Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 57
Filter
1.
Neurochem Res ; 49(7): 1851-1862, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38733521

ABSTRACT

Alzheimer's disease (AD) is an age-dependent neurodegenerative disease that is typically sporadic and has a high social and economic cost. We utilized the intracerebroventricular administration of streptozotocin (STZ), an established preclinical model for sporadic AD, to investigate hippocampal astroglial changes during the first 4 weeks post-STZ, a period during which amyloid deposition has yet to occur. Astroglial proteins aquaporin 4 (AQP-4) and connexin-43 (Cx-43) were evaluated, as well as claudins, which are tight junction (TJ) proteins in brain barriers, to try to identify changes in the glymphatic system and brain barrier during the pre-amyloid phase. Glial commitment, glucose hypometabolism and cognitive impairment were characterized during this phase. Astroglial involvement was confirmed by an increase in glial fibrillary acidic protein (GFAP); concurrent proteolysis was also observed, possibly mediated by calpain. Levels of AQP-4 and Cx-43 were elevated in the fourth week post-STZ, possibly accelerating the clearance of extracellular proteins, since these proteins actively participate in the glymphatic system. Moreover, although we did not see a functional disruption of the blood-brain barrier (BBB) at this time, claudin 5 (present in the TJ of the BBB) and claudin 2 (present in the TJ of the blood-cerebrospinal fluid barrier) were reduced. Taken together, data support a role for astrocytes in STZ brain damage, and suggest that astroglial dysfunction accompanies or precedes neuronal damage in AD.


Subject(s)
Alzheimer Disease , Aquaporin 4 , Astrocytes , Streptozocin , Astrocytes/metabolism , Animals , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Male , Aquaporin 4/metabolism , Connexin 43/metabolism , Blood-Brain Barrier/metabolism , Water/metabolism , Hippocampus/metabolism , Rats, Wistar , Rats , Disease Models, Animal
2.
Neurologia (Engl Ed) ; 38(7): 504-510, 2023 Sep.
Article in English | MEDLINE | ID: mdl-35637138

ABSTRACT

INTRODUCTION: Neuromyelitis optica (NMO) is an inflammatory disease of the central nervous system characterised by attacks of optic neuritis and longitudinally extensive transverse myelitis. The discovery of anti-aquaporin-4 (anti-AQP4) antibodies and specific brain MRI findings as diagnostic biomarkers have enabled the recognition of a broader and more detailed clinical phenotype, known as neuromyelitis optica spectrum disorder (NMOSD). OBJECTIVE: This study aimed to determine the demographic and clinical characteristics of patients with NMO/NMOSD with and without seropositivity for anti-AQP4 antibodies, in 2 quaternary-level hospitals in Bogotá. METHODS: Our study included patients > 18 years of age and diagnosed with NMO/NMOSD and for whom imaging and serology results were available, assessed between 2013 and 2017 at the neurology departments of hospitals providing highly complex care. Demographic, clinical, and imaging data were gathered and compared in patients with and without seropositivity for anti-AQP4 antibodies. RESULTS: The sample included 35 patients with NMO/NMOSD; the median age of onset was 46.5 years (P25-P75, 34.2-54.0); most patients had sensory (n = 25) and motor manifestations (n = 26), and a concomitant autoimmune disease was identified in 6. Twenty patients were seropositive for anti-AQP4 antibodies. Only age and presence of optic nerve involvement showed statistically significant differences between groups (P = .03). CONCLUSIONS: Clinical, imaging, and laboratory variables showed no major differences between patients with and without anti-AQP4 antibodies, with the exception of age of onset and presence of optic nerve involvement (uni- or bilateral); these factors should be studied in greater detail in larger populations.


Subject(s)
Myelitis, Transverse , Neuromyelitis Optica , Humans , Middle Aged , Neuromyelitis Optica/complications , Colombia , Aquaporin 4 , Autoantibodies
3.
Arq. neuropsiquiatr ; Arq. neuropsiquiatr;81(2): 201-211, 2023. tab, graf
Article in English | LILACS-Express | LILACS | ID: biblio-1439429

ABSTRACT

Abstract Neuromyelitis optica spectrum disorder (NMOSD) is a rare and severe inflammatory disorder of the central nervous system (CNS). It is strongly associated with anti-aquaporin 4 antibodies (AQP4-IgG), and it mainly affects young women from non-white ethnicities. However, ~ 5 to 10% of all cases have onset during childhood. Children and adolescents share the same clinical, radiologic, and laboratory presentation as adults. Thus, the same NMOSD diagnostic criteria are also applied to pediatric-onset patients, but data on NMOSD in this population is still scarce. In seronegative pediatric patients, there is a high frequency of the antibody against myelin oligodendrocyte glycoprotein (MOG-IgG) indicating another disease group, but the clinical distinction between these two diseases may be challenging. Three drugs (eculizumab, satralizumab, and inebilizumab) have been recently approved for the treatment of adult patients with AQP4-IgG-positive NMOSD. Only satralizumab has recruited adolescents in one of the two pivotal clinical trials. Additional clinical trials in pediatric NMOSD are urgently required to evaluate the safety and efficacy of these drugs in this population.


Resumo O espectro da neuromielite óptica (ENMO) é uma rara e grave doença inflamatória do sistema nervoso central (SNC), fortemente associada ao anticorpo anti-aquaporina 4 (AQP4-IgG) e que afeta preferencialmente mulheres jovens de etnias não-caucasianas. No entanto, aproximadamente de 5 a 10% de todos os casos se iniciam na infância. Crianças e adolescentes compartilham as mesmas características clínicas, radiológicas e laboratoriais dos adultos. Além disso, o mesmo critério diagnóstico de ENMO é aplicado para pacientes com início na infância. No entanto, dados da população pediátrica são escassos. Em pacientes pediátricos soronegativos, existe uma alta frequência de positividade ao anticorpo contra a glicoproteína na mielina do oligodendrócito (MOG-IgG), indicando outra patologia; porém, a distinção clínica entre as duas doenças é desafiadora. Três medicações (eculizumabe, inebilizumabe e satralizumabe) foram recentemente aprovadas para pacientes adultos com AQP4-IgG. Apenas um dos ensaios pivotais do satralizumabe recrutou adolescentes. Novos ensaios clínicos em pacientes pediátricos com ENMO são necessários para avaliar a segurança e eficácia destas drogas nesta população.

