Norkute A, Hieble A, Braun A, Johann S, Clarner T, Baumgartner W (2009) Cuprizone treatment induces demyelination and astrocytosis in the mouse hippocampus

Norkute A, Hieble A, Braun A, Johann S, Clarner T, Baumgartner W (2009) Cuprizone treatment induces demyelination and astrocytosis in the mouse hippocampus. to review the development and formation of demyelinating CNS lesions without T cell involvement. Here, we talk about both of these non\well-known MS models. It really is our try to explain the pathological hallmarks of MS, and talk about which pathological areas of the disease could be greatest studied in the many animal models obtainable. abnormalities can be found in MS WM that shows up normal by regular MRI 43. As opposed to inflammatory white matter lesions, NAWM pathology is not a focal but a diffuse, widespread process. Several mechanisms leading to NAWM pathology have been proposed although it is still debatable as to which are involved in MS. These include oligodendrocyte stress that AKBA may lead to dysfunctional myelination and impaired neuronal support 46, 106, Wallerian degeneration of axons transected by focal demyelination within near or distant focal white matter lesions 38, tissue hypoperfusion 42 or decrease in iron concentration 54 among other factors. Because there appears to be, at best, a modest relationship between these widespread white matter abnormalities and the focal inflammatory lesion load as defined by MRI 125 it is widely considered that NAWM abnormalities are (at least partly) independent of focal inflammatory lesions, thus being a distinct or separate disease process. Another contributor to NAWM abnormalities is cortical pathology 95. Cortical lesion load correlates with diffuse white matter injury in MS patients. Furthermore, there is a significant correlation between the histopathological extent of cortical demyelination and diffuse changes in the NAWM 71. Underlying mechanisms of this interplay are not completely understood. Most of the proteins, vesicles and organelles required for axon survival have to be continuously synthesized in the cell body, and are then transported along the microtubule network along the axon to their final destination. It appears Plxnc1 feasible that even a modest impairment of this neuronal synthesis and transport machinery, due to cortical demyelination, might finally result in axonal pathology. Of note, NAWM findings are clearly clinical relevant because, in contrast to focal WM lesions, they correlate better with disability and cognitive impairment 93, and less NAWM pathology is detected in patients presenting with a benign disease course 35. Similar to the diffuse white matter damage, tissue damage in the gray matter is also a key component of the disease process, especially during SPMS, and the number of studies investigating gray matter damage in MS has increased exponentially during the past few years. Like NAWM, gray matter involvement can also be extensive involving both the cortex and subcortical gray matter such as the hippocampus or thalamus 47, 49, 79. Results from clinical studies suggest that neuronal damage or neuronal loss critically contributes to functional deficits AKBA in MS patients. It has been shown that disability progression is associated with whole brain atrophy 48, 89, and reduced levels of brain discussed in this review article are EAE models in which myelin damage is augmented with antibodies directed to CNS components, nor was the relevance of B\cells discussed 9. Although MS AKBA is still dominated by concepts of myelin reactive autoaggressive T\cells, analogy to murine EAE models, and a belief that CNS immunoglobulins, including oligoclonal bands, represent meaningless, nonsense antibodies, the effectiveness of B\cell depletion therapy (such as rituximab) clearly points toward an important function of antibodies and/or B\cells in MS pathogenesis 56. Of note, B\cells are extremely diverse members of the universe of adaptive immunity, and have numerous effector functions independent of their differentiation from antibody\secreting plasma cells. In this context it is important to mention that peptide immunization models are B\cell independent because the B\cell receptor that binds mostly conformational rather than short linear epitopes is not involved in antigen capture. Another aim of this review article was to highlight the significance of the cuprizone model to understand pathological processes operant in MS. If we understand which factors link oligodendrocyte degeneration, microglia activation and neurodegeneration, we may well get an insight into cellular and molecular processes of NAWM and gray matter pathology in MS. For example, it has been shown that the chemokine CXCL10, but not CCL2 or CCL3, actively participates in the initiation of.

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