Multiple Sclerosis (MS) is the most common demyelinating condition of the central nervous system (CNS), resulting in paralysis and death. The etiology of MS is unknown. However, genetics, exposure to a pathogen, psychological stress and gender are all implicated in the onset and progression of the disease. An animal model of MS, Theiler’s virus (TMEV) infection, causes a biphasic disease. An early CNS viral infection, if allowed to persist within the CNS, is followed by a chronic CNS autoimmune demyelinating condition that is similar to MS. The development of Theiler’s Virus Induced Demyelination (TVID) is under genetic control: SJL mice are highly susceptible to viral persistence and TVID while CBA mice have an intermediate susceptibility. Chronic restraint stress (RST) administered during the first four weeks of TMEV infection influenced the subsequent development of TVID differentially across strain and sex of mice. TVID was exacerbated by RST in male and female SJL mice, but in the CBA strain, TVID was alleviated by RST in male mice only. This pattern of results in SJL and CBA mice could be seen in the chronic phase of TVID on multiple dependent measures: body weights, behavioral signs of the chronic phase, rotarod performance (an automated measure of motor abilities), and inflammation, demyelination, and axonal loss within the spinal cord. The exacerbation of TVID in SJL mice provides some of the first experimental evidence that coincides with reports of stress precipitating the onset of MS in human patients. The sex dependent alleviation of TVID in CBA mice illustrates the complex interaction between genetic predisposition, gender, stress, and exposure to a pathogen that has been proposed for the development of MS.

The role that various myelin membrane proteins play during development and disease processes is not well understood. To better understand their role in vivo we have crossed transgenic mice possessing a single truncated pmp22 gene with mice expressing yellow fluorescent protein in the cytoplasm of their neurons. The resulting double transgenic mice were examined by a combination of confocal microscopy, transmission electron microscopy, and immunohistochemistry to determine if pmp22 insufficiency alters the structural integrity of myelin, glial cells, axons, or the subcellular milieu of these various components. Axons from mice with pmp22 insufficiency developed sprouts and debris localized to nodes with no signs of degeneration of a Wallerian type. Ultrastructurally, the nodes accumulated tubovesicular structures as well as disrupted cytoskeleton that did not appear to alter axon transport. Together, these results suggest that pmp22 insufficiency leads to a non-lethal axonopathy that is restricted to nodes. / Department of Physiology and Health Science

A number of neurodegenerative diseases like Multiple Sclerosis, Parkinson’s and Alzheimer’s have been linked with iron accumulation in the brain. Iron plays an important role in neural metabolism. However, mechanisms of neural degeneration in iron overload are complex and not clearly understood. We proposed that iron overload may lead to demyelination in B6.Cg-Tg (Thy1-YFPH) 2Jrs/J mice. These mice express spectral variants of GFP (yellow-YFP) at high levels in motor and sensory neurons. Serum iron levels were significantly higher in experimental versus control animals. Brain and spinal cords were harvested and fixed after 4 weeks of iron dextran injections. Tissue slices were stained with Prussian blue, H&E and fluromyelin for light and confocal microscopy. Immunological profile by Flow Cytometric analysis revealed significantly high numbers of CD3+T cells with no differences in CD4:CD8 ratio. This study indicates that iron overload caused a significant inflammation without demyelination in the CNS. / Department of Physiology and Health Science

