Use of induced pluripotent stem cells (iPSCs) and cerebral organoids in modeling the congenital infection and neuropathogenesis induced by Zika virus.

Infection with Zika virus (ZIKV) was recently demonstrated to be associated with damage to the central nervous system, especially microcephaly and the Guillain-Barré syndrome. This finding had alarmed public health agencies and mobilized institutions around the world to search for more information about the virus, its effects, pathophysiological mechanisms, and potential immunizations and treatments. Given the increasing interest in using iPSCs and cerebral organoids to model the congenital infection and neuropathogenesis induced by ZIKV, the aim of this review was to present an up-to-date summary of the publications on the association of ZIKV with microcephaly, using iPSCs and organoids. According to our review, the number of studies has decreased concomitantly with a decrease in the number of cases. The presence of subclinical lesions at birth, which may eventually present cognitive or behavioral problems in the future, suggests that persistent research efforts on the virus should be undertaken by the global health community till the threat is completely wiped out.

Important advances in Alzheimer's disease from the use of induced pluripotent stem cells.

Among the various types of dementia, Alzheimer's disease (AD) is the most prevalent and is clinically defined as the appearance of progressive deficits in cognition and memory. Considering that AD is a central nervous system disease, getting tissue from the patient to study the disease before death is challenging. The discovery of the technique called induced pluripotent stem cells (iPSCs) allows to reprogram the patient's somatic cells to a pluripotent state by the forced expression of a defined set of transcription factors. Many studies have shown promising results and made important conclusions beyond AD using iPSCs approach. Due to the accumulating knowledge related to this topic and the important advances obtained until now, we review, using PubMed, and present an update of all publications related to AD from the use of iPSCs. The first iPSCs generated for AD were carried out in 2011 by Yahata et al. (PLoS One 6:e25788, 2011) and Yaqi et al. (Hum Mol Genet 20:4530-9, 2011). Like other authors, both authors used iPSCs as a pre-clinical tool for screening therapeutic compounds. This approach is also essential to model AD, testing early toxicity and efficacy, and developing a platform for drug development. Considering that the iPSCs technique is relatively recent, we can consider that the AD field received valuable contributions from iPSCs models, contributing to our understanding and the treatment of this devastating disorder.

Adipogenic Mesenchymal Stem Cells and Hyaluronic Acid as a Cellular Compound for Bone Tissue Engineering.

This study investigates the applicability of adipose mesenchymal stem cells (mADSCs) and hyaluronic acid (HA) as a cellular compound for bone tissue engineering. A critical bone defect was created on each femur of 25 rats in vivo, receiving the following 5 graft treatments: I-Control-defect; II-HA; III-mADSCs; IV-mADSCs+HA; and V-previously osteoinduced mADSCs+HA. Evaluation using microcomputed tomography, histomorphometry, and RT-PCR analysis was performed 23 days after implantation. Microcomputed tomography analysis indicated higher means of bone contact surface (BCS) and bone surface density (BSD) for the mADSCs+HA group compared with Control and the HA groups (P < 0.05). Histomorphometric findings showed higher means of bone regeneration in the mADSCs+HA compared with HA and Control groups (P < 0.05). The RT-PCR ratios showed no difference in type 1 collagen (Col1A) gene expression or osteopontin (OP) gene expression, whereas for the osteonectin gene (ON) higher means were found in the HA and mADSCs osteoin+HA groups (P < 0.05). These results suggest that a combination of HA and mADSCs without prior osteoinduction might be applicable for bone tissue regeneration.

MTOR pathway in focal cortical dysplasia type 2: What do we know?

