Role of AQP4 in dexmedetomidine-induced reduction of blood-brain barrier permeability in mechanically ventilated mice: relationship with PKC / 中华麻醉学杂志

Objective:To evaluate the role of aquaporin 4 (AQP4) in dexmedetomidine-induced reduction of blood-brain barrier permeability in mechanically ventilated mice and the relationship with protein kinase C (PKC).Methods:One hundred and fifty clean-grade healthy male C57BL6 mice, weighing 20-25 g, aged 8-12 weeks, were divided into 5 groups ( n=30 each) using a random number table method: control group (group C), mechanical ventilation group (group V), LY317615 group (group L), dexmedetomidine group (group D), and dexmedetomidine+ PMA group (group DP). Group C spontaneously breathed air for 6 h. The animals were mechanically ventilated for 6 h in group V. PKC inhibitor LY3176 15 μg/kg was intraperitoneally injected at 30 min before mechanical ventilation in group L. Dexmedetomidine 50 μg/kg was intraperitoneally injected at 30 min before mechanical ventilation in D and DP groups. PKC activator PMA 15 μg/kg was intraperitoneally injected at 60 min before mechanical ventilation in group DP. Mice were anesthetized at 1 day after mechanical ventilation, then sacrificed and hippocampal tissues were taken for microscopic examination of pathological changes in the hippocampal CA1 and CA3 areas (with a light microscope). Brain tissues were also taken to measure the water content and content of Evans blue (EB) and to detect the expression of PKC and AQP4 (by Western blot). The cognitive function was evaluated using a novel object recognition task at 3 days after mechanical ventilation. Results:Compared with group C, the water content and EB content of brain tissues were significantly increased after mechanical ventilation, the expression of PKC and AQP4 in brain tissues was up-regulated, the percentage of novel object exploration and discrimination index were decreased ( P<0.05), and the histopathological damage in the hippocampal CA1 and CA3 areas was aggravated in group V and group DP. Compared with group V, the water content and EB content of brain tissues were significantly decreased after mechanical ventilation, the expression of PKC and AQP4 in brain tissues was down-regulated, the percentage of novel object exploration and discrimination index were increased ( P<0.05), and the histopathological damage in the hippocampal CA1 and CA3 areas was significantly attenuated in group D and group L. Compared with group D, the water content and EB content of brain tissues were significantly increased after mechanical ventilation, the expression of PKC and AQP4 in brain tissues was up-regulated, the percentage of novel object exploration and discrimination index were decreased ( P<0.05), and the histopathological damage in the hippocampal CA1 and CA3 areas was aggravated in group DP. Conclusions:AQP4 is involved in dexmedetomidine-induced reduction of blood-brain barrier permeability in mechanically ventilated mice, and the mechanism is related to inhibiting activation of PKC.

Relationship between omentin-1,AQP4,and VILIP-1 levels and vascular recanalization after emergency endovascular treatment in patients with acute large vessel occlusion stroke / 中国医科大学学报

Objective To investigate the relationship between omentin-1,aquaporin 4(AQP4),and visinin-like protein 1(VILIP-1)levels and vascular recanalization after emergency endovascular treatment in patients with acute large vessel occlusion stroke(ALVOS)and their combined predictive efficacy.Methods In total,110 patients with ALVOS undergoing emergency endovascular treatment were categorized into a non-reopening group(23 patients)and a reopening group(87 patients)based on whether the blood vessels were re-opened after surgery.Clinical data and omentin-1,AQP4,and VILIP-1 levels were compared between the two groups.Factors influencing postoperative blood vessel reopening were analyzed,and nomograms were drawn to evaluate their predictive performance and calibration.Results Significant differences were observed in the proportion of patients with hypertension;preoperative NIHSS scores;emergency blood glucose;AQP4,VILIP-1,omentin-1,and platelet levels;time from onset to endovascular treatment;preoperative ASPECTS;and proportion of patients undergoing intravenous thrombolysis between the two groups(P＜0.05).Preoperative ASPECTS and omentin-1 levels were independent protective factors associated with postoperative vascular recanalization,whereas the time from onset to endovas-cular treatment,preoperative NIHSS scores,and AQP4 and VILIP-1 levels were independent risk factors associated with postoperative vascular recanalization(P＜0.05).The C-index of the nomogram for predicting postoperative vascular recanalization was 0.994,and the AUC of the nomogram for predicting postoperative vascular recanalization was 0.994,with a calibration degree of 0.975.Conclusion Omentin-1,AQP4,and VILIP-1 levels are important factors affecting vascular recanalization in patients with ALVOS after emergency endovascular treatment.Clinically,monitoring these levels may help to predict and evaluate early vascular recanalization fol-lowing treatment.