4.
Arq. bras. neurocir ; 42(1): 14-18, 2023.
Article in English | LILACS-Express | LILACS | ID: biblio-1570198

ABSTRACT

Objectives The aim of the present study is to analyze if aquaporin-4 (AQP4) may also be a tumor progression marker for meningiomas. Methods This is an immunohistochemistry study realized at the Universidade de São Paulo, São Paulo, state of São Paulo, Brazil: frozen meningioma samples from 81 patients (57 females and 24 males, age range from 22 to 81 years old, average 56.5 14.1 years old), including 57 meningiomas World Health Organization (WHO) grade I (GI); 19 grade II (GII), and 5 grade III (GIII) were analyzed. The relative expression level of AQP4 was analyzed by quantitative polymerase chain reaction (qPCR), using the SYBR Green approach and for staining detection. Tissue sections were routinely processed and subjected to antigen retrieval. Results The expression of AQP4 in meningioma samples ranged from 0 to 10.26, with a median of 0.001 in GI cases, of 0.008 in GII cases, and of 0.006 in GIII cases. Although not statistically significant (p » 0.942), GI meningiomas have a lower median AQP4 expression level than higher malignant grade cases. Conclusion The AQP4 gene and protein expressions presented no association with meningioma malignant progression.


Objetivo O objetivo do presente estudo é analisar se a aquaporina-4 (AQP4) também pode ser um marcador de progressão tumoral para meningiomas. Métodos Trata-se de um estudo imunohistoquímico realizado na Universidade de São Paulo, SP, Brasil. Amostras congeladas de meningioma de 81 pacientes (57 mulheres e 24 homens, faixa etária de 22 a 81 anos, média de 56,5 14,1 anos), incluindo 57 meningiomas grau I (GI) da Organização Mundial da Saúde (OMS); 19 grau II (GII) e 5 grau III (GIII) foram analisados. O nível de expressão relativa de AQP4 foi analisado por reação em cadeia de polimerase quantitativa (qPCR, sigla em inglês), usando a abordagem SYBR Green e para detecção de manchas. As seções de tecido foram rotineiramente processadas e sujeitas a recuperação de antígeno. Resultados A expressão de AQP4 em amostras de meningioma variou de 0 a 10,26, com mediana de 0,001 nos casos GI; 0,008 nos casos GII; e 0,006 nos casos GIII. Embora não sejam estatisticamente significantes (p » 0,942), os meningiomas GI apresentam mediana mais baixa do nível de expressão de AQP4 do que os casos de grau maligno mais alto. Conclusão Expressões de genes e proteínas AQP4 apresentadas na associação com progressão maligna do meningioma.

5.
Arq. bras. neurocir ; 42(2): 165-175, 2023.
Article in English | LILACS-Express | LILACS | ID: biblio-1570720

ABSTRACT

Background Aquaporins (AQPs) are a family of membrane proteins that regulate the osmotic permeability of the plasma membrane. There are described in the literature a total of 13 types of Aquaporins in mammals, each with different places of expression. In addition to water, some AQPs allow the passage of glycerol and ammonia, being called Aquaglyceroproteins. In the central nervous system, AQPs 1 and 4 are expressed, being responsible for the water regulation in the blood-brain barrier. These two AQPs are believed to participate in the pathophysiological process that governs the behavior of various CNS diseases, such as trauma and primary tumors. More particularly, there are quite controversial data in the literature on the expression of AQP4 in tumors and its relationship with disease progression and treatment possibility. Objective This paper aims to perform a literature review on the function and expression of AQP4 in the CNS and primary tumors of this system, to compile what is in the literature on the subject and raise new possible research hypotheses. Methods The PUBMED platform was used for bibliographic survey using "Aquaporin 4," "expression" and "astrocytomas" as keywords. Articles older than 2008 and articles that did not address AQP4 expression in astrocytomas were excluded. In the selected articles, the following topics were investigated: AQP4 structure, brain and tumor localization, and relationship with peritumoral edema. Results Regarding the structure and location of AQP4, the literature presents two isoforms of AQP4: M1 and M23. Both form clusters of AQP4 called "orthogonal arrays of proteins - OAPs." In the tumor tissue, the literature shows a decrease in the formation of OAPs and an increase in the expression of both AQP4 isoforms, besides losing their polarity, diffusing through the cytoplasmic membrane. As for the function of AQP4 in tumors, AQP4 assists in cell migration and invasion, in addition to participating in cell proliferation and apoptosis. Regarding the relationship with cerebral edema, there are controversial knowledge. Studies have shown that increased AQP4 aggravates cytotoxic edema of tumor cells and, by assisting in cell migration and angiogenesis, indirectly assist in the formation of vasogenic edema by breaking the blood-brain barrier. Other studies, however, point to the increase in AQP4 as a protective mechanism to combat vasogenic edema that occurs in tumor formation. Furthermore, the literature presents a therapeutic proposal in which, by inhibiting AQP4 expression, tumor migration and cerebral edema decrease in rats with glioblastoma. Discussion As shown in the literature, there is a difference in histopathological structure between high and low grade gliomas. However, there are common changes between them. These common changes could then be used as a factor of severity or evolution of low-grade to high-grade tumors. Moreover, it is not yet possible to perceive the true relationship of AQP4 expression and increased VEGF evolution of peritumoral edema. Finally, it can be hypothesized that since the expression ratio between AQP4 isoforms in normal tissue is greater than in some tumors, the decrease in this ratio is due either to decreased M23 expression or increased of the isoform M1. Conclusion Further studies are needed to understand the physiology and pathophysiology involving AQP4 in astrocytomas to create effective therapeutic proposals to combat this disease.


