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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.
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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.
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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.
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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.
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Humans , Female , Middle Aged , Musculoskeletal Diseases , Arthritis , Arthritis, Juvenile , Proteins , Carrier Proteins , Amino Acids, Peptides, and ProteinsABSTRACT
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.
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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.
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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.
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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.
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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.
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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.
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Objective:To analyze the clinical features and prognosis factors of aquaporin 4 (AQP4) antibody-positive neuromyelitis optica spectrum disorders related optic neuritis (NMOSD-ON).Methods:An ambidirectional cohort study. From June 1, 2015 to June 1, 2019, 103 patients with AQP4 antibody-positive NMOSD-ON in Department of Neuro-ophthalmology, The First Medical Center of PLA General Hospital were included. All patients of followed-up period were ≥24 months. According to the best corrected visual acuity (BCVA) at the last follow-up, the affected eyes were divided into the low vision group [log of minimum resolution angle (logMAR) BCVA≥1.0] and the non-low vision group (logMAR BCVA<1.0), 66 and 37 cases, respectively. The two groups of patients were compared the genernal clinical characteristics, and the logistic regression model and COX proportional hazard model were used to analyze the relevant factors affecting the patient's visual prognosis and recurrence.Results:Among the 103 cases, 96 cases (93.2%, 96/103) were female; 94 cases (91.3%, 94/103) had unilateral disease; 48 cases (46.6%, 48/103) were the first onset; 85 cases (82.5%, 85/103) were effected by eye pain or orbital pain; 21 cases (20.4%, 21/103) had optic disc edema; 51 cases (49.5%, 51/103) serologically autoimmune antibody test were positive. Orbital magnetic resonance imaging (MRI) was performed in 101 cases. There was no obvious abnormal signal in visual pathways except for 5 cases (5.0%, 5/101); 96 cases (95.0%, 96/101) had abnormal signal in the visual path, and the optic nerve was found in the orbit; 52 cases had abnormal optic nerve in orbital segment (51.5%, 52/101); 37 cases (35.9%, 37/103) recurred within 24 months. The recovery of logMAR BCVA after the first onset and the logMAR BCVA at the first onset, at 6 months of follow-up in two groups were 1.4±1.0, 0.3±0.4, 1.9±0.7 and 0.4±0.5, 2.1±0.6, 0.3±0.4, respectively; and there were statistically significant differences between the two groups of patients at different times ( Z=-4.967,-7.603,-8.027; P<0.001). Logistic regression multivariate analysis showed that recovery of BCVA≥1.0 logMAR after the first onset [odds ratio ( OR)=226.276, P<0.001 ] and the number of attacks ( OR=8.554, P=0.003) were independent risk factors for low vision. Multivariate analysis of the Cox proportional hazards model showed the higher the MRI score [hazard ratio ( HR)=0.588, P=0.007] and plasma exchange ( HR=0.124, P=0.049) in the acute phase were protective factors for recurrence. Conclusions:Vision loss accompanied by eye pain or orbital pain is the main symptom of onset AQP4 antibody-positive NMOSD-ON, a small number of patients have disc edema, 49.5% patients serologically autoimmune antibody test are positive. Abnormal optic nerve signals can be seen in 95.0% of patients in orbital MRI, and 51.5% patients have abnormalities in the orbital optic nerve. The worse the recovery of BCVA after the first onset and the greater the number of attacks are unfavorable factors affecting the prognosis of vision. High MRI scores and plasma exchange in the acute phase are favorable factors to prevent the recurrence of the disease.
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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.
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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.
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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.
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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.