Research progress on the regulatory mechanisms and influencing factors of blood-brain barrier permeability in optic neuromyelitis spectrum diseases / 中华眼底病杂志

Neuromyelitis spectrum disease (NMOSD) is an immune-mediated inflammatory demyelinating disease of the central nervous system. The breakdown of the blood-brain barrier (BBB), as an important link in the pathogenesis of NMOSD, has an important impact on the occurrence, development and prognosis of the disease. It is generally believed that the aquaporin 4 antibody produced in the peripheral circulation crosses the BBB cause damage to the central nervous system, and there are components involved in the destruction of BBB in the occurrence and development of NMOSD disease. At present, little is known about the molecular mechanism of BBB destruction in NMOSD lesions and there is still a lack of systematic theory. Further research and exploration of the regulatory mechanism of BBB permeability and the manifestation of barrier destruction in NMOSD diseases are of great significance for understanding the pathogenesis of NMOSD, so as to achieve early diagnosis and discover new therapeutic and preventive targets.

Comparative study on radiological features between serum aquaporin 4 antibody positive and negative neuromyelitis optica spectrum disorder / 中华放射学杂志

Objective:To investigate the clinical and imaging differences between serum aquaporin 4 (AQP4) antibody positive and negative patients with neuromyelitis optica spectrum disorder (NMOSD).Methods:The clinical data and radiologic findings of 89 NMOSD patients diagnosed at Beijing Tiantan Hospital, Capital Medical University from January 2018 to June 2022 were retrospectively analyzed. There were 17 male cases and 72 female cases, aged 18-74 years. According to the results of serum AQP4 antibody test, the patients were divided into AQP4 antibody positive group and AQP4 antibody negative group, and the differences in clinical data, lesion distribution, lesion characteristics, and brain area volume between the 2 groups were compared using independent sample t-test and χ 2 test, and the correlation between brain area volume and expanded disability status scale (EDSS) scores was further investigated using Spearman correlation analysis. Results:There were 68 cases in the AQP4 antibody positive group and 21 cases in the AQP4 antibody negative group. Patients in both groups were predominantly female, but the percentage of females in the AQP4 antibody-positive group (86.8%, 59/68) was higher than that in the AQP4 antibody-negative group (61.9%, 13/21), with a statistically significant difference (χ 2=4.91, P=0.027). The incidence of optic neuritis in AQP4 antibody negative group (66.7%, 14/21) was higher than that in antibody positive group (41.2%, 28/68), with a statistically significant difference (χ 2=4.18, P=0.041). In the distribution of intracranial lesions on MRI, the probability of lesions involving the brain stem in AQP4 antibody negative group (47.6%, 10/21) was higher than that in AQP4 antibody positive group (23.5%, 16/68), the difference had statistically significance (χ 2=4.50, P=0.034). The volumes of whole brain white matter, right amygdala, right accumbens-area and right ventral diencephalon in AQP4 antibody positive group were lower than those in AQP4 antibody negative group ( P<0.05), and the volumes of the right accumbens-area were negatively correlated with the EDSS scores in AQP4 antibody positive group ( r=-0.628, P=0.009). Conclusion:There are differences in clinical and imaging manifestations between AQP4 antibody positive and AQP4 antibody negative patients, which provides more basis for clinical in-depth understanding of NMOSD.

Pathogenesis of aquaporin-4 immunoglobulin G positive neuromyelitis optica spectrum disorder / 中华神经科杂志

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune demyelinating disease of the central nervous system characterized by the involvement of the optic nerve and spinal cord. The main clinical features are optic neuritis, acute myelitis, and area postrema syndrome. Aquaporin-4 (AQP4)-IgG-positive patients accounted for the majority and compared with AQP4-IgG-negative patients, the clinical symptoms were more severe, the recurrence was more frequent, and the disability rate was higher. The pathogenesis of AQP4-IgG-positive NMOSD is still not clear. This article reviews the research progress of the pathogenesis of AQP4-IgG-positive NMOSD.

Aquaporin 4 and its Relationship with Brain Astrocytomas ­ Literature Review / Aquaporina 4 e sua Relação com Astrocitomas Cerebrais ­ Revisão da Literatura

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.