Introdução As aquaporinas (AQPs) são uma família de proteínas de membrana que regulam a permeabilidade osmótica da membrana plasmática. Existem descritos na literatura um total de 13 tipos de aquaporinas em mamíferos, cada um com diferentes locais de expressão. Além da água, alguns AQPs permitem a passagem de glicerol e amônia, sendo chamados de aquagliceroproteínas. No sistema nervoso central, as AQPs 1 e 4 são expressas, sendo responsáveis pela regulação da água na barreira hematoencefálica. Acredita-se que esses dois AQPs participem do processo fisiopatológico que regula o comportamento de várias doenças do SNC, como trauma e tumores primários. Mais particularmente, há dados bastante controversos na literatura sobre a expressão de AQP4 em tumores e sua relação com a progressão da doença e possibilidade de tratamento. Objetivo Este artigo tem como objetivo realizar uma revisão da literatura sobre a função e expressão da AQP4 no SNC e tumores primários deste sistema, a fim de compilar o que está na literatura sobre o assunto e levantar novas hipóteses de pesquisa possíveis. Método A plataforma PUBMED foi utilizada para levantamento bibliográfico utilizando "Aquaporin 4," "expression" e "astrocitomas" como palavras-chave. Artigos com idade superior a 2008 e artigos que não abordaram a expressão de AQP4 em astrocitomas foram excluídos. Nos artigos selecionados, foram investigados os seguintes tópicos: estrutura da AQP4, localização do cérebro e do tumor e relação com o edema peritumoral. Resultados Em relação à estrutura e localização da AQP4, a literatura apresenta duas isoformas da AQP4: M1 e M23. Ambos formam aglomerados de AQP4 chamados "arranjos ortogonais de proteínas - OAPs." No tecido tumoral, a literatura mostra uma diminuição na formação de OAPs e um aumento na expressão de ambas as isoformas AQP4, além de perder sua polaridade, difundindo através da membrana citoplasmática. Quanto à função da AQP4 nos tumores, a AQP4 auxilia na migração e invasão celular, além de participar da proliferação celular e apoptose. Em relação à relação com o edema cerebral, existem controvérsias. Estudos demonstram que o aumento da AQP4 agrava o edema citotóxico das células tumorais e, auxiliando na migração celular e na angiogênese, auxilia indiretamente na formação de edema vasogênico por quebra da barreira hematoencefálica. Outros estudos, no entanto, apontam para o aumento da AQP4 como mecanismo protetor para combater o edema vasogênico que ocorre na formação de tumores. Além disso, a literatura apresenta uma proposta terapêutica em que, ao inibir a expressão da AQP4, a migração tumoral e o edema cerebral diminuem em ratos com glioblastoma. Discussão Como mostrado na literatura, há uma diferença na estrutura histopatológica entre os gliomas de alto e baixo grau. No entanto, existem mudanças comuns entre eles. Estas alterações comuns poderiam então ser usadas como um fator de gravidade ou evolução de tumores de baixo grau a alto grau. Além disso, ainda não é possível perceber a verdadeira relação entre a expressão da AQP4 e o aumento da evolução do VEGF no edema peritumoral. Finalmente, pode-se supor que, como a razão de expressão entre as isoformas de AQP4 no tecido normal é maior do que em alguns tumores, a diminuição dessa razão é devida à diminuição da expressão de M23 ou ao aumento da isoforma M1. Conclusão: Novos estudos são necessários para compreender a fisiologia e a fisiopatologia da AQP4 em astrocitomas, a fim de criar propostas terapêuticas efetivas para combater essa doença.

6.
Rev. colomb. reumatol ; 29(4)oct.-dic. 2022.
Article in English | LILACS | ID: biblio-1536219

ABSTRACT

Optic neuromyelitis (ONM), also called neuromyelitis optica spectrum (Neuromyelitis Optica Spectrum Disorders, NMOSD) is recognized as an inflammatory autoimmune demyelinating disease of the central nervous system, mediated by autoantibodies against the aquaporin-4 receptor (AQP4-IgG). It predominantly affects the optic nerves and the spinal cord.1-3 It is known that patients with immune disorders are more likely to present other autoimmune diseases, but the relation between juvenile idiopathic arthritis and ONM has not been completely described.5 In this paper, we report a case of a patient with juvenile idiopathic arthritis, presenting with a rapidly progressive neurological condition, who is treated with biological drugs.1-4


La neuromielitis óptica (NMO), también llamada espectro de la neuromielitis óptica (neuromyelitis optica spectrum disorders) se reconoce como una enfermedad inflamatoria, autoinmune, desmielinizante del sistema nervioso central, mediada por autoanticuerpos contra el receptor de acuaporina 4 (AQP4-IgG) que afecta predominantemente a los nervios ópticos y la médula espinal1-3. Es conocido que los pacientes con trastornos inmunitarios tienen más probabilidades de presentar otras enfermedades autoinmunes; sin embargo, no está completamente descrita la asociación entre artritis idiopática juvenil y NMO5. En este escrito se reporta el caso de una paciente que cursa con artritis idiopática juvenil, inició con compromiso neurológico rápidamente progresivo, y es tratada con medicamentos biológicos1-4.


