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1.
Neurol Sci ; 45(3): 1057-1062, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37828389

RESUMO

BACKGROUND: Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disease characterized by rapidly progressive dementia, motor impairments, and psychiatric symptoms. Sensory disturbances were occasionally reported as well. The study aims to describe the sensory symptoms of the disease. METHODS: The CJD Israeli National Database was screened for patients who presented sensory symptoms throughout the disease course. Symptoms, characteristics, and distribution were reviewed and the demographic and clinical data (sex, etiologies of the disease, age of onset, disease duration, neurological exam finding, tau protein level, EEG and MRI findings) were compared with the demographics and clinical data of CJD without sensory symptoms. Then, the patients with sensory symptoms were divided into patients with symptom distribution consistent with peripheral nervous system (PNS) involvement and central nervous system (CNS) involvement. The demographics and clinical data of the 2 groups were compared. RESULTS: Eighty-four CJD patients with sensory symptoms and 645 CJD patients without sensory symptoms were included in the study. Sensory symptoms were more common in genetic E200K CJD patients (14.6% vs. 5.6% respectively, p = 0.0005) (chi-squared test). Numbness and neuropathic pain were the most common symptoms and distribution of symptoms of "stocking gloves" with decreased deep tendon reflexes suggesting peripheral neuropathy in 44% of the patients. In these patients, the classical EEG findings of Periodic Sharp Wave Complexes were less often found (58% vs. 22%, p = 0.02) (chi-squared test). CONCLUSIONS: Sensory symptoms are more common in E200K patients and often follow peripheral neuropathy distribution that suggests PNS involvement.


Assuntos
Síndrome de Creutzfeldt-Jakob , Doenças Neurodegenerativas , Doenças do Sistema Nervoso Periférico , Humanos , Síndrome de Creutzfeldt-Jakob/complicações , Síndrome de Creutzfeldt-Jakob/diagnóstico por imagem , Doenças Neurodegenerativas/diagnóstico , Imageamento por Ressonância Magnética , Diagnóstico Diferencial , Transtornos de Sensação/etiologia , Transtornos de Sensação/diagnóstico , Doenças do Sistema Nervoso Periférico/diagnóstico
2.
Eur J Neurol ; 30(7): 1991-2000, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36916670

RESUMO

BACKGROUND AND PURPOSE: Intramuscular blood flow increases during physical activity and may be quantified immediately following exercise using power Doppler sonography. Post-exercise intramuscular blood flow is reduced in patients with muscular dystrophy, associated with disease severity and degenerative changes. It is not known if intramuscular blood flow is reduced in patients with neuropathy, nor if it correlates with muscle strength and structural changes. The aim was to determine whether blood flow is reduced in patients with polyneuropathy due to Charcot-Marie-Tooth disease type 1 (CMT1) and to compare more affected distal to less affected proximal muscles. METHODS: This was a cross-sectional study including 21 healthy volunteers and 17 CMT patients. Power Doppler ultrasound was used to quantify post-exercise intramuscular blood flow in distal (gastrocnemius) and proximal (elbow flexor) muscles. Intramuscular blood flow was compared to muscle echo intensity, muscle strength, disease severity score, patient age and electromyography. RESULTS: Polyneuropathy patients showed reduced post-exercise blood flow in both gastrocnemius and elbow flexors compared to controls. A more prominent reduction was seen in the gastrocnemius (2.51% vs. 10.34%, p < 0.0001) than in elbow flexors (4.48% vs. 7.03%, p < 0.0001). Gastrocnemius intramuscular blood flow correlated with muscle strength, disease severity and age. Receiver operating characteristic analysis showed that quantification of intramuscular blood flow was superior to echo intensity for detecting impairment in the gastrocnemius (area under the curve 0.962 vs. 0.738, p = 0.0126). CONCLUSION: Post-exercise intramuscular blood flow is reduced in CMT1 polyneuropathy. This reduction is present in both impaired distal and minimally affected proximal muscles, indicating it as an early marker of muscle impairment due to neuropathy.


Assuntos
Doença de Charcot-Marie-Tooth , Humanos , Doença de Charcot-Marie-Tooth/diagnóstico , Estudos Transversais , Músculo Esquelético/diagnóstico por imagem , Ultrassonografia Doppler , Ultrassonografia
3.
Int J Mol Sci ; 24(3)2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36768341