Focal cortical dysplasia (FCD) is the most commonly encountered developmental malformation that causes refractory epilepsy. Focal cortical dysplasia type 2 is one of the most usual neuropathological findings in tissues resected therapeutically from patients with drug-resistant epilepsy. Unlike other types of FCD, it is characterized by laminar disorganization and dysplastic neurons, which compromise the organization of the six histologically known layers in the cortex; the morphology and/or cell location can also be altered. A comprehensive review about the pathogenesis of this disease is important because of the necessity to update the results reported over the past years. Here, we present an updated review through Pubmed about the mammalian target of rapamycin (MTOR) pathway in FCD type 2. A wide variety of aspects was covered in 44 articles related to molecular and cellular biology, including experiments in animal and human models. The first publications appeared in 2004, but there is still a lack of studies specifically for one type of FCD. With the advancement of techniques and greater access to molecular and cellular experiments, such as induced pluripotent stem cells (iPSCs) and organoids, it is believed that the trend is increasing the number of publications contributing to the achievement of new discoveries.

Influence of Zika virus on the cytotoxicity, cell adhesion, apoptosis and inflammatory markers of glioblastoma cells.

Glioblastoma (GBM) is one of the most common types of brain tumor in adults. Despite the availability of treatments for this disease, GBM remains one of the most lethal and difficult types of tumors to treat, and thus, a majority of patients die within 2 years of diagnosis. Infection with Zika virus (ZIKV) inhibits cell proliferation and induces apoptosis, particularly in developing neuronal cells, and thus could potentially be considered an alternative for GBM treatment. In the present study, two GBM cell lines (U-138 and U-251) were infected with ZIKV at different multiplicities of infection (0.1, 0.01 and 0.001), and cell viability, migration, adhesion, induction of apoptosis, interleukin levels and CD14/CD73 cell surface marker expression were analyzed. The present study demonstrated that ZIKV infection promoted loss of cell viability and increased apoptosis in U-138 cells, as measured by MTT and triplex assay, respectively. Changes in cell migration, as determined by wound healing assay, were not observed; however, the GBM cell lines exhibited an increase in cell adhesion when compared with non-tumoral cells (Vero). The Luminex immunoassay showed a significant increase in the expression levels of IL-4 specifically in U-251 cells (MOI 0.001) following exposure to ZIKV. There was no significant change in the expression levels of IFN-γ upon ZIKV infection in the cell lines tested. Furthermore, a marked increase in the percentage of cells expressing the CD14 surface marker was observed in both GBM cell lines compared with in Vero cells; and significantly increased CD73 expression was observed particularly in U-251 cells, when compared with uninfected cells. These findings indicate that ZIKV infection could lead to reduced cell viability, elevated CD73 expression, improved cellular adherence, and higher rates of apoptosis in glioblastoma cells. Further studies are required to explore the potential use of ZIKV in the treatment of GBM.

Cytotoxicity of esthetic, metallic, and nickel-free orthodontic brackets: cellular behavior and viability.

INTRODUCTION: In this study, we evaluated the cellular viability of various esthetic, metallic, and nickel-free orthodontic brackets. METHODS: The sample was divided into 11 groups (n = 8): cellular control, negative control, positive control, metallic, polycarbonate, 2 types of monocrystalline ceramic, 3 types of nickel free, and polycrystalline ceramic brackets. Cell culture (NIH/3T3-mice fibroblasts) was added to the plates of 96 wells containing the specimens and incubated in 5% carbon dioxide at 37°C for 24 hours. Cytotoxicity was analyzed qualitatively and quantitatively. Cell growth was analyzed with an inverted light microscope, photomicrographs were obtained, and the results were recorded as response rates based on modifications of the parameters of Stanford according to the size of diffusion halo of toxic substances. Cell viability was analyzed (MTT assay); a microplate reader recorded the cell viability through the mitochondrial activity in a length of 570 nm. The values were statistically analyzed. RESULTS: All tested brackets had higher cytotoxicity values than did the negative control (P <0.05), with the exception Rematitan and Equilibrium (both, Dentaurum, Ispringen, Germany) (P >0.05), suggesting low toxicity effects. The values showed that only polycarbonate brackets were similar (P >0.05) to the positive control, suggesting high toxicity. CONCLUSIONS: The brackets demonstrated different ranges of cytotoxicity; nickel-free brackets had better biocompatibility than the others. On the other hand, polycarbonate brackets were made of a highly cytotoxic material for the cells analyzed.