Subject(s)
Humans , Female , Middle Aged , Musculoskeletal Diseases , Arthritis , Arthritis, Juvenile , Proteins , Carrier Proteins , Amino Acids, Peptides, and Proteins
7.
Neurotox Res ; 40(5): 1337-1347, 2022 Oct.
Article in English | MEDLINE | ID: mdl-36057040

ABSTRACT

Methylglyoxal (MG) is a reactive dicarbonyl compound formed mostly via the glycolytic pathway. Elevated blood glucose levels can cause MG accumulation in plasma and cerebrospinal fluid in patients with diabetes mellitus and Alzheimer's disease. Under these disease conditions, the high reactivity of MG leads to modification of proteins and other biomolecules, generating advanced glycation end products (AGEs), which are considered mediators in neurodegenerative diseases. We investigated the integrity of the blood-brain barrier (BBB) and astrocyte response in the hippocampus to acute insult induced by MG when it was intracerebroventricularly administered to rats. Seventy-two hours later, BBB integrity was lost, as assessed by the entry of Evans dye into the brain tissue and albumin in the cerebrospinal fluid, and a decrease in aquaporin-4 and connexin-43 in the hippocampal tissue. MG did not induce changes in the hippocampal contents of RAGE in this short interval, but decreased the expression of S100B, an astrocyte-secreted protein that binds RAGE. The expression of two important transcription factors of the antioxidant response, NF-κB and Nrf2, was unchanged. However, hemeoxigenase-1 was upregulated in the MG-treated group. These data corroborate the idea that hippocampal cells are targets of MG toxicity and that BBB dysfunction and specific glial alterations induced by this compound may contribute to the behavioral and cognitive alterations observed in these animals.


Subject(s)
Aquaporins , Pyruvaldehyde , Albumins/metabolism , Animals , Antioxidants/metabolism , Aquaporins/metabolism , Blood Glucose/metabolism , Blood-Brain Barrier/metabolism , Connexins/metabolism , Glycation End Products, Advanced/toxicity , Hippocampus/metabolism , NF-E2-Related Factor 2/metabolism , NF-kappa B/metabolism , Pyruvaldehyde/pharmacology , Rats , Receptor for Advanced Glycation End Products/metabolism
8.
mBio ; 13(5): e0188622, 2022 10 26.
Article in English | MEDLINE | ID: mdl-36036510

ABSTRACT

Pneumococcal meningitis, inflammation of the meninges due to an infection of the Central Nervous System caused by Streptococcus pneumoniae (the pneumococcus), is the most common form of community-acquired bacterial meningitis globally. Aquaporin 4 (AQP4) water channels on astrocytic end feet regulate the solute transport of the glymphatic system, facilitating the exchange of compounds between the brain parenchyma and the cerebrospinal fluid (CSF), which is important for the clearance of waste away from the brain. Wistar rats, subjected to either pneumococcal meningitis or artificial CSF (sham control), received Evans blue-albumin (EBA) intracisternally. Overall, the meningitis group presented a significant impairment of the glymphatic system by retaining the EBA in the CSF compartments compared to the uninfected sham group. Our results clearly showed that during pneumococcal meningitis, the glymphatic system does not function because of a detachment of the astrocytic end feet from the blood-brain barrier (BBB) vascular endothelium, which leads to misplacement of AQP4 with the consequent loss of the AQP4 water channel's functionality. IMPORTANCE The lack of solute drainage due to a dysfunctional glymphatic system leads to an increase of the neurotoxic bacterial material in the CSF compartments of the brain, ultimately leading to brain-wide neuroinflammation and neuronal damage with consequent impairment of neurological functions. The loss of function of the glymphatic system can therefore be a leading cause of the neurological sequelae developing post-bacterial meningitis.


Subject(s)
Glymphatic System , Meningitis, Pneumococcal , Animals , Rats , Albumins/metabolism , Aquaporin 4/genetics , Aquaporin 4/metabolism , Astrocytes/metabolism , Brain/metabolism , Glymphatic System/metabolism , Meningitis, Pneumococcal/metabolism , Rats, Wistar
9.
Mol Neurobiol ; 59(6): 3738-3754, 2022 Jun.
Article in English | MEDLINE | ID: mdl-35381889

ABSTRACT

Iron deficiency anemia is a prevalent health problem among pregnant women and infants, particularly in the developing countries that causes brain development deficits and poor cognitive outcomes. Since tissue iron depletion may impair myelination and trigger cellular hypoxic signaling affecting blood vessels, we studied myelination and the neurovascular unit (NVU) in infant rats born to mothers fed with an iron deficient (ID) or control diet from embryonic day 5 till weaning. Blood samples and brains of rat pups at postnatal day (PND) 14 and 30 were analyzed. PND 14 ID rats had severe microcytic hypochromic anemia that was almost reversed at PND 30 although hypomyelination and astrocyte immature phenotype in the corpus callosum were significant at that age. In CA1 hippocampal region, PND 14 and PND 30 ID rats showed significant reduced expression of the receptor ß of the platelet-derived growth factor localized in pericytes and associated to aquaporin 4 (AQP4) immunopositive capillaries. Shorter AQP4 + capillaries and reduced AQP4 expression were also evidenced in PND 14 and PND 30 ID rats. In addition, pericyte membrane permeability through large-pore channels was transiently increased in ID rats at PND 14 but not at PND 30, while the blood-brain barrier permeability was not affected. Remarkably, transient increased pericyte permeability found in PND 14 ID rats was not directly related to iron depletion, suggesting the involvement of other iron deficiency anemia-induced mechanisms. In summary, severe ID during gestation and lactation produces persistent hypomyelination and significantly affects hippocampal pericytes and astrocytes in the NVU which may trigger impaired neurovascular function.