Neuromyelitis optica spectrum disorders: a review with a focus on children and adolescents / Espectro da neuromielite óptica: uma revisão com ênfase em crianças e adolescentes

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.

Aquaporin-4 Expression in Meningioma Malignancy Progression / Expressão da aquaporina-4 na progressão da malignidade dos meningiomas

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.

Optic neuromyelitis in relation with juvenile idiopathic arthritis: A case report

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.

Aquaporin-4 protein antibody-associated optic neuritis related to neuroendocrine tumor after receiving an inactive COVID-19 vaccine

Neuromyelitis optica (NMO), also known as Devic’s disease, is a rare, autoimmune, and recurrent demyelinating disorder that primarily affects the spinal cord and optic nerve. We report a case with recurrent optic neuritis caused by the paraneoplastic NMO spectrum disorder in the setting of a gastric neuroendocrine tumor 2 weeks after receiving an inactive COVID?19 vaccine.

Clinico-epidemiologic characteristics of optic neuritis in a tertiary eye centre in Eastern India based on the status of serum aquaporin-4 antibody

Purpose: To elucidate the clinico?epidemiologic characteristics of optic neuritis based on the status of serum aquaporin?4 antibody (AQP4?Ab) in patients with optic neuritis (ON). Methods: Medical records of 106 patients with ON and a follow?up of 3 years were reviewed. For each patient, the following data were extracted: medical history, findings of the ocular examination, brain, orbital or spinal MRI, and serological tests for AQP4. The ON was classified as typical or atypical based on disc examination and improvement in vision after intravenous methylprednisolone (IVMP). The clinical findings (typical or atypical), disease course, and outcomes were analyzed according to the serostatus of the ON. Results: 10 patients ((9.4%) were seropositive for AQP4?Ab; all had atypical ON. 96 patients (91%) were seronegative for AQP4?Ab: 36 atypical ON and 60 typical ON. Profound visual impairment at presentation was seen in all patients. However, at the end of the study period, seropositive and seronegative atypical ON had poor visual outcomes as compared to seronegative typical ON (P = 0.002). Five seropositive and four seronegative patients with atypical ON developed transverse myelitis. Bilateral disease with relapse was more in seropositive patients (80%); however, seronegative with atypical ON also had bilateral presentation and relapse in 42% and 41%, respectively. Conclusion: AQP4?Ab seropositive patients mostly present with atypical features such as bilateral recurrent ON, poor visual outcome, and increased incidence of transverse myelitis. However, atypical clinical features can also be seen in seronegative ON with a poor visual outcome and a recalcitrant course.

A case of AQP4-IgG-negative neuromyelitis optica spectrum disorders with initial clinical manifestation of painful trigeminal neuropathy and literature review / 中国医师杂志

Objective:To explore the clinical manifestations and imaging of neuromyelitis optica spectrum disorders (NMOSD) with negative aquaporin-4 immunoglobulin G antibody (AQP4-IgG) with initial clinical manifestation of painful trigeminal neuropathy.Methods:The symptoms, signs, imaging examinations, diagnosis and treatment of a case of AQP4-IgG-negative NMOSD in neurology department of Affiliated Hospital of Southwest Medical University were reported and the relevant literatures were reviewed.Results:In the first episode, the patient started with right-sided facial pain with segmental paresthesia in the left limb. And In the second episode, the patient started with intractable hiccups and vomiting with weakness and paresthesia in the left limb. Magnetic resonance imaging of the skull and spinal cord revealed that the lesion involved the medulla oblongata and cervical medulla. AQP4 antibody, myelin oligodendrocytes glycoprotein (MOG) antibody, myelin basic protein (MBP) antibody and oligoclonal bands(OCB) of serum and cerebrospinal fluid were negative. The clinical diagnosis was AQP4-IgG-negative NMOSD. After treatments with hormonal anti-inflammatory and analgesic therapy, the patient′s facial pain, sensory abnormalities, hiccups, vomiting and limb weakness improved significantly.Conclusions:Painful trigeminal neuropathy may be the initial clinical manifestation of AQP4-IgG-negative NMOSD. NMOSD of presenting solely with painful trigeminal neuropathy is easy to be misdiagnosed and missed. Magnetic resonance examination is helpful for the early diagnosis of NMOSD.