Total Th1/Th2 cytokines profile from peripheral blood lymphocytes in normal pregnancy and preeclampsia syndrome.

To evaluate total Th1/Th2 cytokines in CD3+ cells (immunocompetent T-lymphocytes) and peripheral blood lymphocytes, mostly CD4+ (T helper cells) and CD8+ (T-cytotoxic cells) subpopulations in preeclampsia. Total blood leukocytes and lymphocytes counts, percent cells: CD3+, INF-g+/CD3+, IL-4+/CD3+, and IL-10+/CD3+, CD4+/CD8+ were determined by flow-cytometry. Preeclampsia (n= 26) and normal pregnancy (n= 25) participants were age and gestational age matched. CD4+ lymphocytes count was higher in preeclampsia, compared with normal pregnancy (43.6 ± 5.8 vs 37.6 ± 5.6%; P< 0.001). CD3+ cells Th1/Th2 shift was not detected in preeclampsia, yet may be present in other cell types, such as CD4+ and CD3 - lymphocytes.

Bone marrow mononuclear cell transplant prevents rat depression and modulates inflammatory and neurogenic molecules.

INTRODUCTION: Major depressive disorder is associated with chronic inflammation and deficient production of brain-derived neurotrophic factor (BDNF). Bone marrow mononuclear cell (BMMC) transplantation has an anti-inflammatory effect and has been proven effective in restoring non-depressive behavior. This study investigated whether BMMC transplantation can prevent the development of depression or anxiety in chronic mild stress (CMS), as well as its effect on inflammatory and neurogenic molecules. METHOD: Three groups of animals were compared: BMMC-transplanted animals subjected to CMS for 45 days, CMS non-transplanted rats, and control animals. After the CMS period, the three groups underwent the following behavioral tests: sucrose preference test (SPT), eating-related depression test (ERDT), social avoidance test (SAT), social interaction test (SIT), and elevated plus maze test (EPMT). Transplanted cell tracking and measurement of the expression of high-mobility group box 1 (HMGB1), interleukin-1ß (IL-1ß), tumor necrosis factor (TNFα), and BDNF were performed on brain and spleen tissues. RESULTS: BMMC transplantation prevented the effects of CMS in the SPT, ERDT, SAT, and SIT, while prevention was less pronounced in the EPMT. It was found to prevent increased HMGB-1 expression induced by CMS in the hippocampus and spleen, increase BDNF expression in both tissues, and prevent increased IL-1ß expression in the hippocampus alone, while no effect of the transplant was observed in the TNFα expression. In addition, no transplanted cells were found in either the brain or spleen. CONCLUSIONS: BMMC transplantation prevents the development of depression and anxiety-like behavior triggered by CMS. It could prevent increased HMGB-1 and IL-1ß expression in the hippocampus and increased BDNF expression in the same tissue. Cell treatment represents a further perspective in the research and treatment of depression and possible mood disorders.

[Prevalence of metabolic syndrome in indigenous people over 40 years of age in Rio Grande do Sul, Brazil]. / Prevalência da síndrome metabólica em indígenas com mais de 40 anos no Rio Grande do Sul, Brasil.