RESUMO

Diabetic encephalopathy (DE) is an inflammation-associated diabetes mellitus (DM) complication. Inflammation and coagulation are linked and are both potentially modulated by inhibiting the thrombin cellular protease-activated receptor 1 (PAR1). Our aim was to study whether coagulation pathway modulation affects DE. Diabetic C57BL/6 mice were treated with PARIN5, a novel PAR1 modulator. Behavioral changes in the open field and novel object recognition tests, serum neurofilament (NfL) levels and thrombin activity in central and peripheral nervous system tissue (CNS and PNS, respectively), brain mRNA expression of tumor necrosis factor α (TNF-α), Factor X (FX), prothrombin, and PAR1 were assessed. Subtle behavioral changes were detected in diabetic mice. These were accompanied by an increase in serum NfL, an increase in central and peripheral neural tissue thrombin activity, and TNF-α, FX, and prothrombin brain intrinsic mRNA expression. Systemic treatment with PARIN5 prevented the appearance of behavioral changes, normalized serum NfL and prevented the increase in peripheral but not central thrombin activity. PARIN5 treatment prevented the elevation of both TNF-α and FX but significantly elevated prothrombin expression. PARIN5 treatment prevents behavioral and neural damage in the DE model, suggesting it for future clinical research.


Assuntos
Diabetes Mellitus Experimental , Receptor PAR-1 , Trombina , Animais , Camundongos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Modelos Animais de Doenças , Inflamação/metabolismo , Camundongos Endogâmicos C57BL , Protrombina/metabolismo , Receptor PAR-1/antagonistas & inibidores , Receptor PAR-1/metabolismo , Receptores de Trombina/metabolismo , RNA Mensageiro/metabolismo , Estreptozocina , Trombina/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
4.
J Neuroinflammation ; 19(1): 138, 2022 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-35690769

RESUMO

BACKGROUND: Inflammation and coagulation are linked and pathogenic in neuroinflammatory diseases. Protease-activated receptor 1 (PAR1) can be activated both by thrombin, inducing increased inflammation, and activated protein C (aPC), inducing decreased inflammation. Modulation of the aPC-PAR1 pathway may prevent the neuroinflammation associated with PAR1 over-activation. METHODS: We synthesized a group of novel molecules based on the binding site of FVII/aPC to the endothelial protein C receptor (EPCR). These molecules modulate the FVII/aPC-EPCR pathway and are therefore named FEAMs-Factor VII, EPCR, aPC Modulators. We studied the molecular and behavioral effects of a selected FEAM in neuroinflammation models in-vitro and in-vivo. RESULTS: In a lipopolysaccharide (LPS) induced in-vitro model, neuroinflammation leads to increased thrombin activity compared to control (2.7 ± 0.11 and 2.23 ± 0.13 mU/ml, respectively, p = 0.01) and decreased aPC activity (0.57 ± 0.01 and 1.00 ± 0.02, respectively, p < 0.0001). In addition, increased phosphorylated extracellular regulated kinase (pERK) (0.99 ± 0.13, 1.39 ± 0.14, control and LPS, p < 0.04) and protein kinase B (pAKT) (1.00 ± 0.09, 2.83 ± 0.81, control and LPS, p < 0.0002) levels indicate PAR1 overactivation, which leads to increased tumor necrosis factor-alpha (TNF-α) level (1.00 ± 0.04, 1.35 ± 0.12, control and LPS, p = 0.02). In a minimal traumatic brain injury (mTBI) induced neuroinflammation in-vivo model in mice, increased thrombin activity, PAR1 activation, and TNF-α levels were measured. Additionally, significant memory impairment, as indicated by a lower recognition index in the Novel Object Recognition (NOR) test and Y-maze test (NOR: 0.19 ± 0.06, -0.07 ± 0.09, p = 0.03. Y-Maze: 0.50 ± 0.03, 0.23 ± 0.09, p = 0.02 control and mTBI, respectively), as well as hypersensitivity by hot-plate latency (16.6 ± 0.89, 12.8 ± 0.56 s, control and mTBI, p = 0.01), were seen. FEAM prevented most of the molecular and behavioral negative effects of neuroinflammation in-vitro and in-vivo, most likely through EPCR-PAR1 interactions. CONCLUSION: FEAM is a promising tool to study neuroinflammation and a potential treatment for a variety of neuroinflammatory diseases.


Assuntos
Proteína C , Receptor PAR-1 , Animais , Receptor de Proteína C Endotelial/metabolismo , Fator VII/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/toxicidade , Camundongos , Doenças Neuroinflamatórias , Proteína C/metabolismo , Proteína C/uso terapêutico , Receptor PAR-1/metabolismo , Transdução de Sinais , Trombina/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
5.
Lupus ; 31(7): 855-863, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35575144

