According to magnetic resonance imaging (MRI) studies, the severity of cognition loss is relative to the cerebral white matter lesions associated with MS progression. strong class=”kwd-title” Keywords: demyelination, behavioral disorders, behavioral tests Introduction Multiple sclerosis (MS) is a chronic neurological autoimmune disease characterized by erosions of myelin, the protective nerve sheath, with a partial preservation or complete loss of axonal activity and nerve transmission.1 However, remyelination is often possible once inflammation subsides and is mediated by oligodendrocytes, which secrete myelin. Remyelination process can be explained as the phenomenon of newer myelin sheath formation around the damaged axons. It is better explained as more the number of oligodendrocytes around the affected neurons, the faster the process of remyeliantion. Inadequate number of oligodendrocytes may lead to improper or no myelin formation, resulting in abnormal neuronal functioning.2 MS has affected more than 1 million people worldwide. The symptoms of MS are weakness, loss of senses, shuffling gait, loss of vision, and cognition.3,4 The main driving force involved in the pathology of MS is inflammation, which enhances autoreactivity, followed by demyelination and neuronal damage.5 Histopathological studies have also confirmed multicentered inflammatory lesions, which spread throughout the brain and spinal cord.6 Autoreactive Midecamycin T-cells are the key players involved in disease generation, breaking down the margin of autoreactivity and self-tolerance, and multiple etiological factors are responsible for this activation. The existence of autoreactive T-cells is evident in both normal and MS patients, but they turn active and seem to be devastating only in MS.7 Among all the T-cell clones, CD8 subtype is found to be more associated with the disease, both in number and infiltration when assessed in the brain and spinal cord. CD8 T-cells were also found to be persistent in blood and cerebrospinal fluid (CSF), implying the fact that Midecamycin they were activated consistently by an antigen driving the long-lasting autoimmune reactivity.8 In brief, a group of activated T-cell subclones specific to the myelin protein will penetrate the bloodCbrain barrier (BBB), being potentiated by the existing inflammatory cytokines, while the resting T-cells have a restricted access to the BBB.9 The coupling of T-cell surface molecules C integrins, selectins, and cadherins C with the corresponding adhesion molecules present in brain capillary endothelial cells facilitates the entry of T-cells. Once the T-cells gain entry, they unleash the autoimmune reactions targeting the myelin antigen. The activation of antibody-producing B-cells further enhances this Midecamycin autoreactivity, thus driving the degeneration of neurons.10 Figure 1 shows MS pathogenesis. Symptom severity, disability levels, and rate of disease progression vary with each individual and even differs in the same patient with time.11 Significant sex differences were identified among MS patients, with a majority of females displaying the symptoms compared to males. Open in a separate window Figure 1 Pathogenesis of MS. Notes: Lymphocytes activated due to various insults (inflammation, Sparcl1 antigen presentation, free radicals, etc) will invade the bloodCbrain barrier. Initially, they bind with the cell adhesion molecules present on the capillary endothelium and gain access into the brain. Once inside, the reactive cells attract both the immune cell traffic (T- and B-cells) and mediate the devastating cascade. Cytotoxic T-cells release granzymes, and activated B-cells produce antibodies against the myelin sheath, thus mediating the demyelination process. Abbreviations: MS, multiple sclerosis; Abs, antibodies. Also, MS was found to affect women at an early age (18C30 years), while it affected men at a later stage of life (30C40 years). These dissimilarities were possibly due to the protective effects of testosterone in men. Another interesting aspect observed in MS was the cessation of disease symptoms in pregnant women who were in the third trimester. The elevated levels of estriol were anticipated to be responsible for the protective effect, and the same was observed in mice models as well.12 The introduction of biomarkers has revolutionized the understanding of the disease pathology and its diagnostics. Some of the recent advancements are the discovery of elevated levels of astrocyte and axonal cytoskeletal proteins, namely, glial fibrillary acidic protein and neurofilament light protein in the CSF corresponding to MS progression. 13 The elevated levels of the 14-3-3 protein in the CSF corresponded to the disease progression and disability, while a close correlation was established with the downregulation of cystatin-C, a protease Midecamycin inhibitor that neutralizes the actions of lysosomal cathepsins modulating lymphocytic activation.14 Some other recently found potential biomarkers associated with the disease are osteopontin and pentosidine.15,16 Based on the symptoms, MS is categorized into Midecamycin four subtypes..