Subject(s)
Anemia, Iron-Deficiency , Iron Deficiencies , Anemia, Iron-Deficiency/complications , Anemia, Iron-Deficiency/metabolism , Animals , Animals, Newborn , Female , Hippocampus/metabolism , Humans , Iron/metabolism , Lactation , Pregnancy , Rats
10.
BMC Neurol ; 22(1): 95, 2022 Mar 16.
Article in English | MEDLINE | ID: mdl-35296261

ABSTRACT

INTRODUCTION: Neuromyelitis optica spectrum disorders (NMOSD) is a rare inflammatory and demyelinating disease of the central nervous system (CNS) more frequent in women and Afro-descendants. No previous epidemiological or prognostic study has been conducted in the region of the state of Bahia, Brazilian Northeast. OBJECTIVE: To evaluate clinical and prognostic aspects in patients with NMOSD from a cohort in northeastern Brazil. MATERIAL AND METHODS: A single-center retrospective study was conducted with consecutive patients diagnosed with NMOSD. Clinical and epidemiological characteristics were described. The degree of disability was expressed by the Expanded Disability Status Scale (EDSS). Worsening disability were analyzed through negative binomial regression adjusted for disease duration. RESULTS: Ninety-one patients were included, 72 (79.1%) female and 67 (73.6%) afro descendants. Mean age at onset was 36 (± 14) years and 73.3% were anti-aquaporin-4 antibody positive. Isolated transverse myelitis (32.9%) and isolated optic neuritis (22.4%) were the most frequent initial clinical syndromes. After multivariate analysis, optic neuritis (RR = 0.45; 95% CI = 0.23 - 0.88; p = 0.020) and dyslipidemia (RR = 0.40; 95% CI = 0.20 - 0.83; p = 0.014) were associated with slower disease progression. Area postrema involvement (RR = 6.70; 95% CI = 3.31 - 13.54; p < 0.001) and age at onset (RR = 1.03; 95% CI = 1.01 - 1.05; p = 0.003) were associated with faster disease progression. CONCLUSIONS: In the first clinical and prognostic study in northeastern Brazil, we identified area postrema involvement, age at onset, optic neuritis at fist syndrome and dyslipidemia as the main prognostic factors associated with disease progression.


Subject(s)
Neuromyelitis Optica , Adult , Aquaporin 4 , Brazil/epidemiology , Female , Humans , Male , Middle Aged , Neuromyelitis Optica/complications , Neuromyelitis Optica/diagnosis , Neuromyelitis Optica/epidemiology , Prognosis , Retrospective Studies , Young Adult
11.
Nanomedicine ; 41: 102531, 2022 04.
Article in English | MEDLINE | ID: mdl-35114406

ABSTRACT

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory and autoimmune disease whose biomarker is the anti-AQP4-IgG autoantibody that binds to aquaporin-4 (AQP4) protein. We introduced a nanosensor with a sensitivity of 84.6%, higher than the CBA's 76.5%. Using silver nanoparticles (AgNPs), we detected not only seropositive but also some false-negative patients previously classified with CBA. It consisted of AgNPs coated with one of a panel of 5 AQP4 epitopes. The ability in detecting the anti-AQP4-IgG in NMOSD patients depended on the epitope and synergy could be obtained by combining different epitopes. We demonstrated that NMOSD patients could easily be distinguished from healthy subjects and patients with multiple sclerosis. Using the most sensitive AQP461-70 peptide, we established a calibration curve to estimate the concentration of anti-AQP4-IgG in seropositive NMOSD patients. The ability to enhance the accuracy of the diagnosis may improve the prognosis of 10-27% of anti-AQP4-IgG seronegative patients worldwide.


Subject(s)
Metal Nanoparticles , Neuromyelitis Optica , Aquaporin 4 , Colorimetry , Humans , Immunoglobulin G , Neuromyelitis Optica/diagnosis , Silver
12.
J Neuroinflammation ; 18(1): 208, 2021 Sep 16.
Article in English | MEDLINE | ID: mdl-34530847

ABSTRACT

Neuromyelitis optica (NMO) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) characterized by acute optic neuritis (ON) and transverse myelitis (TM). NMO is caused by a pathogenic serum IgG antibody against the water channel aquoporin 4 (AQP4) in the majority of patients. AQP4-antibody (AQP4-ab) presence is highly specific, and differentiates NMO from multiple sclerosis. It binds to AQP4 channels on astrocytes, triggering activation of the classical complement cascade, causing granulocyte, eosinophil, and lymphocyte infiltration, culminating in injury first to astrocyte, then oligodendrocytes followed by demyelination and neuronal loss. NMO spectrum disorder (NMOSD) has recently been defined and stratified based on AQP4-ab serology status. Most NMOSD patients experience severe relapses leading to permanent neurologic disability, making suppression of relapse frequency and severity, the primary objective in disease management. The most common treatments used for relapses are steroids and plasma exchange.Currently, long-term NMOSD relapse prevention includes off-label use of immunosuppressants, particularly rituximab. In the last 2 years however, three pivotal clinical trials have expanded the spectrum of drugs available for NMOSD patients. Phase III studies have shown significant relapse reduction compared to placebo in AQP4-ab-positive patients treated with satralizumab, an interleukin-6 receptor (IL-6R) inhibitor, inebilizumab, an antibody against CD19+ B cells; and eculizumab, an antibody blocking the C5 component of complement. In light of the new evidence on NMOSD pathophysiology and of preliminary results from ongoing trials with new drugs, we present this descriptive review, highlighting promising treatment modalities as well as auspicious preclinical and clinical studies.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Autoantibodies/metabolism , Immunosuppressive Agents/therapeutic use , Neuromyelitis Optica/drug therapy , Neuromyelitis Optica/metabolism , Animals , Antibodies, Monoclonal, Humanized/pharmacology , Aquaporin 4/immunology , Aquaporin 4/metabolism , Astrocytes/drug effects , Astrocytes/immunology , Astrocytes/metabolism , Autoantibodies/drug effects , Autoantibodies/immunology , Azathioprine/pharmacology , Azathioprine/therapeutic use , Clinical Trials, Phase III as Topic/methods , Humans , Immunosuppressive Agents/pharmacology , Neuromyelitis Optica/immunology
13.
J Neuroimmunol ; 360: 577697, 2021 11 15.
Article in English | MEDLINE | ID: mdl-34461359

ABSTRACT

Zika virus (ZIKV) infection has been associated with the development of Neuromyelitis Optica Spectrum Disorder (NMOSD). ZIKV-induced antibodies that putatively cross-react to aquaporin-4 (AQP4) protein are suggested to cause inflammation of the optic nerve. A region of similarity between AQP4 and the ZIKV NS2B protein was identified. Our data showed that ZIKV-associated NMOSD patients develop anti-AQP4 antibodies, but not anti-ZIKV NS2B antibodies, revealing that cross-reacting antibodies are not the underlying cause of this phenotype. ZIKV infection in mice showed persistent viral replication in the eye tissue, suggesting that NMOSD symptoms are consequence of viral infection of the optic nerve cells.


