2020 produced a total of 23 studies. Overall, these papers report that patients may exhibit a wide range of neurological manifestations, including encephalopathy, encephalitis, seizures, cerebrovascular events, acute polyneuropathy, headache, hypogeusia, and hyposmia, as well as some non-specific symptoms. Whether these features can be an indirect and unspecific consequence of the pulmonary disease or a generalized inflammatory state on the CNS remains to be determined; also, they may rather reflect direct SARS-CoV-2-related neuronal damage. Hematogenous versus transsynaptic propagation, the role of the angiotensin II converting enzyme receptor-2, the spread across the blood-brain barrier, the impact of the hyperimmune response (the so-called "cytokine storm"), and the possibility of virus persistence within some CNS resident cells are still debated. The different levels and severity of neurotropism and neurovirulence in patients with COVID-19 might be explained by a combination of viral and host factors and by their interaction.


Assuntos
Betacoronavirus/fisiologia , Sistema Nervoso Central/virologia , Infecções por Coronavirus/patologia , Pneumonia Viral/patologia , Animais , Betacoronavirus/isolamento & purificação , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/virologia , Encefalopatias/complicações , Encefalopatias/patologia , Sistema Nervoso Central/metabolismo , Infecções por Coronavirus/virologia , Encefalite/complicações , Encefalite/patologia , Humanos , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/virologia
7.
J Neurovirol ; 26(5): 619-630, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32839951

RESUMO

The recent pandemic outbreak of coronavirus is pathogenic and a highly transmittable viral infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2). In this time of ongoing pandemic, many emerging reports suggested that the SARS-CoV-2 has inimical effects on neurological functions, and even causes serious neurological damage. The neurological symptoms associated with COVID-19 include headache, dizziness, depression, anosmia, encephalitis, stroke, epileptic seizures, and Guillain-Barre syndrome along with many others. The involvement of the CNS may be related with poor prognosis and disease worsening. Here, we review the evidence of nervous system involvement and currently known neurological manifestations in COVID-19 infections caused by SARS-CoV-2. We prioritize the 332 human targets of SARS-CoV-2 according to their association with brain-related disease and identified 73 candidate genes. We prioritize these 73 genes according to their spatio-temporal expression in the different regions of brain and also through evolutionary intolerance analysis. The prioritized genes could be considered potential indicators of COVID-19-associated neurological symptoms and thus act as a possible therapeutic target for the prevention and treatment of CNS manifestations associated with COVID-19 patients.


Assuntos
Betacoronavirus/patogenicidade , Encéfalo/metabolismo , Infecções por Coronavirus/genética , Interações Hospedeiro-Patógeno/genética , Proteínas do Tecido Nervoso/genética , Pneumonia Viral/genética , Proteínas Virais/genética , Encéfalo/patologia , Encéfalo/virologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Depressão , Tontura/complicações , Tontura/genética , Tontura/patologia , Tontura/virologia , Encefalite/complicações , Encefalite/genética , Encefalite/patologia , Encefalite/virologia , Síndrome de Guillain-Barré/complicações , Síndrome de Guillain-Barré/genética , Síndrome de Guillain-Barré/patologia , Síndrome de Guillain-Barré/virologia , Cefaleia/complicações , Cefaleia/genética , Cefaleia/patologia , Cefaleia/virologia , Humanos , Proteínas do Tecido Nervoso/classificação , Proteínas do Tecido Nervoso/metabolismo , Transtornos do Olfato/complicações , Transtornos do Olfato/genética , Transtornos do Olfato/patologia , Transtornos do Olfato/virologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Mapeamento de Interação de Proteínas , Convulsões/complicações , Convulsões/genética , Convulsões/patologia , Convulsões/virologia , Índice de Gravidade de Doença , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/virologia , Proteínas Virais/metabolismo
8.
PLoS One ; 15(7): e0236162, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32697807