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Animals , Rats , Brain/metabolism , Aquaporin 1/metabolism , Aquaporin 4/metabolism , Hyponatremia/metabolism , Immunoblotting , Rats, Sprague-Dawley , Electrophoresis, Polyacrylamide GelABSTRACT
Objective:To observe the expression of vascular endothelial growth factor (VEGF) and aquaporin 4 (AQP4) in the inner limiting membrane (ILM) of diabetic retinopathy (DR) with macular edema, and analyze the correlation between VEGF and AQP4 expression.Methods:A cross-sectional study. From September 2019 to September 2020, 38 eyes of 38 patients with DR and idiopathic macular hole (iMH) who underwent vitrectomy (PPV) combined with ILM stripping at the Hangzhou campus of The Affiliated Eye Hospital of Wenzhou Medical University at Hangzhou were included in the study. Among them, there were 25 males and 13 females who aged 37-76 years old, average age was 59±10 years old; All eye included 15 right eyes and 23 left eyes. iMH and DR included 9 eyes in 9 cases and 29 eyes in 29 cases, respectively, and they were divided into iMH group and DR group. The DR group was divided into DME group and no DME group according to whether it was accompanied by diabetic macular edema (DME), with 14 eyes and 15 eyes respectively. After the stripped ILM tissue was fixed, immunofluorescence analysis was performed to obtain a picture of the fluorescence mode of AQP4 and VEGF, and the fluorescence intensity value of VEGF and AQP4 was measured by Image J software. The differences of VEGF and AQP4 immunofluorescence values in the specimens between groups were compared by one-way analysis of variance. The correlation between the fluorescence intensity of AQP4 and the fluorescence intensity of VEGF was analyzed by Pearson correlation analysis.Results:The average fluorescence intensity valuesof VEGF and AQP4 in ILM specimens of DME group, no DME group and iMH group were 38.96±7.53, 28.25±3.12, 30.07±4.84 and 49.07±8.73, 37.96±6.45, 38.08±5.04, respectively. The average fluorescence intensity of VEGF and AQP4 in the ILM specimens of the DME group was significantly higher than that of the no DME group and iMH group, and the difference was statistically significant ( F=13.977, 9.454; P<0.05). The average fluorescence intensity values of VEGF and AQP4 on IML specimens in the DR group were 33.80±7.91, 43.76±9.44, respectively. The results of Pearson correlation analysis showed that the fluorescence intensity of VEGF and AQP4 in the ILM specimens of the DR group was significantly positively correlated ( r=0.597, P=0.003). Conclusions:The expressions of VEGF and AQP4 in ILM of eyes with DR and DME are significantly increased compared with those without DME. The expression of VEGF and AQP4 in ILM of eyes with DR is positively correlated.
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Objective:To explore the effect of aquaporin 4 (AQP4) regulated by miR-320a on a cell model of Alzheimer′s disease.Methods:A rat adrenal pheochromocytoma cell line (PC12) was induced into neurons using nerve growth factor (NGF). The morphology of the PC12 cells and the neurons was observed, and ubiquitin carboxy terminal hydrolase L1 (Uch-L1) and neurofilament protein (NFP) were detected. Levels of microtubule-associated protein (MAP2) and AQP4 target genes were related to the mRNA expression of NFP to determine the neuron-inducing effect. The neurons were then randomly divided into a control group (given no treatment), an miR-320a mimic transfection group (cultured by adding 50nmol/L miR-320a as a mimic agent), an miR-320a inhibitor group (cultured by adding 50nmol/L miR-320a as an inhibitor), an Aβ treatment group (cultured by adding Aβ), an Aβ+ miR-320a mimic group (cultured by adding both 50nmol/L miR-320a and Aβ), and an Aβ+ miR-320a inhibitor group (also cultured by adding Aβ, but with 50nmol/L miR-320a as an inhibitor). Cell activity was measured by the CCK8 method. Reverse-transcription polymerase chain reactions were used to detect the relative expression of the target gene miR-320a, AQP4, B-cell bcl2-associated X (Bax), and B-cell bcl-2 (Bcl-2) mRNA. Western blotting was employed to detect the relative expression of AQP4, Bax and Bcl-2 proteins.Results:After PC12 was induced by 50μg/L NGF, the expression of Uch-L1 genes in the induced neuron was significantly down-regulated compared with the PC12. The expressions of NFP, MAP2 and AQP4 genes were significantly up-regulated, and the relative expressions of MAP2 and AQP4 proteins increased significantly. Compared with the control group, the apoptosis and cell activity of neurons in the treatment group increased, the mRNA and protein expressions of miR-320a, AQP4, bcl-2, AQP4 and Bcl-2 decreased significantly, and the mRNA and protein expressions of Bax increased significantly. Compared with the Aβ-treated group, the cell activity of the Aβ+ Mir-320a mimic group increased significantly, the mRNA and protein expressions of miR-320a, AQP4 and Bcl-2 increased significantly, and the mRNA and protein expressions of Bax decreased significantly. Compared with the Aβ+ miR-320a mimic group, the cell activity of the Aβ+ miR-320a inhibitor group decreased significantly, the mRNA and protein expressions of miR-320a, AQP4 and Bcl-2 decreased significantly, and the mRNA and protein expressions of Bax increased significantly.Conclusion:miR-320a can up-regulate AQP4 expression in a cell model of Alzheimer′s disease, reduce apoptosis and increase the cell survival rate.