Role of miR-205-3p in oncosis in astrocytes subjected to oxygen-glucose deprivation and restoration: relationship with AQP4 / 中华麻醉学杂志

Objective:To evaluate the role of miR-205-3p in oncosis in astrocytes subjected to oxygen-glucose deprivation and restoration (OGD/R) and the relationship with aquaporin4 (AQP4).Methods:Primary astrocytes were cultured in vitro to the logarithmic growth phase and divided into 5 groups ( n=16 each) using a random number table method: control group (C group), OGD/R group (O group), OGD/R+ miR-205-3p mimic group (M group), OGD/R+ miR-205-3p inhibitor group (I group), and OGD/R+ negative control group (NC group). Cells were cultured routinely in C group.Cells were subjected to 4 h of oxygen-glucose deprivation in a 37℃ anaerobic incubator (containing 94% N 2, 1% O 2 and 5% CO 2) followed by restoration of O 2-glucose supply for 24 h in O group.Cells in M, I and NC groups were transfected with miR-205-3p mimic, miR-205-3p inhibitor and miR-205-3p negative control for 48 h, respectively, and then cells were subjected to 4 h of oxygen-glucose deprivation followed by restoration of O 2-glucose supply for 24 h. The cell viability was evaluated by CCK-8 assay, the cell injury and oncosis were analyzed by flow cytometry, the expression of AQP4 mRNA was detected by quantitative reverse transcription-polymerase chain reaction, and the expression of AQP4 and porimin was detected by Western blot. Results:Compared with C group, the expression of miR-205-3p was significantly down-regulated, the cell viability was decreased, the rates of cell injury and oncosis were increased, and the expression of AQP4 protein and mRNA and porimin was up-regulated in O group ( P<0.05). Compared with O group, the expression of miR-205-3p was significantly up-regulated, the cell viability was increased, the rates of cell injury and oncosis were decreased, and the expression of AQP4 protein and mRNA and porimin was down-regulated in M group, the expression of miR-205-3p was significantly down-regulated, the cell viability was decreased, the rates of cell injury and oncosis were increased, and the expression of AQP4 protein and mRNA and porimin was up-regulated in I group ( P<0.05), and no significant changes were found in NC group( P>0.05). Conclusions:miR-205-3p is involved in oncosis in astrocytes subjected to OGD/R, which is associated with regulation of AQP4 expression.

Magnetic resonance imaging characteristics of brain lesions in myelin oligodendrocyte glycoprotein antibody associated demyelinating diseases and aquaporin-4 antibody positive neuromyelitis optica spectrum disorders / 中华神经科杂志

Objective:To investigate the distribution and morphological characteristics of brain magnetic resonance imaging (MRI) lesions in patients with myelin oligodendrocyte glycoprotein (MOG) antibody related demyelinating diseases and aquaporin-4 (AQP4) antibody positive neuromyelitis optica spectrum disorders (NMOSD) and their clinical value in early diagnosis.Methods:A total of 35 patients with MOG antibody related demyelinating diseases [20 males and 15 females; aged 31 (25, 43) years] and 36 patients with AQP4 antibody positive NMOSD [3 males and 33 females; aged 42 (29, 54) years] were collected retrospectively from September 2018 to June 2021 in Chenzhou First People′s Hospital and the Affiliated Hospital of Qingdao University which were classified as MOG group and AQP4 positive group respectively. All patients underwent routine cranial MRI scanning before treatment and the location, shape and quantity of intracranial lesions were recorded. Wilcoxon rank sum test was used to compare the number of different types of lesions between the two groups. Logistic regression analysis was used to evaluate the significance of different lesions for the two diseases.Results:There were 7 types of lesions with significant differences in different parts and shapes. Stepwise Logistic regression showed that cortical and juxtacortical lesions ( OR=21.91, 95% CI 3.09-61.69, P<0.05) and infratentorial peripheral white matter lesions ( OR=10.48, 95% CI 2.00-18.89, P<0.05) were the most important risk factors in the MOG group. The incidence of cortical and juxtacortical lesions in the MOG group was 51.4% (18/35), which was higher than that in the AQP4 positive group (2.8%, 1/36; χ2=19.02, P<0.01). The incidence of infratentorial peripheral white matter lesions in the MOG group was 31.4% (11/35), which was higher than that in the AQP4 positive group (5.6%, 2/36; χ2=6.31, P<0.05). Receiver operating characteristic (ROC) curve showed that peripheral lesions [including 6 types of lesions such as supratentorial soft meningitis, cortical encephalitis, cortical and juxtacortical lesions, infratentorial soft meningitis, infratentorial soft meningeal demyelination and infratentorial peripheral lesions, area under curve (AUC)=0.93] were more important than cortical and juxtacortical lesions (AUC=0.75) and central lesions (supratentorial paraventricular white matter lesions, diencephalon, infratentorial paraventricular lesions,AUC=0.64), which had higher diagnostic efficiency. Conclusions:The incidence of intracranial lesions in MOG antibody related demyelinating disease was higher than that in AQP4 positive NMOSD, and the distribution and morphology of intracranial MRI lesions in the two diseases had their characteristic manifestations. Identifying the distribution patterns of peripheral lesions (distributed along pia mater) and central lesions (distributed along ependyma) had a certain reference significance for distinguishing the two groups of diseases.