RESUMO

HIV cerebrospinal fluid (CSF) escape is defined by a concentration of HIV-1 RNA in CSF above the lower limit of quantification of the employed assay and equal to or greater than the plasma HIV-1 RNA level in the presence of treatment-related plasma viral suppression, while CSF discordance is similarly defined by equal or higher CSF than plasma HIV-1 RNA in untreated individuals. During secondary CSF escape or discordance, disproportionate CSF HIV-1 RNA develops in relation to another infection in addition to HIV-1. We performed a retrospective review of people living with HIV receiving clinical care at Sahlgrenska Infectious Diseases Clinic in Gothenburg, Sweden who developed uncomplicated herpes zoster (HZ) and underwent a research lumbar puncture (LP) within the ensuing 150 days. Based on treatment status and the relationship between CSF and plasma HIV-1 RNA concentrations, they were divided into 4 groups: i) antiretroviral treated with CSF escape (N = 4), ii) treated without CSF escape (N = 5), iii) untreated with CSF discordance (N = 8), and iv) untreated without CSF discordance (N = 8). We augmented these with two additional cases of secondary CSF escape related to neuroborreliosis and HSV-2 encephalitis and analyzed these two non-HZ cases for factors contributing to CSF HIV-1 RNA concentrations. HIV-1 CSF escape and discordance were associated with higher CSF white blood cell (WBC) counts than their non-escape (P = 0.0087) and non-discordant (P = 0.0017) counterparts, and the CSF WBC counts correlated with the CSF HIV-1 RNA levels in both the treated (P = 0.0047) and untreated (P = 0.002) group pairs. Moreover, the CSF WBC counts correlated with the CSF:plasma HIV-1 RNA ratios of the entire group of 27 subjects (P = <0.0001) indicating a strong effect of the CSF WBC count on the relation of the CSF to plasma HIV-1 RNA concentrations across the entire sample set. The inflammatory response to HZ and its augmenting effect on CSF HIV-1 RNA was found up to 5 months after the HZ outbreak in the cross-sectional sample and, was present for one year after HZ in one individual followed longitudinally. We suggest that HZ provides a 'model' of secondary CSF escape and discordance. Likely, the inflammatory response to HZ pathology provoked local HIV-1 production by enhanced trafficking or activation of HIV-1-infected CD4+ T lymphocytes. Whereas treatment and other systemic factors determined the plasma HIV-1 RNA concentrations, in this setting the CSF WBC counts established the relation of the CSF HIV-1 RNA levels to this plasma set-point.


Assuntos
Encefalite/etiologia , Infecções por HIV/complicações , HIV-1/isolamento & purificação , Herpes Zoster/etiologia , Leucocitose/etiologia , RNA Viral/líquido cefalorraquidiano , Adulto , Estudos Transversais , Encefalite/líquido cefalorraquidiano , Encefalite/patologia , Feminino , Infecções por HIV/virologia , Herpes Zoster/líquido cefalorraquidiano , Herpes Zoster/patologia , Herpesvirus Humano 3/isolamento & purificação , Humanos , Leucocitose/líquido cefalorraquidiano , Leucocitose/patologia , Estudos Longitudinais , Masculino , Estudos Retrospectivos
9.
World Neurosurg ; 140: 46-48, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32479911

RESUMO

BACKGROUND: Reports on neurologic manifestations of coronavirus disease 2019 (COVID-19) have attracted broad attention. We present an unusual case of COVID-19-associated encephalitis mimicking a glial tumor. CASE DESCRIPTION: A 35-year-old woman presented with headache and seizures. T2 fluid-attenuated inverse recovery imaging showed hyperintensities in the left temporal lobe. Magnetic resonance spectroscopy showed an elevated choline peak. Imaging findings were suggestive of high-grade glioma. Antiepileptic medication failed to achieve seizure control. A left anterior temporal lobectomy was performed. The patient had no postoperative deficits, and her symptoms completely improved. Histologic examination revealed encephalitis. Postoperatively, our patient tested positive for COVID-19. CONCLUSIONS: Our case raises awareness of neurologic manifestations of the disease and their potential to mimic glial tumors. For prompt diagnosis and prevention of transmission, clinicians should consider COVID-19 in patients with similar presentation.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/complicações , Diagnóstico Diferencial , Encefalite/virologia , Glioma/diagnóstico , Pneumonia Viral/complicações , Adulto , Infecções por Coronavirus/patologia , Encefalite/diagnóstico , Encefalite/patologia , Feminino , Glioma/patologia , Cefaleia/virologia , Humanos , Pandemias , Pneumonia Viral/patologia , Convulsões/patologia , Convulsões/virologia , Lobo Temporal/patologia , Lobo Temporal/virologia
12.
Radiology ; 297(1): E223-E227, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32437314

RESUMO

Diffuse leukoencephalopathy and juxtacortical and/or callosal microhemorrhages were brain imaging features in critically ill patients with coronavirus disease 2019. Coronavirus disease 2019 (COVID-19) has been reported in association with a variety of brain imaging findings such as ischemic infarct, hemorrhage, and acute hemorrhagic necrotizing encephalopathy. Herein, the authors report brain imaging features in 11 critically ill patients with COVID-19 with persistently diminished mental status who underwent MRI between April 5 and April 25, 2020. These imaging features include (a) confluent T2 hyperintensity and mild restricted diffusion in bilateral supratentorial deep and subcortical white matter (in 10 of 11 patients) and (b) multiple punctate microhemorrhages in juxtacortical and callosal white matter (in seven of 11 patients). The authors also discuss potential pathogeneses.