Subject(s)
Antibodies, Viral/immunology , Aquaporin 4/immunology , Autoantibodies/immunology , Neuromyelitis Optica/immunology , Zika Virus/immunology , Animals , Antibodies, Viral/blood , Autoantibodies/blood , Cross Reactions , Epitopes/immunology , Humans , Immunoglobulin G/blood , Immunoglobulin G/immunology , Mice , Mice, Inbred C57BL , Molecular Mimicry , Neuromyelitis Optica/etiology , Optic Nerve/virology , Viral Nonstructural Proteins/immunology , Virus Replication , Zika Virus/physiology , Zika Virus Infection/complications , Zika Virus Infection/immunology , Zika Virus Infection/virology
14.
Mol Neurobiol ; 58(10): 5178-5193, 2021 Oct.
Article in English | MEDLINE | ID: mdl-34263427

ABSTRACT

Aquaporin-4 (AQP4) is the target of the specific immunoglobulin G autoantibody (AQP4-IgG) produced in patients with neuromyelitis optica spectrum disorders (NMOSD). Previous studies demonstrated that AQP4-IgG binding to astrocytic AQP4 leads to cell-destructive lesions. However, the early physiopathological events in Müller cells in the retina are poorly understood. Here, we investigated the consequences of AQP4-IgG binding to AQP4 of Müller cells, previous to the inflammatory response, on two of AQP4's key functions, cell volume regulation response (RVD) and cell proliferation, a process closely associated with changes in cell volume. Experiments were performed in a human retinal Müller cell line (MIO-M1) exposed to complement-inactivated sera from healthy volunteers or AQP4-IgG positive NMOSD patients. We evaluated AQP4 expression (immunofluorescence and western blot), water permeability coefficient, RVD, intracellular calcium levels and membrane potential changes during hypotonic shock (fluorescence videomicroscopy) and cell proliferation (cell count and BrdU incorporation). Our results showed that AQP4-IgG binding to AQP4 induces its partial internalization, leading to the decrease of the plasma membrane water permeability, a reduction of swelling-induced increase of intracellular calcium levels and the impairment of RVD in Müller cells. The loss of AQP4 from the plasma membrane induced by AQP4-IgG positive sera delayed Müller cells' proliferation rate. We propose that Müller cell dysfunction after AQP4 removal from the plasma membrane by AQP4-IgG binding could be a non-inflammatory mechanism of retinal injury in vivo, altering cell volume homeostasis and cell proliferation and consequently, contributing to the physiopathology of NMOSD.


Subject(s)
Aquaporin 4/blood , Cell Membrane/metabolism , Ependymoglial Cells/metabolism , Immunoglobulin G/metabolism , Neuromyelitis Optica/blood , Retina/metabolism , Aquaporin 4/administration & dosage , Biomarkers/blood , Cell Line, Transformed , Cell Membrane/pathology , Cell Proliferation/physiology , Cell Size , Ependymoglial Cells/pathology , Homeostasis/physiology , Humans , Immunoglobulin G/administration & dosage , Neuromyelitis Optica/pathology , Retina/injuries , Retina/pathology
15.
Int. j. morphol ; 39(1): 64-69, feb. 2021. ilus, tab, graf
Article in English | LILACS | ID: biblio-1385315

ABSTRACT

SUMMARY: The expression of aquaporin-1 (AQP1) in choroid plexus and aquaporin-4 (AQP4) in astrocyte of the hippocampal formation (HF) was studied in the rat to determine the role of AQP1 and AQP4 in the pathophysiology of systemic hyponatremia (SH). SH was induced by coadministration of dextrose solution intraperitoneally and through subcutaneous implantation of an osmotic minipump containing 8-deamino-arginin vasopressin (50ng/µl/h) for 24 and 48 h. Twenty- four and 48 h after the drug administration, there were significant reductions in Na+ concentration (111 ± 5 and 104 ± 2 mmol) and serum osmolarity (240 ± 13 and 221 ± 14 mOsm/L) as compared with control values (140 ± 4.7 mmol and 296 ± 5.2 mOsm/L), (p<0.01). The expression of AQP1 in the choroid plexus was increased three to five times from 24 h to 48 h after SH (329.86 ± 10.2 % and 531.5 ± 4.4 %, n=4, p<0.01). In contrast, AQP4 expression was significantly decreased up to 48 h after SH (36 ± 9 %, n=4, p<0.01). Quantitative immunoblotting revealed significant decreases of neuronal proteins in the HF after 24 to 48 h of SH. Therefore, we suggest that altered expression of AQP1 and AQP4 plays important role in the pathogenesis of systemic hyponatremia.


RESUMEN: En este análisis se estudió la expresión de acuaporina-1 (AQP1) en plexo coroideo y acuaporina-4 (AQP4) en astrocitos de la formación hipocampal (FH) en ratas para determinar el papel de AQP1 y AQP4 en la fisiopatología de la hiponatremia sistémica (HS). La HS fue inducida mediante la coadministración de solución de dextrosa por vía intraperitoneal y mediante la implantación subcutánea de una minibomba osmótica que contenía vasopresina 8-desaminoarginina (50 ng /µ l / h) durante 24 y 48 h. Veinticuatro y 48 h después de la administración del fármaco, hubo reducciones significativas en la concentración de Na + (111 ± 5 y 104 ± 2 mmol) y la osmolaridad sérica (240 ± 13 y 221 ± 14 mOsm /µL) en comparación con los valores de control (140 ± 4,7 mmol y 296 ± 5,2 mOsm / L), (p <0,01). La expresión de AQP1 en el plexo coroideo se incrementó de tres a cinco veces de 24 a 48 h después de HS (329,86 ± 10,2 % y 531,5 ± 4,4 %, n = 4, p <0,01). Por el contrario, la expresión de AQP4 se redujo significativamente hasta 48 h después de HS (36 ± 9 %, n = 4, p <0,01). La inmunotransferencia cuantitativa reveló disminuciones significativas de proteínas neuronales en el FH después de 24 a 48 h de SH. Por lo tanto, sugerimos que la expresión alterada de AQP1 y AQP4 juega un papel importante en la patogénesis de la hiponatremia sistémica.