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Objective:To compare the clinical features of patients with anti-myelin oligodendrocyte glycoprotein immunoglobulin G antibody (MOG-IgG) positive and anti-aquaporin 4 immunoglobulin G antibody (AQP4-IgG) positive optic neuritis or neuromyelitis optic spectrum disorders (NMOSD) along with optic neuritis, and to analyze prognostic factors.Methods:A total of 106 consecutive inpatients with optic neuritis as the main manifestation and with positive serum antibodies were collected in Department of Neurology, Beijing Tongren Hospital, Capital Medical University from July 2018 to August 2019. The patients were divided into MOG-IgG-positive optic neuritis (MOG-ON) group (35 cases) and AQP4-IgG-positive optic neuritis (AQP4-ON) group (71 cases) according to serum antibody type. The average follow-up period was 14.9 months (5-26 months). The clinical features and outcomes of patients with different serotypes of optic neuritis were compared, and the prognostic factors for different outcomes were analyzed.Results:Compared with AQP4-ON patients, MOG-ON patients were more common in males [37.1%(13/35) vs 15.5%(11/71), χ2=6.274], binocular involvement [48.6%(17/35) vs 19.7%(14/71), χ2=9.432], ocular pain [82.9%(29/35) vs 62.0%(44/71), χ2=4.770], papilledema [63.5%(33/52) vs 36.5%(31/85), χ2=9.442] and peripapillary hemorrhage [15.4%(8/52) vs 2.4%(2/85), χ2=6.286], and were rare in abnormality of other autoimmune indexes [11.4%(4/35) vs 52.1%(37/71), χ2=16.360] (all of them P<0.05). Similar to AQP4-ON, supratentorial and infratentorial tissues, the long segments of the cervical and thoracic cord and all parts of visual pathway were widely involved in MOG-ON, but the anterior segment of optic nerve in orbital was more frequently involved in MOG-ON than in AQP4-ON (χ2=17.506, P<0.001), while the optic nerve sheath was less involved in MOG-ON than in AQP4-ON (χ2=4.075, P=0.044). The proportion of corrected visual acuity ≥ 0.5 in MOG-ON patients (92.3%, 48/52) post three-month of disease onset was higher than that in AQP4-ON patients (50.0%, 34/68) (χ 2=24.374, P<0.001). Positive serum MOG-IgG was a favorable factor for vision acuity recovery in optic neuritis [ OR (95% CI): 11.537(2.090-63.690)], while older onset age [ OR (95% CI): 0.945 (0.908-0.983)], involvement with other nervous system [ OR(95% CI): 0.116 (0.031-0.439)], and involvement of optic nerve sheath [ OR(95% CI): 0.246 (0.066-0.916)] were adverse factors. The recurrence rate of MOG-ON (37.1%, 13/35) was lower than that of AQP4-ON (59.2%, 42/71; χ 2=4.550, P=0.033). The presence of other nervous system involvement was the promoting factor of optic neuritis recurrence [ OR (95% CI): 6.908 (2.312-20.634)]. Conclusions:Compared with AQP4-ON, MOG-ON patients are more common in men, presenting with binocular painful vision loss, optic disc edema and peri-disc hemorrhage, and involvement of the anterior orbital segment of the optic nerve, while involvement of the optic nerve sheath and other autoimmune index abnormalities are relatively rare. MOG-ON patients have better vision recovery and fewer recurrence after treatment than AQP4-ON. Older age of onset, participation of other nervous system, and immersion of optic nerve sheath, are adverse factors for recovery of optic neuritis, and involvement of other nervous system is also a promoting factor for recurrence of optic neuritis.