Assuntos
Encéfalo , Hemorragia Cerebral , Infecções por Coronavirus , Leucoencefalopatias , Pandemias , Pneumonia Viral , Adulto , Betacoronavirus , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Hemorragia Cerebral/diagnóstico por imagem , Hemorragia Cerebral/patologia , Hemorragia Cerebral/virologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico por imagem , Infecções por Coronavirus/patologia , Encefalite/diagnóstico por imagem , Encefalite/patologia , Encefalite/virologia , Feminino , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/patologia , Leucoencefalopatias/virologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico por imagem , Pneumonia Viral/patologia , Estudos Retrospectivos
14.
BMC Neurol ; 20(1): 125, 2020 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-32268889

RESUMO

BACKGROUND: Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative condition characterized by the loss of neurons and the presence of eosinophilic nuclear inclusions in the central and peripheral nervous system, skin and visceral organs. In this paper, we present a case of NIID with recurrent encephalitic attacks that remained stable and nonprogressive for seven years; no such case has previously been reported. CASE PRESENTATION: A 63-year-old female was hospitalized due to light-headedness, vomiting, unstable gait and cognitive impairment. Seven years prior, she had experienced an episode of light-headedness, central facial paralysis, unstable gait, aphasia, nausea, vomiting and loss of consciousness. She regained consciousness within 12 h, and her other symptoms were completely resolved within one week. During the present hospitalization, a brain magnetic resonance imaging (MRI) examination detected high signal intensity on diffusion-weighted imaging (DWI) of the bilateral frontal grey matter-white matter junction. We reviewed the patient's previous MRI results and found that she had also had high signal intensity on DWI of the bilateral frontal grey matter-white matter junction seven years prior. In the intervening seven years, the high signal intensity in the frontal lobes had spread along the grey matter-white matter junction, but the deep white matter remained unaffected. Skin biopsy was performed, and intranuclear inclusions were found in adipocytes, fibroblasts and sweat gland cells. GGC repeat expansions in the NOTCH2NLC (Notch 2 N-terminal like C) gene confirmed the diagnosis of NIID. She received supportive treatment such as nutrition support therapy and vitamin B and C supplementation, as well as symptomatic treatment during hospitalization. The patient's symptoms were completely relieved within one week. CONCLUSION: This is a detailed report of a case of NIID with multiple reversible encephalitic attacks, diagnosed by clinical symptoms, intranuclear inclusions, characteristic DWI signals, and genetic tests.


Assuntos
Encefalite/patologia , Doenças Neurodegenerativas/diagnóstico , Biópsia , Disfunção Cognitiva/patologia , Imagem de Difusão por Ressonância Magnética , Feminino , Humanos , Corpos de Inclusão Intranuclear , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Pele/patologia
15.
Proc Natl Acad Sci U S A ; 117(12): 6708-6716, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32161123

RESUMO

Antibodies against neuronal receptors and synaptic proteins are associated with a group of ill-defined central nervous system (CNS) autoimmune diseases termed autoimmune encephalitides (AE), which are characterized by abrupt onset of seizures and/or movement and psychiatric symptoms. Basal ganglia encephalitis (BGE), representing a subset of AE syndromes, is triggered in children by repeated group A Streptococcus (GAS) infections that lead to neuropsychiatric symptoms. We have previously shown that multiple GAS infections of mice induce migration of Th17 lymphocytes from the nose into the brain, causing blood-brain barrier (BBB) breakdown, extravasation of autoantibodies into the CNS, and loss of excitatory synapses within the olfactory bulb (OB). Whether these pathologies induce functional olfactory deficits, and the mechanistic role of Th17 lymphocytes, is unknown. Here, we demonstrate that, whereas loss of excitatory synapses in the OB is transient after multiple GAS infections, functional deficits in odor processing persist. Moreover, mice lacking Th17 lymphocytes have reduced BBB leakage, microglial activation, and antibody infiltration into the CNS, and have their olfactory function partially restored. Th17 lymphocytes are therefore critical for selective CNS entry of autoantibodies, microglial activation, and neural circuit impairment during postinfectious BGE.