Multiple sclerosis (MS) is an idiopathic neurodegenerative, demyelinating disease of the central nervous system (CNS). MS affects females more than males (3:1) and pregnancy reduces the number of relapses especially during the third trimester when 17-beta-estradiol (E2) and estriol (E3) are at their highest levels. In order to study the role of estrogens as potential therapeutic agents for MS we investigated their role in Theiler's murine encephalomyelitis virus (TMEV)-induced demyelination (TVID). SJL female mice were infected intracranially with Theiler's virus or PBS. The mice in the treatment groups were clinically scored and at week 20 they were ovarectomized (OVx) and given a subdermal pellet containing either 1) 0.1mg of E2, 2) 5mg of E3, or 3) placebo. Four weeks after treatment initiation, the mice were sacrificed and tissue samples were collected and vertebral columns and brains were fixed and placed in paraffin for histological analysis using either hematoxylin and eosin (H&E) stain for general anatomic features or Weil's stain for myelin. No signs of clinical disease developed in any of the sham-infected mice. Prior to ovariectomy, infected mice had developed significant clinical scores indicative of demyelination. Mice in the placebo and E3-treatment groups deteriorated rapidly whereas the E2-treated mice improved significantly during the course of the treatment. Uteri were used to assess hormonal effects post-ovariectomy. Hormone treated groups were significantly different from placebo, indicating hormones were present. Hormone treatment showed significant differences among treatment groups for both inflammation and demyelination. E2-treatment significantly decreased inflammation compared to placebo and E3. E2 was also effective in reducing demyelination compared to placebo groups but not E3. E3 treatment was effective in reducing inflammation compared to placebo, but no significance was found for demyelination. Both E3 and E2 treated mice developed lower antibody levels against TMEV. The improvement in clinical signs, inflammation, demyelination, and the reduction of antibody levels in 17-beta-estradiol-treated mice indicate a therapeutic potential for the treatment of MS.

Thesis (Ph.D.)--University of Western Australia, 2007.

Thesis (M.S.)--Ball State University, 2009. / Title from PDF t.p. (viewed on Apr. 16, 2010). Includes bibliographical references (p. 36-37).

No description available.

No description available.

Adaptation to osmotic imbalance is crucial for cell survival and many organisms have developed complex mechanisms to counteract the changes induced by aniosmolarity. In mammals, the central nervous system is one of the most vulnerable organs after sudden changes in osmolarity. This is best exemplified by two common clinical disorders, brain edema resulting from acute hyponatremia and brain dehydration after hypernatremia. In clinical practice, hyponatremia is the most common electrolyte disorder and carries a significant mortality and morbidity. However, correction of hyponatremia should be undertaken with great caution as failure to adapt to rapid changes in chronic hyponatremia will cause rapid and fatal demyelination of the central nervous system. This syndrome is called osmotic demyelination syndrome (ODS) or central pontine myelinolysis. In this work, we investigated the pathophysiology and new diagnostic and treatments tools for osmotic demyelination syndrome. Using a rat model, we demonstrated the efficacy of the neuroprotective agent minocycline in osmotic demyelination syndrome. We also compared treatment with dexamethasone and re-lowering of serum sodium after rapid correction of hyponatremia and we showed that re-lowering of serum sodium is better than administration of dexamethasone. We explored the mechanisms underlying brain demyelination in ODS and demonstrated that the rupture of the blood brain barrier is not necessary for demyelination and that activated microglia does not play a key role in brain demyelination but can potentiate the lesions induced by rapid correction of hyponatremia. We also investigated the role of astrocytes during the development of osmotic demyelination and demonstrated that astrocytes are a major component of the physiopathology of osmotic demyelination. We showed that early and massive astrocyte apoptosis delineates the regions of future myelin damage and found that astrocyte death induces severe upregulation of myelinolytic cytokines and destruction of astrocyte oligodendrocyte junctions with subsequent disruption of panglial syncitium. <p>Finally, as there are currently no markers of demyelination, we investigated the astroglial protein S100B in ODS and found a significant release of S100B during development of ODS, which correlated with astrocyte damage. We also showed that the increase in S100B is prevented by protective treatment of hyponatremia with urea and demonstrated that serum levels of S100B could be used as a prognosis factor in ODS .<p>All together, our work has revealed a central role of astrocytes in the pathophysiology of ODS and clarified the importance of blood barrier dysfunction and microglial activation. This work also proposes new diagnostic and treatment tools for ODS. <p> / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished

Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2016-03-03T13:38:21Z No. of bitstreams: 2 Tese - Vânia Beatriz Lopes - 2015.pdf: 1571381 bytes, checksum: 95d706025dea6373e88193f8224608f3 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2016-03-03T13:44:17Z (GMT) No. of bitstreams: 2 Tese - Vânia Beatriz Lopes - 2015.pdf: 1571381 bytes, checksum: 95d706025dea6373e88193f8224608f3 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2016-03-03T13:44:17Z (GMT). No. of bitstreams: 2 Tese - Vânia Beatriz Lopes - 2015.pdf: 1571381 bytes, checksum: 95d706025dea6373e88193f8224608f3 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2015-11-09 / Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq / The cysticercosis is endemic and is considered neglected by the World Health Organization. The neurocysticercosis (NCC) is the most common and severe form of cysticercosis, accounting for over 50,000 deaths annually. The use of experimental models in research, has been essential to the advancement of knowledge of various diseases, such as in understanding the pathophysiology, immune response and parasite host reactions. This study aimed to characterize the cellular immune response in situ and systemic, and the role of inflammatory cells in triggering changes in myelin standards. For this, we used an experimental model to evaluate the NCC intraventricular concentrations of cytokine in situ and systemically, by spleen cell culture, and changes in parenchymal patterns and periventricular desmielinizarão throughout the experimental period. No changes were detected in cytokine concentration at the infection site. Systemically, it is observed the presence of IL-10 initially and after 30 days of infection, there is a significant presence of all the cytokines analyzed as IL-4, IL-10, IL-17 and IFN-γ in the infected group. At the end of the infection, the Th2 profile was predominant. In evaluating pathological observed breaking the blood-brain barrier (BBB) allowing the initial influx of inflammatory cells in the two groups. At 30 days, there was a mixed inflammatory process, ventriculomegaly, foamy macrophages and periventricular desmielinizarão. At the end of the infection, predominance of mononuclear cells, ventriculomegaly, foamy macrophages and demyelination in the parenchyma mostly. In conclusion, the systemic immune response of BALB / c mice induced by cysticercus T. crassiceps, was characterized by a Th2-type immune profile and desmielinizarão parenchymal infection possibly at the end of the inflammatory process as well as the compressive effect on the parenchyma of the parasite brain. / A cisticercose é uma doença endêmica e é considerada negligenciada pela Organização Mundial de Saúde. A neurocisticercose (NCC) é a forma mais frequente e grave da cisticercose, sendo responsável por mais de 50 mil mortes anuais. A utilização de modelos experimentais em pesquisa tem sido essencial para o avanço do conhecimento de diversas doenças, como no entendimento da fisiopatologia, da resposta imune e das relações parasito hospedeiro. O presente estudo objetivou a caracterização da resposta imune celular in situ e sistêmica, e o papel das células inflamatórias em desencadear alterações nos padrões de mielina. Para isto, utilizou-se um modelo experimental de NCC intraventricular para avaliar as concentrações de citocinas in situ e sistemicamente, pela cultura de células do baço, e as alterações nos padrões de desmielinizarão periventricular e parenquimal ao longo do período experimental. Não foram detectadas alterações nas concentrações de citocinas no local da infecção. Sistemicamente, observa-se a presença de IL-10 inicialmente e aos 30 dias de infecção, observa-se a presença significante de todas as citocinas analisadas como, IL-4, IL-10, IL-17 e IFN-γ no grupo infectado. No final da infecção, o perfil Th2, foi predominante. Na avaliação anatomopatológica observou quebra da barreira hemato encefálica (BHE), que permitiu o influxo inicial de células inflamatórias nos dois grupos analisados. Aos 30 dias, observou-se processo inflamatório misto, ventriculomegalia, macrófagos espumosos e desmielinizarão periventricular. No final da infecção, predomínio de células mononucleares, ventriculomegalia, macrófagos espumosos e desmielinização no parênquima em sua maioria. Em conclusão, a resposta imune sistêmica dos camundongos BALB/c induzida por cisticercos de T. crassiceps, foi caracterizada por um perfil imune do tipo Th2e desmielinizarão parenquimal no final da infecção possivelmente pelo processo inflamatório como também pelo efeito compressivo do parasito sobre o parênquima encefálico.