Subject(s)
Animals , Rats , Brain/metabolism , Aquaporin 1/metabolism , Aquaporin 4/metabolism , Hyponatremia/metabolism , Immunoblotting , Rats, Sprague-Dawley , Electrophoresis, Polyacrylamide Gel
16.
Mult Scler Relat Disord ; 49: 102742, 2021 Apr.
Article in English | MEDLINE | ID: mdl-33454601

ABSTRACT

BACKGROUND: Myelin oligodendrocyte glycoprotein antibodies (MOG-ab) have been described in aquaporin-4-antibodies(AQP4-ab)-negative neuromyelitis optica spectrum disorder (NMOSD) patients. We aimed to evaluate the percentage of AQP4-ab-negative NMOSD patients who are positive for MOG-ab in a cohort of Argentinean patients included in RelevarEM (Clinical Trials registry number NCT03375177). METHODS: RelevarEM is a longitudinal, strictly observational multiple sclerosis (MS) and NMOSD registry in Argentina. Of 3031 consecutive patients (until March 2020), 165 patients with phenotype of suspected NMOSD, whose relevant data for the purpose of this study were available, were included. Data on demographic, clinical, paraclinical and treatment in AQP4-ab (positive, negative and unknown) and MOG-ab (positive and negative) patients were evaluated. RESULTS: A total of 165 patients (79 AQP4-Ab positive, 67 AQP4-Ab negative and 19 unknown) were included. Of these, 155 patients fulfilled the 2015 NMOSD diagnostic criteria. Of 67 AQP4-Ab-negative patients, 36 (53.7%) were tested for MOG-Ab and 10 of them (27.7%) tested positive. Serum AQP4-ab levels were tested by means of cell-based assay (CBA) in 48 (35.2%), based on tissue-based indirect immunofluorescence assays in 58 (42.6%) and enzyme-linked immunosorbent assay in 4 (2.9%). All MOG-ab were tested by CBA. Optic neuritis (90%) was the most frequent symptom at presentation and optic nerve lesions the most frequent finding (80%) in neuroimaging of MOG-ab-associated disease. Of these, six (60%) patients were under immunosuppressant treatments at latest follow-up. CONCLUSION: We observed that 27.7% (10/36) of the AQP4-ab-negative patients tested for MOG-ab were positive for this antibody, in line with results from other world regions.


Subject(s)
Multiple Sclerosis , Neuromyelitis Optica , Aquaporin 4 , Argentina/epidemiology , Autoantibodies , Humans , Multiple Sclerosis/diagnosis , Multiple Sclerosis/epidemiology , Myelin-Oligodendrocyte Glycoprotein , Neuromyelitis Optica/diagnostic imaging , Neuromyelitis Optica/epidemiology , Registries
17.
Mult Scler ; 27(6): 973-976, 2021 05.
Article in English | MEDLINE | ID: mdl-32909895

ABSTRACT

Neurologic complications are being recognized as important outcomes of coronavirus disease 2019 (COVID-19). Pathogenesis is varied and incompletely understood, and may include neuroinvasion, indirect post-infectious neuroinflammation, and cerebrovascular pathologies. We present a case of COVID-19-related encephalomyeloradiculitis with clinical and magnetic resonance imaging characteristics of neuromyelitis optica spectrum disorders that was associated with anti-aquaporin-4 antibodies. Our case suggests post-infectious autoimmunity as a mechanism in at least a subset of patients with COVID-19-related neurologic disease.


Subject(s)
Aquaporin 4/immunology , Autoantibodies/analysis , Autoimmune Diseases/etiology , COVID-19/complications , Encephalomyelitis/etiology , Radiculopathy/etiology , Azathioprine/therapeutic use , Brain/diagnostic imaging , COVID-19/diagnostic imaging , Encephalomyelitis/diagnostic imaging , Encephalomyelitis/immunology , Female , Humans , Immunosuppressive Agents/therapeutic use , Magnetic Resonance Imaging , Middle Aged , Neuromyelitis Optica/diagnostic imaging , Neuromyelitis Optica/etiology , Plasma Exchange , Radiculopathy/diagnostic imaging , Radiculopathy/immunology , Spine/diagnostic imaging
18.
Mult Scler Relat Disord ; 48: 102683, 2021 Feb.
Article in English | MEDLINE | ID: mdl-33338945