OBJECTIVE: To investigate the prevalence of the metabolic syndrome (MS) among indigenous people older than 40 years of age from two cities in the State of Rio Grande do Sul, southern Brazil. METHODS: A descriptive, analytic, cross-sectional study was conducted in two municipalities, Porto Alegre and Nonoai, between July and August 2009. A total of 150 indigenous people older than 40 years of age (range: 40-104 years), participated in the study. MS prevalence was determined based on National Cholesterol Education Program - Adult Treatment Panel III criteria. Blood samples and anthropometric data were collected. The participants also answered a questionnaire on eating habits, which was then contrasted to the 10 steps to healthy eating proposed by the World Health Organization and recommended by the Brazilian Ministry of Health. RESULTS: MS prevalence was 65.3%, affecting women more than men (P < 0.001). Changes in waist circumference, fasting glucose, and HDL-cholesterol and presence of hypertension, hypertriglyceridemia, and obesity were associated with MS. Age, smoking, and sedentary lifestyle were not associated with MS. Indigenous people with MS had a poor diet, with low intake of fruit and vegetables, low levels of physical activity, high consumption of sweets and soft drinks, and high prevalence of obesity. CONCLUSIONS: A high prevalence of MS was observed among the indigenous people surveyed, especially in women. Education and motivation for healthy behaviors is possibly the best way to manage MS and promote health in a population that is still neglected by public health policies.

Case Report: Placental Maternal Vascular Malperfusion Affecting Late Fetal Development and Multiorgan Infection Caused by SARS-CoV-2 in Patient With PAI-1 4G/5G Polymorphism.

Background: Pregnant women are susceptible to the novel coronavirus (SARS-CoV-2), and the consequences for the fetus are still uncertain. Here, we present a case of a pregnant woman with subclinical hypothyroidism and a plasminogen activator inhibitor type 1 (PAI-1) 4G/5G polymorphism who was infected with SARS-CoV-2 at the end of the third trimester of pregnancy, with unexpected evolution of death of the newborn 4 days postpartum. Methods: Nested PCR was performed to detect the virus, followed by ssDNA sequencing. Results: Transplacental transmission of SARS-CoV-2 can cause placental inflammation, ischemia, and neonatal viremia, with complications such as preterm labor and damage to the placental barrier in patients with PAI-1 4G/5G polymorphism. Conclusion: We showed a newborn with several damages potentially caused due to the PAI-1 polymorphisms carried by the mother infected with SARS-CoV-2 during pregnancy.

A new waterborne chitosan-based polyurethane hydrogel as a vehicle to transplant bone marrow mesenchymal cells improved wound healing of ulcers in a diabetic rat model.

Foot ulcers, a common complication of diabetes, can cause physical incapacity and are derived from several factors, including poor wound healing. New therapeutic strategies are needed to minimize this complication for the sake of patients' health. We therefore developed a new chitosan- polyurethane hydrogel membrane (HPUC) and the test results confirmed that HPUC present low cytotoxicity and improved wound healing when used with mononuclear bone marrow fraction cells in the diabetic rat model. The biodegradable hydrogels were produced in block copolymer networks with a combination of chitosan blocks and biodegradable polyurethane. The membranes were characterized by FTIR, 13C-NMR and thermogravimetry. Swelling and hydrolytic degradation were also evaluated. The non-solubility of the membranes in good solvents and the chemical characterization confirmed that the network structure was formed between the PU and the chitosan through urea/urethane bonds. The findings confirm that the HPUC have interesting properties that make them suitable for wound healing applications.

Correlation between IL-31 and sCD40L plasma levels in Fingolimod-treated patients with Relapsing-Remitting Multiple Sclerosis (RRMS).