ABSTRACT
Neurodegenerative disease is a type of disease characterized by the progressive loss of neurons, the cause of which is not clear. Aquaporin-4 (AQP4) is a member of the aquaporin family, which plays an important role in maintaining water homeostasis in the brain. In recent years, researchers found that AQP4 has the functions of draining brain metabolic wastes and participating in material exchange through the glmphatic system. This review aims to summarize the current researches of AQP4 in the pathogenesis and progression of neurodegenerative diseases such as Parkinson′s disease and Alzheimer′s disease, and to propose future research directions.
ABSTRACT
Objective:To investigate the effect of hyperbaric oxygen combined with RNA interference (RNAi) technology targeting aquaporin-4 (AQP-4) on improving cognitive function in rats with traumatic brain injury (TBI), and to explore its mechanism.Methods:Totally 112 adult male SD rats were randomly divided into four groups: control group, hyperbaric oxygen(HBO) group, AQP-4 RNAi group and combined treatment group, with 28 rats in each group.The TBI model of rat was established by hydraulic percussion and siRNA targeting aquaporin 4 was constructed. Rats were given corresponding intervention according to their groups.Then the modified neurological severity scores(mNSS)was evaluated on the 7th day and 21th day after operation. Morris water maze test was carried out from the 21st day to 25th day after operation and the percentage of target quadrant and daily escape latency were recorded.The changes of the brain permeability of blood-brain barrier and moisture in brain tissues were measured by Evans blue fluorometry and a wet-dry-weighing technique respectively. The protein expression levels of AQP-4, Caspase-3, Bcl-2, MMP-2 and MMP-9 were detected by Western blot method. The mRNA expression of AQP-4 in TBI brain tissue was measured by RT-PCR method, and the apoptosis rate of TBI brain cells was detected by TUNEL and AnnexinV methods on the 7th day after operation. SPSS 23.0 and Graphpad Prism 7.0 softwares were used for data analysis.One-way ANOVA was used for inter group comparison.Repeated measurement ANOVA was used for Morris results, and the LSD- t test was used for pairwise comparisons. Results:The results of mNSS showed that there were significant differences among the groups on the 7th day and 21st day after operation ( F=4.89, 7.59, both P<0.05). The scores of each treatment group were lower than that of the control group, and the effect of the combined treatment group was the best (7th day: t=3.98, -7.75, both P<0.05; 21st day: t=47.82, 7.94, both P<0.05). The results of Morris water maze test showed that the time and group interaction of rats in the target quadrant residence time and escape latency were not statistically significant( F=1.83, 8.42, both P>0.05). The escape latency and the percentage of stay in the target quadrant in the combined treatment group were better than those in other groups on the 24th and 25th day after operation (all P<0.05). Evans blue staining showed that the contents of Evans blue in AQP-4 RNAi group, hyperbaric oxygen group and combined treatment group were lower than that in the control group(all P<0.05), and that in the combined treatment group was the lowest( t=6.19, P<0.05). The results of dry-wet specific gravity method showed that the water content of brain tissue in the combined treatment group((68.15±1.52)%) was the lowest, and that in the AQP-4 RNAi group((76.71±1.06)%) was lower than that in the HBO group ((80.23±1.43)%)( t=4.38, P<0.05). The results of Western blot showed that the protein levels of AQP-4, Caspase-3, MMP-2 and MMP-9 in the combined treatment group were significantly lower than those in other groups(all P<0.05), while the expression of Bcl-2 was increased in the combined treatment group( P<0.05). RT-PCR results (gray value ratio) showed that AQP-4 mRNA levels in AQP-4 RNAi group(0.61±0.21), HBO group (0.83±0.12), combined treatment group(0.22±0.05) and CON group (1.31 ± 0.25) were significantly different( F=175.05, P<0.05), while the AQP-4 mRNA levels decreased in AQP-4 RNAi group which was better than that in hyperbaric oxygen group ( t=5.25, P<0.05). The decrease was the most obvious in the combined treatment group ( t=58.94, P<0.05). The results of TUNEL and AnnexinV showed that the treatment groups were more effective than the control group in inhibiting neuronal apoptosis, especially in the combined treatment group ( P<0.01). Conclusion:The combination of targeted AQP-4 RNAi and hyperbaric oxgen can effectively promote the recovery of neurological and cognitive function, and the mechanism may be related to protecting the integrity of blood-brain barrier, alleviating brain edema and inhibiting apoptosis of nerve cells after TBI.