RESUMO

Antiphospholipid syndrome (APS) affects the brain by both hypercoagulation and immunological mechanisms. APS is characterized by several autoantibodies binding to a thrombolytic complex including beta-2-glycoprotein I (ß2-GPI) and annexin A2 (ANXA2). Teriflunomide, an oral drug for the treatment of multiple sclerosis (MS), has a cytostatic effect on B cells and is therefore a potential antibody-targeting treatment for APS. In this study, we assessed the effect of teriflunomide in two APS mouse models by inducing autoantibody formation against ß2-GPI and ANXA2 in female BALB/c mice. The ANXA2 model displayed a behavioral change suggesting an anti-anxiety effect in open field and forced swim tests, early in the course of the disease. This effect was normalized following teriflunomide treatment. Conversely, behavioral tests done later during the study demonstrated depression-like behavior in the ANXA2 model. No behavioral changes were seen in the ß2-GPI model. Total brain IgG levels were significantly elevated in the ANXA2 model but not in the teriflunomide treated group. No such change was noted in the brains of the ß2-GPI model. High levels of serum autoantibodies were induced in both models, and their levels were not lowered by teriflunomide treatment. Teriflunomide ameliorated behavioral changes in mice immunized with ANXA2 without a concomitant change in serum antibody levels. These findings are compatible with the effect of teriflunomide on neuroinflammation.Teriflunomide ameliorated behavioral and brain IgG levels in mice immunized with ANXA2 without a concomitant change in serum antibody levels. These findings are compatible with an effect of teriflunomide on the IgG permeability to the brain and neuroinflammation.


Assuntos
Ansiolíticos , Síndrome Antifosfolipídica , Lúpus Eritematoso Sistêmico , Animais , Anexinas , Síndrome Antifosfolipídica/complicações , Autoanticorpos , Crotonatos , Modelos Animais de Doenças , Feminino , Humanos , Hidroxibutiratos , Imunoglobulina G , Lúpus Eritematoso Sistêmico/complicações , Camundongos , Camundongos Endogâmicos BALB C , Nitrilas , Toluidinas , beta 2-Glicoproteína I
6.
Acta Neurol Scand ; 146(5): 586-589, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35974683

RESUMO

BACKGROUND: The largest cluster of genetic Creutzfeldt- Jakob Disease (CJD) exists in Libyan Jews carrying the E200K mutation in the PRNP gene. However, there is another cluster of genetic CJD with E200K mutation in families of Turkish-Jewish origin. AIMS: In this retrospective study, we aim to describe the demographic and clinical features of this population of patients. MATERIAL AND METHODS: The Israeli National CJD database was searched for demographic, clinical, imaging, and laboratory data of genetic CJD patients of Libyan and Turkish ancestry with the E200K mutation. The data of Libyan and Turkish patients were compared with notice similar or different demographic or clinical courses. RESULTS: Four hundred and twenty-three patients with CJD of Libyan (L) ancestry and 27 patients with CJD of Turkish (T) ancestry were identified. There were no significant differences in demographic and clinical data between the two populations (age of onset: T = 62 ± 8.8, L = 60 ± 9.7; age of death: T = 63 ± 8.6, L = 61 ± 9.7; and disease duration: T = 7.8 ± 8.4 months, L = 9.6 ± 13.6 months). Rapidly progressive dementia was the most common presentation in both groups, followed by pure cerebellar onset. The levels of tau protein in CSF did not differ between groups (T = 1290 ± 397.6 pg/ml, L = 1276 ± 594.2 pg/ml). MRI and EEG showed classical CJD features in most patients in both groups. DISCUSSION: The E200K mutation is the most common mutation among gCJD patients and was reported in different ethnical populations, suggesting several independent haplotypes of the mutation. The Turkish-Jew cluster, first described in this study, shares similar demographic and clinical features with the bigger cluster of Libyan-Jews CJD patients. CONCLUSION: E200K gCJD patients of Turkish ancestry share similar demographic and clinical features to patients of Libyan descent, suggesting a common origin of both populations.


Assuntos
Síndrome de Creutzfeldt-Jakob , Síndrome de Creutzfeldt-Jakob/epidemiologia , Síndrome de Creutzfeldt-Jakob/genética , Demografia , Humanos , Judeus/genética , Mutação/genética , Estudos Retrospectivos , Proteínas tau
7.
Neurol Sci ; 43(7): 4275-4279, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35257261

RESUMO

BACKGROUND: Creutzfeldt-Jacob disease (CJD) is a fatal neuro-degenerative disease, characterized by rapid and intense deterioration, mainly cognitive, leading to death. The typical onset of the disease is around the age of 67. PURPOSE: To characterize the demographic and clinical features of the population of CJD patients with late-onset disease. METHODS: In this retrospective study, the Israeli national database of prion diseases was screened for CJD patients with disease age of onset > 80 years between 1960 and 2016. Patient's demographic and clinical data were collected including sex, type of disease (sporadic/ genetic), clinical presentation, lab results including tau protein level, imaging, and EEG characteristics. Then, the clinical and demographic data of patients with late onset (> 80 years) (L) and patients with usual age of onset (< 80 years) (U) were compared. RESULTS: The study included 728 patients, 23 patients (3.3%) with late-onset disease (82.2.4±4 years, range 80-88) and 705 with usual disease onset (61.31 ± 9.47 years, range 34-80). Sporadic CJD was more common in the late-onset group (18/23 patients (78.2%) (L) vs. 256/705 patients (36.3%) (U)) (p = 0.0001, chi-square test). Classical EEG finding of periodic sharp wave activity were seen more often in the late-onset patients (55% (L) vs. 32.5% (U)) (p = 0.05, chi-square test). The rest of the demographic and clinical features were similar in both groups. CONCLUSION: Late- and usual-onset diseases are similar in most of demographic and clinical features suggesting a common disease type with normal distribution of age of onset.