INTRODUCTION: Multiple Sclerosis (MS) is a chronic, autoimmune, demyelinating disease of the central nervous system (CNS). Currently, several protocols are described for the different phases of MS. In this longitudinal study, we aim to quantify the concentration of plasma cytokines of MS patients treated with Fingolimod alone or after Glatiramer Acetate (GA) or Interferon-beta (IFN-ß), in order to compeer both treatments and describes if it is possible to use them as biomarkers. OBJECTIVE: Compare the two different types of drug treatment and describes possible immune biomarkers in RRMS patients treated with Fingolimod alone or after GA or IFN-ß. MATERIALS AND METHODS: This is a controlled, non-randomized clinical trial. Plasma concentrations of IL-31, sCD40L and nine others cytokines were evaluated in two groups of patients with a one-year follow-up. Group 1 (n = 12): RRMS patients treated with GA or IFN-ß for at least six months before the study who changed therapy to Fingolimod after six months, and Group 2 (n = 12): naïve RRMS patients who started treatment with Fingolimod. We used ANOVA two-way to analyze the cytokines and Spearman coefficient to evaluate the correlation. RESULTS: Although Group 2 started with a greater number of relapses per disease duration, Fingolimod treatment was effective in decreasing this parameter, as well as EDSS over 12 months. However, the treatment with GA or IFN-ß on Group 1 showed a tendency to increase the number of relapses after 6 months of follow-up, which decrease when the therapy was changed to Fingolimod. After the evaluation of 11 cytokines in one year, we found that IL-31 and sCD40L were the biomarkers that demonstrated a more difference when compared to the classical ones, following the clinical pattern over the treatment period. CONCLUSIONS: Our study describes the existence of two promising plasmatic biomarkers (IL-31 and sCD40L), which reduced plasmatic levels in RRMS patients followed the treatment time of Fingolimod, despite that more studies are needed to prove their efficiency.

Intravenous infusion of bone marrow mononuclear cells promotes functional recovery and improves impaired cognitive function via inhibition of Rho guanine nucleotide triphosphatases and inflammatory signals in a model of chronic epilepsy.

Temporal lobe epilepsy is the most common form of intractable epilepsy in adults. More than 30% of individuals with epilepsy have persistent seizures and have drug-resistant epilepsy. Based on our previous findings, treatment with bone marrow mononuclear cells (BMMC) could interfere with early and chronic phase epilepsy in rats and in clinical settings. In this pilocarpine-induced epilepsy model, animals were randomly assigned to two groups: control (Con) and epileptic pre-treatment (Ep-pre-t). The latter had status epilepticus (SE) induced through pilocarpine intraperitoneal injection. Later, seizure frequency was assessed using a video-monitoring system. Ep-pre-t was further divided into epileptic treated with saline (Ep-Veh) and epileptic treated with BMMC (Ep-BMMC) after an intravenous treatment with BMMC was done on day 22 after SE. Analysis of neurobehavioral parameters revealed that Ep-BMMC had significantly lower frequency of spontaneous recurrent seizures (SRS) in comparison to Ep-pre-t and Ep-Veh groups. Hippocampus-dependent spatial and non-spatial learning and memory were markedly impaired in epileptic rats, a deficit that was robustly recovered by treatment with BMMC. Moreover, long-term potentiation-induced synaptic remodeling present in epileptic rats was restored by BMMC. In addition, BMMC was able to reduce abnormal mossy fiber sprouting in the dentate gyrus. Molecular analysis in hippocampal tissue revealed that BMMC treatment down-regulates the release of inflammatory cytokine tumor necrosis factor-α (TNF-α) and Allograft inflammatory factor-1 (AIF-1) as well as the Rho subfamily of small GTPases [Ras homolog gene family member A (RhoA) and Ras-related C3 botulinum toxin substrate 1 (Rac)]. Collectively, delayed BMMC treatment showed positive effects when intravenously infused into chronic epileptic rats.

Experimental Models of Neuroimmunological Disorders: A Review.

Immune-mediated inflammatory diseases of the central nervous system (CNS) are a group of neurological disorders in which inflammation and/or demyelination are induced by cellular and humoral immune responses specific to CNS antigens. They include diseases such as multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), acute disseminated encephalomyelitis (ADEM) and anti-NMDA receptor encephalitis (NMDAR encephalitis). Over the years, many in vivo and in vitro models were used to study clinical, pathological, physiological and immunological features of these neuroimmunological disorders. Nevertheless, there are important aspects of human diseases that are not fully reproduced in the experimental models due to their technical limitations. In this review, we describe the preclinical models of neuroimmune disorders, and how they contributed to the understanding of these disorders and explore potential treatments. We also describe the purpose and limitation of each one, as well as the recent advances in this field.