Glymphatic system in Parkinson′s disease / 中华神经科杂志

Parkinson′s disease is a degenerative disease of the central nervous system with abnormal protein deposition in the brain as the main pathological changes. The onset of Parkinson′s disease is related to abnormal deposition protein removal disorders, and the relevant mechanisms are still unclear. The glymphatic system is a metabolic waste and abnormal protein deposition removal system in the brain. In recent years, studies have shown that the changes of aquaporin 4, perivascular space and dural lymphatic vessels in Parkinson′s disease are closely related to the level of relevant pathological proteins in cerebrospinal fluid, leading to the occurrence and development of Parkinson′s disease. The researches on structure and biomarkers of the glymphatic system in Parkinson′s disease in recent years are reviewed in this article.

Glymphatic system and cerebral edema after ischemic stroke / 国际脑血管病杂志

Glymphatic system is a fluid transport and material clearance system found in recent years. It promotes the flow and exchange of cerebrospinal fluid and interstitial fluid, remove metabolic waste, and maintain the stability of the internal environment of the brain through the perivascular space and aquaporin 4 on astrocytes. Recent studies have shown that the glymphatic system plays an important role in the intake and discharge of the fluid in brain, and the changes of glymphatic system may be an important reason for brain edema after ischemic stroke. This article reviews the pathophysiological mechanism and related therapeutic targets of glymphatic system in the formation of cerebral edema after ischemic stroke, in order to provide new ideas for the treatment of cerebral edema after ischemic stroke.

Relapse risk analysis in anti-aquaporin 4-IgG positive neuromyelitis optica spectrum disorders patients treated with immunosuppressant / 中华神经科杂志

Objective:To investigate the relapse risk factors of anti-aquaporin 4 (AQP4)-IgG positive neuromyelitis optica spectrum disorders (NMOSD) patients treated with immunosuppressant.Methods:Data (from January 2011 to June 2021) of AQP4-IgG positive NMOSD patients treated with immunosuppressant for longer than 5 years from MSNMObase, a hospital-based electronic registry for multiple sclerosis and related disorders in Peking Union Medical College Hospital, were collected. Clinical features and risk factor differences between patients with and without relapse under the immunosuppressive therapy were analyzed.Results:One hundred and twelve patients with AQP4-IgG positive NMOSD were included, 105 (93.8%) of which were female. The disease onset age was (34.9±11.3) years, 13(11.6%) had an older disease onset age than 50 years (late onset), and the disease duration was 8.1 (6.6, 11.4) years. Sixty-four (57.1%) patients had relapse, and the proportion of late onset patients was significantly lower in relapse group than in non-relapse group [4/64(6.3%) vs 9/48(18.8%), χ2=4.18, P=0.041]. Compared with those without relapse, both the annualized relapse rate (ARR) before treatment [1.07 (0.36, 2.25) vs 0.34 (0, 1.11), Z=2.92, P=0.003] and the proportion of patients with relapse before treatment [54/64(84.4%) vs 33/48(68.8%), χ2=3.86, P=0.049] were significantly higher for patients in relapse group. Multivariate Logistic regression analysis revealed the relapse risk of late-onset patients was lower than that of early-onset patients ( HR=0.26, 95% CI 0.10-0.73, P=0.010) and patients with higher ARR before treatment showed a higher risk of relapse under the immunosuppressive therapy ( HR=1.55,95% CI 1.26-1.91, P<0.001). Conclusion:AQP4-IgG positive NMOSD patients with younger disease onset age than 50 years or with frequent relapses before treatment had a higher relapse risk under the immunosuppressive therapy, and they may need highly effective treatments.