Assuntos
Síndrome de Creutzfeldt-Jakob , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/epidemiologia , Síndrome de Creutzfeldt-Jakob/genética , Humanos , Transtornos de Início Tardio , Estudos Retrospectivos
8.
Isr Med Assoc J ; 25(12): 853-854, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-37584409

RESUMO

Endovascularly retrieved clots may be a potential resource for diagnosing stroke etiology. This method may influence secondary prevention treatment. We measure thrombin activity eluted by serially washing clots. We concluded that an assay measuring the change in thrombin in clots retrieved during acute stroke endovascular thrombectomy procedures may serve as a diagnostic marker of the origin of the clot. The suggested mechanism for these differences may be the clot location before its retrieval, with high blood flow causing thrombin washout in atherosclerotic clots, in contrast to atrium appendage low blood flow retaining high thrombin levels.


Assuntos
Fibrilação Atrial , AVC Isquêmico , Acidente Vascular Cerebral , Trombose , Humanos , Trombina , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/complicações , Trombose/etiologia , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/etiologia , AVC Isquêmico/complicações
9.
Int J Mol Sci ; 23(2)2022 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-35055169

RESUMO

The aim of this study was to characterize the distribution of the thrombin receptor, protease activated receptor 1 (PAR1), in the neuroretina. Neuroretina samples of wild-type C57BL/6J and PAR1-/- mice were processed for indirect immunofluorescence and Western blot analysis. Reverse transcription quantitative real-time PCR (RT-qPCR) was used to determine mRNA expression of coagulation Factor X (FX), prothrombin (PT), and PAR1 in the isolated neuroretina. Thrombin activity following KCl depolarization was assessed in mouse neuroretinas ex vivo. PAR1 staining was observed in the retinal ganglion cells, inner nuclear layer cells, and photoreceptors in mouse retinal cross sections by indirect immunofluorescence. PAR1 co-localized with rhodopsin in rod outer segments but was not expressed in cone outer segments. Western blot analysis confirmed PAR1 expression in the neuroretina. Factor X, prothrombin, and PAR1 mRNA expression was detected in isolated neuroretinas. Thrombin activity was elevated by nearly four-fold in mouse neuroretinas following KCl depolarization (0.012 vs. 0.044 mu/mL, p = 0.0497). The intrinsic expression of coagulation factors in the isolated neuroretina together with a functional increase in thrombin activity following KCl depolarization may suggest a role for the PAR1/thrombin pathway in retinal function.


Assuntos
Carboidratos Epimerases/metabolismo , Cetona Oxirredutases/metabolismo , Receptor PAR-1/genética , Receptor PAR-1/metabolismo , Neurônios Retinianos/metabolismo , Animais , Técnicas de Inativação de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Cloreto de Potássio/farmacologia , Protrombina/metabolismo , Células Fotorreceptoras Retinianas Cones/metabolismo , Células Ganglionares da Retina/metabolismo , Segmento Interno das Células Fotorreceptoras da Retina/metabolismo , Rodopsina/metabolismo
10.
Int J Mol Sci ; 23(18)2022 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-36142385

RESUMO

Background. Due to the interactions between neuroinflammation and coagulation, the neural effects of lipopolysaccharide (LPS)-induced inflammation (1 mg/kg, intraperitoneal (IP), n = 20) and treatment with the anti-thrombotic enoxaparin (1 mg/kg, IP, 15 min, and 12 h following LPS, n = 20) were studied in C57BL/6J mice. Methods. One week after LPS injection, sensory, motor, and cognitive functions were assessed by a hot plate, rotarod, open field test (OFT), and Y-maze. Thrombin activity was measured with a fluorometric assay; hippocampal mRNA expression of coagulation and inflammation factors were measured by real-time-PCR; and serum neurofilament-light-chain (NfL), and tumor necrosis factor-α (TNF-α) were measured by a single-molecule array (Simoa) assay. Results. Reduced crossing center frequency was observed in both LPS groups in the OFT (p = 0.02), along with a minor motor deficit between controls and LPS indicated by the rotarod (p = 0.057). Increased hippocampal thrombin activity (p = 0.038) and protease-activated receptor 1 (PAR1) mRNA (p = 0.01) were measured in LPS compared to controls, but not in enoxaparin LPS-treated mice (p = 0.4, p = 0.9, respectively). Serum NfL and TNF-α levels were elevated in LPS mice (p < 0.05) and normalized by enoxaparin treatment. Conclusions. These results indicate that inflammation, coagulation, neuronal damage, and behavior are linked and may regulate each other, suggesting another pharmacological mechanism for intervention in neuroinflammation.