Analysis of genes involved in cell proliferation, adhesion, and control of apoptosis during embryonic neurogenesis in Induced Pluripotent Stem Cells (iPSCs) from patients with Focal Cortical Dysplasia.

Focal cortical dysplasia (FCD) is a malformation of cortical development which is strongly associated with drug-refractory epilepsy. Certain studies have demonstrated an increase in mTOR signaling in patients with FCD on the basis of observation of phosphorylated molecules. The aim of the present study was to verify the differences in genes involved in cell proliferation, adhesion, and control of apoptosis during embryonic neurogenesis in iPSCs derived from the Focal Cortical Dysplasia. Fibroblasts were obtained from the skin biopsies of patients with FCD (n = 2) and controls (n = 2). iPSCs were generated by exposing the fibroblasts to viral vectors that contained the Yamanaka factors (OCT4, SOX2, KLF4, and c-MYC genes) responsible for promoving cell reprogramation. The fibroblasts and iPSCs were tested during different phases of neurodifferentiation for migration capacity and expression of the genes involved in the PI3K pathway. Fibroblasts of patients with FCD migrated with greater intensity during the first two time points of analyses. iPSCs did not exhibit any difference in cell migration between the groups. Fibroblasts, brain tissue, and iPSCs of the patients with FCD exhibited a significant reduction in the relative expression values of 4EBP-1. During neurodevelopment, the iPSCs from patients with FCD exhibited a reduction in the expression of cIAP-1, cIAP-2, PI3K, ß-Catenin and 4EBP-1 gene. We suggest that the differences observed in the migration potential of adult cells and in the gene expression related to the fundamental processes involved in normal brain development during the neurodifferentiation process might be associated with cortical alteration in the patients with FCD.

Detection of autoantibodies in central nervous system inflammatory disorders: Clinical application of cell-based assays.

The identification of autoantibodies in central nervous system (CNS) inflammatory disorders improves diagnostic accuracy and the identification of patients with a relapsing disease. Usual methods to detect autoantibodies are usually divided into 3 categories: tissue-based assays, protein-based assays and cell-based assays (CBA). Tissue-based assays are commonly used for initial identification of autoantibodies based on staining patterns and co-localization. Once the antigen is known, autoantibodies can be detected using other antigen-specific methods based on recombinant proteins and CBA using transfected cells expressing the protein in their cell membranes. Compared to traditional methods using recombinant proteins such as ELISA and western blot, the CBA have advantage of detecting conformational sensitive antibodies using natively folded proteins in the cell membrane. This article reviews the utility of CBA into the clinical practice.

Transition of cervical carcinoma in situ to invasive cancer: role of p16 INK4a expression in progression and in recurrence.

To investigate the expression of p16(INK4a) in cervical carcinoma and its relation to the transition of carcinoma in situ to invasive carcinoma, and its role in recurrence of cervical lesions as well, a series of 90 patients with cervical carcinoma (49 with in situ lesion and 41 with invasive lesion) were selected from July 2001 and September 2002. Groups with in situ and invasive lesions were paired for a series of risk variables for cervical cancer and followed up for 60 months. The follow-up visits occurred every 6 months in the first three years and annually up to the fifth year. It was observed that 87.9% of the patients with invasive lesion showed overexpression of p16(INK4a), in comparison with 37.6% of those with in situ lesion (X(2): 13.68; 2 df; p=0.0002; OR: 12.08), demonstrating overexpression of p16(INK4a) as a risk of invasion of the basal layer by dysplastic cells. We also observed an association between overexpression of p16(INK4a) and staging of cancer (X(2): 18.38; 6 df; p=0.0003). A prospective analysis, when controlled for interaction with cervical lesion groups (by Cox regression), demonstrated a risk of recurrence of 4.83 times attributed to overexpression of p16(INK4a), albeit not statistically significant (p=0.14).