Neuromyelitis optica spectrum disorders / 中华神经科杂志

Neuromyelitis optica spectrum disorders (NMOSD) is an immune mediated inflammatory demyelinating disease of the central nervous system. Optic neuritis and longitudinally extensive transverse myelitis are the main clinical signs, and the etiology is mainly related to aquaporin 4 (AQP4) antibody. AQP4 is the target antigen of immune attack. NMOSD is characterized by optic neuritis, longitudinally extended transverse myelitis, medulla area postrema syndrome, brainstem syndrome, diencephalic syndrome and cerebral syndrome. In recent years, the etiological mechanism, clinical diagnosis and monoclonal antibodies targeting new mechanisms of NMOSD have made great progress, which promoted the development of clinical neurology.

Effect of p38 mitogen-activated protein kinase pathway on hydrocephalus and aquaporin 4 expression in rats / 中华神经医学杂志

Objective:To observe the regulatory effect of p38 mitogen-activated protein kinase (p38 MAPK) on aquaporin 4 (AQP4) in rats after hydrocephalus, and to explore its significance in hydrocephalus prevention.Methods:Fifty SD rats were randomly divided into sham-operated group ( n=10), hydrocephalus group ( n=20), and hydrocephalus+inhibitor (SB203580) group (SB group, n=20). The rat models of hydrocephalus in the latter two groups were prepared by intracerebroventricular injection of kaolin suspension; rats in the sham-operated group were injected with same amount of normal saline into the lateral ventricle. The p38 MAPK specific inhibitor SB203580 (10 mg/kg) was intraperitoneally injected into the rats of SB group on the 8 th d of modeling for 7 consecutive d; same volume of dimethylsulfoxide was given to the rats of hydrocephalus group on the 8 th d of modeling for 7 consecutive d; rats in the sham-operated group did not give any treatment. The severity of hydrocephalus in these rats was observed by MRI. The inflammatory factor tumor necrosis factor (TNF)-α level in the cerebrospinal fluid was detected by enzyme-linked immunosorbent assay (ELISA). The AQP4 and TNF-α mRNA expressions were detected by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). The phosphorylated p38 MAPK and AQP4 expressions in the periventricular brain tissues were detected by Western blotting and immunohistochemistry. Results:No hydrocephalus developed in sham-operated group and hydrocephalus developed in the latter two groups. As compared with sham-operated group, hydrocephalus group and SB group had significantly increased lateral ventricle volume, significantly aggravated periventricular edema, significantly higher EVAN's index, and statistically increased brain water content ( P<0.05). Two weeks after modeling, the TNF-α expression levels in cerebrospinal fluid of sham-operated group, hydrocephalus group and SB group were (20.49±0.96), (42.04±3.17), and (28.00±3.71) pg/mL, respectively, with significant differences ( F=186.000, P<0.001); the TNF-α expression level in SB group was significantly higher than that in sham-operated group and significantly lower than that in hydrocephalus group ( P<0.05). Two weeks after modeling, the TNF-α and AQP4 mRNA expression levels in brain tissues of the three groups were significantly different ( P<0.05); the TNF-α and AQP4 mRNA expression levels in hydrocephalus group were significantly higher than those in sham-operated group and SB group ( P<0.05). Correlation analysis showed that there was a positive linear correlation between AQP4 mRNA expression and TNF-α mRNA expression in hydrocephalus group ( r=0.511, P=0.026), and there was a positive linear correlation between AQP4 protein expression and phosphorylated p38 MAPK protein expression in hydrocephalus group and SB group ( r=0.560, P=0.013; r=0.463, P=0.030). Immunohistochemical staining results showed that AQP4 expression was abundant in glial cells of the three groups; the p38 MAPK distribution was uniform and non-polar; the phosphorylated p38 MAPK protein expression in the hydrocephalus group was significantly higher than that in the sham-operated group, and that in the SB group returned to the level of the sham-operated group. Conclusion:The p38 MAPK pathway is involved in the positive regulation of AQP4 expression, which could be inhibited by SB203580.

Recent adanvces in pathogenesis and immunological sequential therapy of neuromyelitis optica spectrum disorder / 中华神经医学杂志

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory demyelinating disease of the central nervous system. Its pathogenesis is complex and mainly related to aquaporin 4 antibody. NMOSD typically follows a relapsing course leading to progressive aggravation of neurological deficits, making prevention of relapse being the key to NMOSD treatment. In addition to traditional non-specific immunosuppressants, new targeted drugs have gradually shown unique advantages in sequential treatment of NMOSD due to their significant efficacy and fewer adverse reactions. This article summarizes and reviews the pathogenesis of NMOSD and the safety and efficacy of immunosequential therapy drugs.