Assuntos
Enoxaparina , Lipopolissacarídeos , Animais , Modelos Animais de Doenças , Enoxaparina/farmacologia , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , Receptor PAR-1 , Trombina , Fator de Necrose Tumoral alfa/metabolismo
11.
J Neurosci Res ; 99(3): 966-976, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33296953

RESUMO

Many coagulation factor proteases are increased in the brain during ischemic stroke. One of these proteases is plasmin. In this study we established a novel method for direct quantitative measurement of plasmin activity in male mouse brain slices using a sensitive fluorescent substrate in the presence of specific protease inhibitors. In both the ischemic and contralateral hemispheres, plasmin activity increased 3, 6, and 24 hr following stroke in comparison to healthy mice (F(3, 72) = 39.5, p < 0.0001, repeated measures ANOVA) after the induction of permanent middle cerebral artery occlusion (PMCAo). Plasmin activity was higher in the ischemic hemisphere (F(1,36) = 9.1, p = 0.005) and there was a significant interaction between time and ischemic hemisphere (F(3,36) = 4.4, p = 0.009). Plasmin activity was correlated with infarct volume (R2  = 0.5289, p = 0.0009 by Spearman). The specificity of the assay was verified utilizing tissue-type plasminogen activator (tPA)-deficient mice which, as expected, had significantly lower levels of plasmin 24 hr following ischemia compared to wild-type mice (ischemic (0.6 ± 0.23 and 1.94 ± 0.5, respectively), p = 0.049 and contralateral hemispheres (0.13 ± 0.14 and 0.75 ± 0.10, respectively), p = 0.018 by t test). There is a time-dependent increase in plasmin levels and an association of higher levels of plasmin with larger infarct volumes in an experimental stroke model. This suggests caution in the use of recombinant tPA (rtPA) and that plasmin inhibition in the brain may be a therapeutic target in acute ischemic stroke.


Assuntos
Ensaios Enzimáticos/métodos , Fibrinolisina/metabolismo , AVC Isquêmico/enzimologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Infarto Encefálico/patologia , Infarto da Artéria Cerebral Média , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Ativador de Plasminogênio Tecidual/deficiência
12.
Lupus ; 30(5): 775-784, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33554716

RESUMO

INTRODUCTION: Antiphospholipid syndrome (APS) is an autoimmune disorder manifested by thromboembolic events, recurrent spontaneous abortions and elevated titers of circulating antiphospholipid antibodies. In addition, the presence of antiphospholipid antibodies seems to confer a fivefold higher risk for stroke or transient ischemic attack. Although the major antigen of APS is ß2 glycoprotein I, it is now well established that antiphospholipid antibodies are heterogeneous and bind to various targets. Recently, antibodies to Annexin A2 (ANXA2) have been reported in APS. This is of special interest since data indicated ANXA2 as a key player in fibrinolysis. Therefore, in the present study we assessed whether anti-ANXA2 antibodies play a pathological role in thrombosis associated disease. MATERIALS AND METHODS: Mice were induced to produce anti-ANXA2 antibodies by immunization with ANXA2 (iANXA2) and control mice were immunized with adjuvant only. A middle cerebral artery occlusion stroke model was applied to the mice. The outcome of stroke severity was assessed and compared between the two groups. RESULTS: Our results indicate that antibodies to ANXA2 lead to a more severe stroke as demonstrated by a significant larger stroke infarct volume (iANXA2 133.9 ± 3.3 mm3 and control 113.7 ± 7.4 mm3; p = 0.017) and a more severe neurological outcome (iANXA2 2.2 ± 0.2, and control 1.5 ± 0.18; p = 0.03). CONCLUSIONS: This study supports the hypothesis that auto-antibodies to ANXA2 are an independent risk factor for cerebral thrombosis. Consequently, we propose screening for anti-ANXA2 antibodies should be more widely used and patients that exhibit the manifestations of APS should be closely monitored by physicians.