Effects of human aging on periodontal tissues.

Loss of teeth is frequently associated with periodontal disease in older adults. The aim of this review was to present the effects of aging on the periodontal tissues. Aging alone does not lead to critical loss of periodontal attachment in healthy elderly persons. The effects of aging on periodontal tissues are based on molecular changes in the periodontal cells, which intensify bone loss in elderly patients with periodontitis. These effects may be associated with (1) alterations in differentiation and proliferation of osteoblasts and osteoclasts; (2) an increase in periodontal cell response to the oral microbiota and mechanical stress leading to the secretion of cytokines involved in osseous resorption; and (3) systemic endocrine alterations in the elderly people.

Migration and Synaptic Aspects of Neurons Derived from Human Induced Pluripotent Stem Cells from Patients with Focal Cortical Dysplasia II.

Malformations of cortical development (MCDs) include many different Central Nervous System (CNS) disorders related to a complex process of cortex formation. In children with refractory epilepsy to drug treatment undergoing surgery, focal cortical dysplasia (FCD), one of the MCDs, is considered the most common structural brain lesion found. This study aimed to study the possible alterations in neural differentiation process of human induced pluripotent stem cells (hiPSCs) related to migration and synaptic aspects from fibroblasts of two individuals affected by FCD type IIb (45-year-old male and 12-year-old female) and normal individuals. At the days 14th, 22nd and 35th, hiPSCs were neural differentiated and analyzed. Using qRT-PCR approach, the expression of 9 genes associated with synaptic and neural migration were quantified. Diagnostic of both patients was consistent with FCD type IIb. Our results showed that in all processes and groups, individuals with dysplasia presented alterations in most part of the genes in relation to control individuals. According to our results, it is suggested that the different expressions are mainly involved in alterations of the expression of receptors and capture sites, timing, coupling of synaptic vesicles with the presynaptic membrane, regulation of ion channel and synaptic exocytosis, imbalance of the apoptosis process and abnormal microtubules that may also contribute to delays in synaptogenesis. Thus, brain formation with dysplasia is probably influenced by these genes studied.

Role of Glutamatergic Excitotoxicity in Neuromyelitis Optica Spectrum Disorders.

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disorder mediated by immune-humoral responses directed against central nervous system (CNS) antigens. Most patients are positive for specific immunoglobulin G (IgG) auto-antibodies for aquaporin-4 (AQP4), a water channel present in astrocytes. Antigen-antibody binding promotes complement system cascade activation, immune system cell infiltration, IgG deposition, loss of AQP4 and excitatory amino acid transporter 2 (EAAT2) expression on the astrocytic plasma membrane, triggering necrotic destruction of spinal cord tissue and optic nerves. Astrocytes are very important cells in the CNS and, in addition to supporting other nerve cells, they also regulate cerebral homeostasis and control glutamatergic synapses by modulating neurotransmission in the cleft through the high-affinity glutamate transporters present in their cell membrane. Specific IgG binding to AQP4 in astrocytes blocks protein functions and reduces EAAT2 activity. Once compromised, EAAT2 cannot take up free glutamate from the extracellular space, triggering excitotoxicity in the cells, which is characterized by overactivation of glutamate receptors in postsynaptic neurons. Therefore, the longitudinally extensive myelitis and optic neuritis lesions observed in patients with NMOSD may be the result of primary astrocytic damage triggered by IgG binding to AQP4, which can activate the immune-system cascade and, in addition, downregulate EAAT2. All these processes may explain the destructive lesions in NMOSD secondary to neuroinflammation and glutamatergic excitotoxicity. New or repurposed existing drugs capable of controlling glutamatergic excitotoxicity may provide new therapeutic options to reduce tissue damage and permanent disability after NMOSD attacks.