Assuntos
Encéfalo/patologia , Modelos Animais de Doenças , Encefalite/etiologia , Encefalomielite Autoimune Experimental/etiologia , Doença de Hashimoto/etiologia , Transtornos do Olfato/etiologia , Infecções Estreptocócicas/complicações , Células Th17/imunologia , Animais , Autoanticorpos/imunologia , Gânglios da Base/imunologia , Gânglios da Base/patologia , Barreira Hematoencefálica , Encéfalo/imunologia , Encefalite/metabolismo , Encefalite/patologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Feminino , Doença de Hashimoto/metabolismo , Doença de Hashimoto/patologia , Camundongos , Microglia/imunologia , Microglia/patologia , Neurônios/imunologia , Neurônios/patologia , Transtornos do Olfato/metabolismo , Transtornos do Olfato/patologia , Percepção Olfatória , Streptococcus pyogenes/fisiologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Células Th17/patologia
17.
Clin Sci (Lond) ; 134(7): 765-776, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32219335

RESUMO

BACKGROUND: In order to modulate microglial phenotypes in vivo, M1 microglia were depleted by administration of gadolinium chloride and the expression of M2 microglia was induced by IL-4 administration in an animal model of sepsis to better characterize the role of microglial phenotypes in sepsis-induced brain dysfunction. METHODS: Wistar rats were submitted to sham or cecal ligation and perforation (CLP) and treated with IL-4 or GdCl3. Animals were submitted to behavioral tests 10 days after surgery. In a separated cohort of animals at 24 h, 3 and 10 days after surgery, hippocampus was removed and cytokine levels, M1/M2 markers and CKIP-1 levels were determined. RESULTS: Modulation of microglia by IL-4 and GdCl3 was associated with an improvement in long-term cognitive impairment. When treated with IL-4 and GdCl3, the reduction of pro-inflammatory cytokines was apparent in almost all analyzed time points. Additionally, CD11b and iNOS were increased after CLP at all time points, and both IL-4 and GdCl3 treatments were able to reverse this. There was a significant decrease in CD11b gene expression in the CLP+GdCl3 group. IL-4 treatment was able to decrease iNOS expression after sepsis. Furthermore, there was an increase of CKIP-1 in the hippocampus of GdCl3 and IL-4 treated animals 10 days after CLP induction. CONCLUSIONS: GdCl3 and IL-4 are able to manipulate microglial phenotype in an animal models of sepsis, by increasing the polarization toward an M2 phenotype IL-4 and GdCl3 treatment was associated with decreased brain inflammation and functional recovery.


Assuntos
Anti-Inflamatórios/farmacologia , Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Disfunção Cognitiva/prevenção & controle , Encefalite/prevenção & controle , Gadolínio/farmacologia , Hipocampo/efeitos dos fármacos , Interleucina-4/farmacologia , Microglia/efeitos dos fármacos , Sepse/tratamento farmacológico , Animais , Antígeno CD11b/metabolismo , Proteínas de Transporte/metabolismo , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Disfunção Cognitiva/psicologia , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalite/metabolismo , Encefalite/patologia , Encefalite/fisiopatologia , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia , Mediadores da Inflamação/metabolismo , Microglia/metabolismo , Microglia/patologia , Óxido Nítrico Sintase Tipo II/metabolismo , Fenótipo , Ratos Wistar , Sepse/metabolismo , Sepse/patologia , Sepse/fisiopatologia , Fatores de Tempo
18.
Mol Immunol ; 121: 159-166, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32222586

RESUMO

Methamphetamine (METH) is a major public health and safety problem worldwide. METH is psychostimulant that activates microglia via the toll-like receptor (TLR) 4/MD2 complex, modulating the abundant production of pro-inflammatory cytokines in the central nervous system (CNS). The TLR4/MD2 complex on the surface of microglia recognizes pathogen-associated molecular patterns such as lipopolysaccharide (LPS) resulting in brain tissue inflammation and neuronal damage. Since METH has been associated with microglia-induced neurotoxicity, we hypothesized that METH impairs the expression of TLR4 and activation of NF-κB in NR-9460 microglia-like cells after LPS challenge. We demonstrated that METH decreases the distribution and expression of TLR4 receptors on the surface of microglia-like cells after incubation with endotoxin. Moreover, METH impairs the TLR4/MD2 complex signaling pathways, compromises the activation of NF-κB, and reduces the production of pro-inflammatory mediators in microglia-like cells upon LPS stimulation. Interestingly, microglia-like cells treated with METH and challenged with LPS showed considerable cellular morphological changes including enlarged nuclei and ruffled surface. Our results suggest that METH may have a significant impact on microglial-induced neuroinflammation, neurotoxicity, and the CNS defense against infection. It also highlights the importance of studying the effects of METH on the molecular and cellular components of users' CNS immunity. Finally, animal studies exploring the role of METH on the effectors functions of microglia after antigenic exposure are necessary to understand drug-related inflammation and neural damage in users.