Assuntos
Anexina A2/imunologia , Síndrome Antifosfolipídica/imunologia , Autoanticorpos/imunologia , Trombose Intracraniana/metabolismo , Adulto , Animais , Anexina A2/administração & dosagem , Anexina A2/metabolismo , Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/metabolismo , Autoanticorpos/metabolismo , Autoimunidade/imunologia , Modelos Animais de Doenças , Feminino , Fibrinólise/imunologia , Humanos , Infarto da Artéria Cerebral Média/imunologia , Infarto da Artéria Cerebral Média/fisiopatologia , Injeções Subcutâneas , Trombose Intracraniana/etiologia , Ataque Isquêmico Transitório/imunologia , Camundongos , Camundongos Endogâmicos BALB C/imunologia , Pessoa de Meia-Idade , Fatores de Risco , Índice de Gravidade de Doença , Acidente Vascular Cerebral/imunologia , beta 2-Glicoproteína I/metabolismo
13.
Int J Mol Sci ; 22(24)2021 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-34948217

RESUMO

Axonal and neuronal pathologies are a central constituent of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), induced by the myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide. In this study, we investigated neurodegenerative manifestations in chronic MOG 35-55 induced EAE and the effect of glatiramer acetate (GA) treatment on these manifestations. We report that the neuronal loss seen in this model is not attributed to apoptotic neuronal cell death. In EAE-affected mice, axonal damage prevails from the early disease phase, as revealed by analysis of neurofilament light (NFL) leakage into the sera along the disease duration, as well as by immunohistological examination. Elevation of interstitial glutamate concentrations measured in the cerebrospinal fluid (CSF) implies that glutamate excess plays a role in the damage processes inflicted by this disease. GA applied as a therapeutic regimen to mice with apparent clinical symptoms significantly reduces the pathological manifestations, namely apoptotic cell death, NFL leakage, histological tissue damage, and glutamate excess, thus corroborating the neuroprotective consequences of this treatment.


Assuntos
Acetato de Glatiramer/farmacologia , Ácido Glutâmico/metabolismo , Filamentos Intermediários/metabolismo , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Fármacos Neuroprotetores/farmacologia , Animais , Axônios/efeitos dos fármacos , Axônios/metabolismo , Líquido Cefalorraquidiano/efeitos dos fármacos , Líquido Cefalorraquidiano/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/metabolismo , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito/metabolismo , Peptídeos/metabolismo
14.
Clin Immunol ; 214: 108384, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32171889

RESUMO

Chronic fatigue syndrome, postural orthostatic tachycardia syndrome, complex regional pain syndrome and silicone implant incompatibility syndrome are a subject of debate among clinicians and researchers. Both the pathogenesis and treatment of these disorders require further study. In this paper we summarize the evidence regarding the role of autoimmunity in these four syndromes with respect to immunogenetics, autoimmune co-morbidities, alteration in immune cell subsets, production of autoantibodies and presentation in animal models. These syndromes could be incorporated in a new concept of autoimmune neurosensory dysautonomia with the common denominators of autoantibodies against G-protein coupled receptors and small fiber neuropathy. Sjogren's syndrome, which is a classical autoimmune disease, could serve as a disease model, illustrating the concept. Development of this concept aims to identify an apparently autoimmune subgroup of the disputable disorders, addressed in the review, which may most benefit from the immunotherapy.


Assuntos
Doenças Autoimunes do Sistema Nervoso/complicações , Disfunção Cognitiva/etiologia , Síndromes da Dor Regional Complexa/etiologia , Síndrome de Fadiga Crônica/etiologia , Síndrome da Taquicardia Postural Ortostática/etiologia , Disautonomias Primárias/complicações , Próteses e Implantes/efeitos adversos , Silicones/efeitos adversos , Neuropatia de Pequenas Fibras/complicações , Especificidade de Anticorpos , Autoanticorpos/imunologia , Autoantígenos/imunologia , Doenças Autoimunes do Sistema Nervoso/imunologia , Doenças Autoimunes do Sistema Nervoso/psicologia , Doenças Autoimunes do Sistema Nervoso/terapia , Autoimunidade , Disfunção Cognitiva/imunologia , Síndromes da Dor Regional Complexa/imunologia , Síndromes da Dor Regional Complexa/psicologia , Síndromes da Dor Regional Complexa/terapia , Síndrome de Fadiga Crônica/imunologia , Síndrome de Fadiga Crônica/psicologia , Síndrome de Fadiga Crônica/terapia , Humanos , Técnicas de Imunoadsorção , Imunoterapia , Síndrome da Taquicardia Postural Ortostática/imunologia , Síndrome da Taquicardia Postural Ortostática/psicologia , Síndrome da Taquicardia Postural Ortostática/terapia , Disautonomias Primárias/psicologia , Disautonomias Primárias/terapia , Receptores Acoplados a Proteínas G/imunologia , Síndrome de Sjogren/complicações , Síndrome de Sjogren/imunologia , Neuropatia de Pequenas Fibras/psicologia , Neuropatia de Pequenas Fibras/terapia
16.
Int J Mol Sci ; 21(7)2020 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-32244492

