Neurospheres: a potential in vitro model for the study of central nervous system disorders.

Neurogenesis was believed to end after the period of embryonic development. However, the possibility of obtaining an expressive number of cells with functional neuronal characteristics implied a great advance in experimental research. New techniques have emerged to demonstrate that the birth of new neurons continues to occur in the adult brain. Two main rich sources of these cells are the subventricular zone (SVZ) and the subgranular zone of the hippocampal dentate gyrus (SGZ) where adult neural stem cells (aNSCs) have the ability to proliferate and differentiate into mature cell lines. The cultivation of neurospheres is a method to isolate, maintain and expand neural stem cells (NSCs) and has been used extensively by several research groups to analyze the biological properties of NSCs and their potential use in injured brains from animal models. Throughout this review, we highlight the areas where this type of cell culture has been applied and the advantages and limitations of using this model in experimental studies for the neurological clinical scenario.

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.

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.

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.