Assuntos
Estimulantes do Sistema Nervoso Central/toxicidade , Encefalite/induzido quimicamente , Metanfetamina/toxicidade , Microglia/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Citocinas/imunologia , Citocinas/metabolismo , Encefalite/imunologia , Encefalite/patologia , Humanos , Lipopolissacarídeos/imunologia , Camundongos , Microglia/citologia , Microglia/imunologia , NF-kappa B/imunologia , NF-kappa B/metabolismo , Transdução de Sinais/imunologia , Receptor 4 Toll-Like/imunologia , Receptor 4 Toll-Like/metabolismo
19.
Infect Dis (Lond) ; 52(6): 419-422, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32067542

RESUMO

A child with pre-B acute lymphoblastic leukaemia (ALL) developed fatal encephalitis associated with human coronavirus OC43 (HCoV-OC43). During chemotherapy the child had a persistent HCoV-OC43 respiratory infection and later developed progressive encephalitis. Cerebrospinal fluid was negative for pathogens including HCoV-OC43, but a brain biopsy was HCoV-OC43-positive by metagenomic next-generation sequencing.


Assuntos
Infecções por Coronavirus/virologia , Coronavirus Humano OC43/fisiologia , Encefalite/virologia , Encéfalo/patologia , Encéfalo/virologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/patologia , Coronavirus Humano OC43/isolamento & purificação , Encefalite/imunologia , Encefalite/mortalidade , Encefalite/patologia , Evolução Fatal , Humanos , Hospedeiro Imunocomprometido , Lactente
20.
J Neuroinflammation ; 17(1): 43, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005256

RESUMO

BACKGROUND: A hallmark of temporal lobe epilepsy (TLE) is brain inflammation accompanied by neuronal demise. Accumulating evidence demonstrates that Rev-Erbα is involved in regulating neuroinflammation and determining the fate of neurons. Therefore, we studied the expression and cellular distribution of Rev-Erbα in the epileptogenic zone of TLE and the effect of treatment with the Rev-Erbα specific agonist SR9009 in the pilocarpine model. METHODS: The expression pattern of Rev-Erbα was investigated by western blotting, immunohistochemistry, and immunofluorescence labeling in patients with TLE. Next, the effects of SR9009 on neuroinflammation, neuronal apoptosis, and neuronal loss in the mouse hippocampus 7 days after status epilepticus (SE) were assessed by western blotting, immunofluorescence labeling staining, and TUNEL staining. RESULTS: The western blotting, immunohistochemistry, and immunofluorescence labeling results revealed that Rev-Erbα was downregulated in the epileptogenic zone of TLE patients and mainly localized in neurons, astrocytes, and presumably microglia. Meanwhile, the expression of Rev-Erbα was decreased in the hippocampus and temporal neocortex of mice treated with pilocarpine in the early post-SE and chronic phases. Interestingly, the expression of Rev-Erbα in the normal hippocampus showed a 24-h rhythm; however, the rhythmicity was disturbed in the early phase after SE, and this disturbance was still present in epileptic animals. Our further findings revealed that treatment with SR9009 inhibited NLRP3 inflammasome activation, inflammatory cytokine (IL-1ß, IL-18, IL-6, and TNF-α) production, astrocytosis, microgliosis, and neuronal damage in the hippocampus after SE. CONCLUSIONS: Taken together, these results suggested that a decrease in Rev-Erbα in the epileptogenic zone may contribute to the process of TLE and that the activation of Rev-Erbα may have anti-inflammatory and neuroprotective effects.


Assuntos
Anti-Inflamatórios/farmacologia , Encefalite/genética , Encefalite/prevenção & controle , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/metabolismo , Fármacos Neuroprotetores , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/biossíntese , Pirrolidinas/farmacologia , Tiofenos/farmacologia , Adolescente , Adulto , Animais , Convulsivantes , Citocinas/metabolismo , Encefalite/patologia , Epilepsia do Lobo Temporal/patologia , Regulação da Expressão Gênica , Gliose/patologia , Gliose/prevenção & controle , Hipocampo/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/agonistas , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Pilocarpina , Estado Epiléptico/patologia , Estado Epiléptico/prevenção & controle , Lobo Temporal/patologia , Adulto Jovem
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