RESUMO

BACKGROUND: Neural inflammation is linked to coagulation. Low levels of thrombin have a neuroprotective effect, mediated by activated protein C (APC). We describe a sensitive novel method for the measurement of APC activity at the low concentrations found in neural tissue. METHODS: APC activity was measured using a fluorogenic substrate, Pyr-Pro-Arg-AMC, cleaved preferentially by APC. Selectivity was assessed using specific inhibitors and activators. APC levels were measured in human plasma, in glia cell lines, in mice brain slices following mild traumatic brain injury (mTBI) and systemic lipopolysaccharide (LPS) injection, and in cerebrospinal fluid (CSF) taken from viral meningoencephalitis patients and controls. RESULTS: Selectivity required apixaban and alpha-naphthylsulphonylglycyl-4-amidinophenylalanine piperidine (NAPAP). APC levels were easily measurable in plasma and were significantly increased by Protac and CaCl2. APC activity was significantly higher in the microglial compared to astrocytic cell line and specifically lowered by LPS. Brain APC levels were higher in posterior regions and increased by mTBI and LPS. Highly elevated APC activity was measured in viral meningoencephalitis patients CSF. CONCLUSIONS: This method is selective and sensitive for the measurement of APC activity that significantly changes during inflammation in cell lines, animal models and human CSF.


Assuntos
Encéfalo/metabolismo , Líquido Cefalorraquidiano/metabolismo , Neuroglia/metabolismo , Proteína C/metabolismo , Animais , Concussão Encefálica/metabolismo , Linhagem Celular , Dipeptídeos , Receptor de Proteína C Endotelial/metabolismo , Humanos , Inflamação/metabolismo , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Modelos Animais , Piperidinas , Pirazóis , Piridonas , Receptor PAR-1 , Trombina
17.
Int J Mol Sci ; 21(4)2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32075060

RESUMO

Apolipoprotein E (APOE) ε4 gene allele and type 2 diabetes mellitus (T2DM) are prime risk factors for Alzheimer's disease (AD). Despite evidence linking T2DM and apoE4, the mechanism underlying their interaction is yet to be determined. In the present study, we employed a model of APOE-targeted replacement mice and high-fat diet (HFD)-induced insulin resistance to investigate diabetic mechanisms associated with apoE4 pathology and the extent to which they are driven by peripheral and central processes. Results obtained revealed an intriguing pattern, in which under basal conditions, apoE4 mice display impaired glucose and insulin tolerance and decreased insulin secretion, as well as cognitive and sensorimotor characteristics relative to apoE3 mice, while the HFD impairs apoE3 mice without significantly affecting apoE4 mice. Measurements of weight and fasting blood glucose levels increased in a time-dependent manner following the HFD, though no effect of genotype was observed. Interestingly, sciatic electrophysiological and skin intra-epidermal nerve fiber density (IENFD) peripheral measurements were not affected by the APOE genotype or HFD, suggesting that the observed sensorimotor and cognitive phenotypes are related to central nervous system processes. Indeed, measurements of hippocampal insulin receptor and glycogen synthase kinase-3ß (GSK-3ß) activation revealed a pattern similar to that obtained in the behavioral measurements while Akt activation presented a dominant effect of diet. HFD manipulation induced genotype-independent hyperlipidation of apoE, and reduced levels of brain apoE in apoE3 mice, rendering them similar to apoE4 mice, whose brain apoE levels were not affected by the diet. No such effect was observed in the peripheral plasma levels of apoE, suggesting that the pathological effects of apoE4 under the control diet and apoE3 under HFD conditions are related to the decreased levels of brain apoE. Taken together, our data suggests that diabetic mechanisms play an important role in mediating the pathological effects of apoE4 and that consequently, diabetic-related therapy may be useful in treating apoE4 pathology in AD.


Assuntos
Apolipoproteína E4/metabolismo , Diabetes Mellitus Tipo 2/patologia , Doença de Alzheimer/etiologia , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Apolipoproteína E4/deficiência , Apolipoproteína E4/genética , Apolipoproteínas E/sangue , Encéfalo/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Dieta Hiperlipídica , Genótipo , Teste de Tolerância a Glucose , Hipocampo/metabolismo , Humanos , Locomoção , Memória de Curto Prazo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Medição da Dor , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
18.
Int J Mol Sci ; 21(10)2020 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-32408605

RESUMO

Glia cells are involved in upper motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Protease activated receptor 1 (PAR1) pathway is related to brain pathologies. Brain PAR1 is located on peri-synaptic astrocytes, adjacent to pyramidal motor neurons, suggesting possible involvement in ALS. Brain thrombin activity in superoxide dismutase 1 (SOD1) mice was measured using a fluorometric assay, and PAR1 levels by western blot. PAR1 was localized using immunohistochemistry staining. Treatment targeted PAR1 pathway on three levels; thrombin inhibitor TLCK (N-Tosyl-Lys-chloromethylketone), PAR1 antagonist SCH-79797 and the Ras intracellular inhibitor FTS (S-trans-trans-farnesylthiosalicylic acid). Mice were weighed and assessed for motor function and survival. SOD1 brain thrombin activity was increased (p < 0.001) particularly in the posterior frontal lobe (p = 0.027) and hindbrain (p < 0.01). PAR1 levels were decreased (p < 0.001, brain, spinal cord, p < 0.05). PAR1 and glial fibrillary acidic protein (GFAP) staining decreased in the cerebellum and cortex. SOD1 mice lost weight (≥17 weeks, p = 0.047), and showed shorter rotarod time (≥14 weeks, p < 0.01). FTS 40mg/kg significantly improved rotarod scores (p < 0.001). Survival improved with all treatments (p < 0.01 for all treatments). PAR1 antagonism was the most efficient, with a median survival improvement of 10 days (p < 0.0001). Our results support PAR1 pathway involvement in ALS.


Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Encéfalo/metabolismo , Modelos Animais de Doenças , Receptor PAR-1/metabolismo , Superóxido Dismutase-1/metabolismo , Esclerose Lateral Amiotrófica/genética , Animais , Astrócitos/metabolismo , Peso Corporal/efeitos dos fármacos , Farneseno Álcool/análogos & derivados , Farneseno Álcool/farmacologia , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Neurônios Motores/metabolismo , Mutação , Pirróis/farmacologia , Quinazolinas/farmacologia , Salicilatos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase-1/genética , Análise de Sobrevida , Tosilina Clorometil Cetona/farmacologia
19.
J Neural Transm (Vienna) ; 126(5): 607-611, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30498951

RESUMO

Previous studies have suggested that disease duration in Creutzfeldt-Jakob disease (CJD) may be related to the radiological findings or cerebrospinal fluid (CSF) tau levels; however, it is not yet established whether clinical, radiological, and laboratory findings at diagnosis can predict survival or have a prognostic value. The aim of this study was to examine whether the disease duration is correlated with clinical, radiological, and laboratory variables. The study population consisted of consecutive familial CJD (fCJD) patients that were assessed within 1 week from the diagnosis including the CJD neurological scale (CJD-NS), Minimental Status Examination, Frontal Assessment Battery, NIH Stroke Scale, and the expanded disability status scale. In addition, a single MRI study was done and measurements of the extent of the cortical and subcortical involvement were performed. CSF was examined as part of the workout, and tau levels were determined. Sixty-nine fCJD patients were included in the study (43 males, mean age 59.3 ± 8.4, range 44-79 years). The mean disease duration was 7.3 ± 6.9 months (median 5.6 months, range 2-20 months). A significant correlation was found between the disease duration and the CJD-NS, the disease burden as reflected by the degree of cortical involvement by DWI, and the CSF tau levels. The findings of the current study reveal that several findings at disease onset including the disease severity, the cortical changes, and the tau levels are each individually correlated with disease duration and can be used by the clinician as a tool to predict the disease course and prognosis.


Assuntos
Síndrome de Creutzfeldt-Jakob/líquido cefalorraquidiano , Síndrome de Creutzfeldt-Jakob/patologia , Proteínas tau/líquido cefalorraquidiano , Adulto , Idoso , Encéfalo/patologia , Progressão da Doença , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Priônicas/genética , Prognóstico
20.
Acta Neurol Scand ; 140(5): 366-371, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31393995

RESUMO

INTRODUCTION: Previous studies showed concordance between the typical Periodic Sharp Wave Complex (PSWC) activity in EEG of Creutzfeldt-Jakob Disease (CJD) patients and the MRI findings, while the concordance with slow activity in EEG is less established. The aim of this study was to better characterize the association between MRI findings and EEG changes using quantitative EEG (qEEG) analysis. METHODS: The demographics, clinical features, and the MRI findings of 12 familial E200K patients with CJD were gathered. EEG test was done and reviewed for the typical PSWC and for the non-specific slow activity. A possible association between the MRI findings and the EEG activity was examined. Then, EEG was analyzed using qEEG tool, and the association between the qEEG finding and the MRI was examined. RESULTS: Twelve patients were included in the study (67% women). Cortical MRI lesions finding were seen in 6/12 (50%) of the patients, and deep gray mater lesions were seen in 8/12 patients (67%). EEG showed the classic PSWC in 6/12 (50%) of the patients where slow activity was seen in 10/12 (83%). Slow activity and cortical MRI findings were associated in only 2/6 (33%) where deep gray matter findings and the slow activity had concordance of 4/8 (50%). qEEG analysis improved this concordance between slow activity and cortical findings to 3/6 (50%) and with the deep gray matter findings to 5/8 (63%). CONCLUSIONS: Quantitative EEG analysis modesty but not significantly, improves the association of EEG slow activity in familial E200K CJD patients with MRI findings.


Assuntos
Síndrome de Creutzfeldt-Jakob/fisiopatologia , Eletroencefalografia/métodos , Imageamento por Ressonância Magnética/métodos , Adulto , Idoso , Síndrome de Creutzfeldt-Jakob/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
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