ABSTRACT

BACKGROUND: Neuromyelitis Optica Spectrum Disorder (NMOSD) is a severe inflammatory demyelinating disease of the central nervous system that often causes disability. Based on evidence from prospective and retrospective studies, Rituximab (RTX) has been used as the first-line of therapy in NMOSD. Nevertheless, evidence of the impact of RTX on relapse rate and disability in Ecuadorian patients with NMOSD is lacking. OBJECTIVE: To evaluate the impact of RTX in an Ecuadorian cohort of patients with NMOSD. MATERIALS AND METHODS: A retrospective study was conducted in a cohort of patients with NMOSD who received treatment with RTX in a third-level hospital in Quito, Ecuador. Digital medical records of NMOSD patients were reviewed to attain sociodemographic data, disease characteristics, and treatment with RTX. The annualized relapse rate ARR, as well as the degree of disability measured through the expanded disability scale (EDSS), was established before and after treatment. RESULTS: Twenty-three patients with NMOSD treated with RTX were included, the mean age of onset of the disease was 37.2 years (range, 13-64.5). The average duration of disease was 8.5 years (range, 1.3-34.4). Positivity for antibodies against aquaporin-4 (AQP4-IgG) was identified in 78% of the patients. The mean duration of the treatment with RTX was 40 months (range, 12-61). After the RTX therapy, the number of relapses was reduced in 91% (21/23) of cases. The annualized relapsed rate (ARR) was reduced with RTX from 1.89 to 0.12 (p <0.001). The mean EDSS was also reduced from 4.8 to 3.9 (p = 0.014). In all patients, the mean EDSS was reduced or stabilized with RTX. Overall, the drug was well tolerated, the most frequent adverse events were infections which were present in 65.2% of cases. CONCLUSIONS: Though with the limitations of and observational study, our data support RTX effectiveness and safety in an Ecuadorian cohort of patients with NMOSD.


Subject(s)
Neuromyelitis Optica , Adolescent , Adult , Aquaporin 4 , Ecuador/epidemiology , Humans , Immunologic Factors/therapeutic use , Middle Aged , Neuromyelitis Optica/drug therapy , Neuromyelitis Optica/epidemiology , Prospective Studies , Recurrence , Retrospective Studies , Rituximab/therapeutic use , Young Adult
19.
Neurologia (Engl Ed) ; 2020 Nov 05.
Article in English, Spanish | MEDLINE | ID: mdl-33162220

ABSTRACT

INTRODUCTION: Neuromyelitis optica (NMO) is an inflammatory disease of the central nervous system characterised by attacks of optic neuritis and longitudinally extensive transverse myelitis. The discovery of anti-aquaporin-4 (anti-AQP4) antibodies and specific brain MRI findings as diagnostic biomarkers have enabled the recognition of a broader and more detailed clinical phenotype, known as neuromyelitis optica spectrum disorder (NMOSD). OBJECTIVE: This study aimed to determine the demographic and clinical characteristics of patients with NMO/NMOSD with and without seropositivity for anti-AQP4 antibodies, in 2 quaternary-level hospitals in Bogotá. METHODS: Our study included patients > 18 years of age and diagnosed with NMO/NMOSD and for whom imaging and serology results were available, assessed between 2013 and 2017 at the neurology departments of hospitals providing highly complex care. Demographic, clinical, and imaging data were gathered and compared in patients with and without seropositivity for anti-AQP4 antibodies. RESULTS: The sample included 35 patients with NMO/NMOSD; the median age of onset was 46.5 years (P25-P75, 34.2-54.0); most patients had sensory (n = 25) and motor manifestations (n = 26), and a concomitant autoimmune disease was identified in 6. Twenty patients were seropositive for anti-AQP4 antibodies. Only age and presence of optic nerve involvement showed statistically significant differences between groups (p = .03). CONCLUSIONS: Clinical, imaging, and laboratory variables showed no major differences between patients with and without anti-AQP4 antibodies, with the exception of age of onset and presence of optic nerve involvement (uni- or bilateral); these factors should be studied in greater detail in larger populations.

20.
Rev. chil. neuro-psiquiatr ; Rev. chil. neuro-psiquiatr;58(2): 161-170, jun. 2020.
Article in Spanish | LILACS | ID: biblio-1115481

ABSTRACT

Resumen El espectro de Neuromielitis óptica (NMOSD por su sigla en inglés) corresponde a un conjunto de manifestaciones clínicas derivadas de un proceso inflamatorio y desmielinizante del sistema nervioso central, que causa lesiones primariamente en la médula espinal y nervios ópticos, pero también en otras regiones como tronco encefálico, diencéfalo o áreas cerebrales específicas. La mayoría de los pacientes con NMOSD son seropositivos para autoanticuerpos contra AQP4, el principal canal de agua de los astrocitos, sin embargo, existe un porcentaje no despreciable de pacientes, cercano al 25%, quienes son seronegativos para estos anticuerpos y en quienes la presencia de anticuerpos dirigidos contra mielina (anti-MOG) podrían tener un rol patogénico, el cual a la fecha no ha sido bien dilucidado. La evidencia científica actual, ha permitido reconocer que AQP4-IgG es patogénico en NMOSD, probablemente por un mecanismo que involucra citotoxicidad celular dependiente de la activación del complemento, generando infiltración leucocitaria, liberación de citokinas y disrupción de la barrera hemato-encefálica, lo cual lleva a muerte de oligodendrocitos, pérdida de mielina y muerte neuronal. Este artículo presenta una revisión basada en la evidencia, la cual enfatiza los principales aspectos de la patogénesis de NMOSD.


Neuromyelitis Optica Spectrum Disorders (NMOSD) is a set of clinical manifestations derived from an inflammatory and demyelinating process of the central nervous system that causes lesions primarily in spinal cord and optic nerves but also in other regions such as brainstem, diencephalon or specific brain areas. Most patients with NMOSD are seropositive for autoantibodies against AQP4, the major water channel of astrocytes, however there is a non-negligible percentage of patients, close to 25%, who are seronegative for these antibodies and in whom the presence of antibodies directed against myelin (anti-MOG) could have a pathogenic role that to date has not been well elucidated. Current scientific evidence has allowed recognize that AQP4-IgG is pathogenic in NMOSD, probably by a mechanism involving complement dependent cellular cytotoxicity, causing leucocyte infiltration, cytokine release and blood-brain barrier disruption, which leads to oligodendrocyte death, myelin loss and neuron death. This article presents an evidence-based review, which emphasizes the main aspects in NMOSD pathogenesis.


Subject(s)
Humans , Optic Nerve , Brain , Brain Stem , Central Nervous System , Neuromyelitis Optica
SELECTION OF CITATIONS
SEARCH DETAIL