Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2006. / Härtill 4 uppsatser.

Thesis (M.Sc.). / Written for the Dept. of Biology. Title from title page of PDF (viewed 2009/13/07). Includes bibliographical references.

Thesis (Ph. D.)--Virginia Commonwealth University, 2009. / Prepared for: Dept. of Biochemistry. Bibliography: leaves 147-171. Also available on the Internet.

Thesis (M.S.)--University of Missouri-Columbia, 2005. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file viewed on (January 22, 2007) Includes bibliographical references.

Thesis (Ph.D.)--Ohio University, June, 2005. / Title from PDF t.p. Includes bibliographical references (p. 130-137)

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

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Long-term exposure to inorganic arsenic (iAs) through drinking water has been associated with cognitive impairment in children and adults; however, the related pathogenic mechanisms have not been completely described. Increased or chronic inflammation in the brain is linked to impaired cognition and neurodegeneration; iAs induces strong inflammatory responses in several cells, but this effect has been poorly evaluated in central nervous system (CNS) cells. Because astrocytes are the most abundant cells in the CNS and play a critical role in brain homeostasis, including regulation of the inflammatory response, any functional impairment in them can be deleterious for the brain. We propose that iAs could induce cognitive impairment through inflammatory response activation in astrocytes. In the present work, rat cortical astrocytes were acutely exposed in vitro to the monomethylated metabolite of iAs (MMA(III)), which accumulates in glial cells without compromising cell viability. MMA(III) LD50 in astrocytes was 10.52 μM, however, exposure to sub-toxic MMA(III) concentrations (50-1000 nM) significantly increased IL-1β, IL-6, TNF-α, COX-2, and MIF-1 gene expression. These effects were consistent with amyloid precursor protein (APP) and β-secretase (BACE-1) increased gene expression, mainly for those MMA(III) concentrations that also induced TNF-α over-expression. Other effects of MMA(III) on cortical astrocytes included increased proliferative and metabolic activity. All tested MMA(III) concentrations led to an inhibition of intracellular lactate dehydrogenase (LDH) activity. Results suggest that MMA(III) induces important metabolic and functional changes in astrocytes that may affect brain homeostasis and that inflammation may play a major role in cognitive impairment-related pathogenicity in As-exposed populations.

Chronic pain is a major health problem worldwide. We have recently demonstrated the analgesic effect of the nitroxyl donor, Angeli's salt (AS) in models of inflammatory pain. In the present study, the acute and chronic analgesic effects of AS was investigated in chronic constriction injury of the sciatic nerve (CCI)-induced neuropathic pain in mice. Acute (7th day after CCI) AS treatment (1 and 3 mg/kg; s.c.) reduced CCI-induced mechanical, but not thermal hyperalgesia. The acute analgesic effect of AS was prevented by treatment with 1H-[1,2, 4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ, a soluble guanylate cyclase inhibitor), KT5823 (an inhibitor of protein kinase G [PKG]) or glibenclamide (GLB, an ATP-sensitive potassium channel blocker). Chronic (7-14 days after CCI) treatment with AS (3 mg/kg, s.c.) promoted a sustained reduction of CCI-induced mechanical and thermal hyperalgesia. Acute AS treatment reduced CCI-induced spinal cord allograft inflammatory factor 1 (known as Iba-1), interleukin-1β (IL-1β), and ST2 receptor mRNA expression. Chronic AS treatment reduced CCI-induced spinal cord glial fibrillary acidic protein (GFAP), Iba-1, IL-1β, tumor necrosis factor-α (TNF-α), interleukin-33 (IL-33) and ST2 mRNA expression. Chronic treatment with AS (3 mg/kg, s.c.) did not alter aspartate aminotransferase, alanine aminotransferase, urea or creatinine plasma levels. Together, these results suggest that the acute analgesic effect of AS depends on activating the cGMP/PKG/ATP-sensitive potassium channel signaling pathway. Moreover, chronic AS diminishes CCI-induced mechanical and thermal hyperalgesia by reducing the activation of spinal cord microglia and astrocytes, decreasing TNF-α, IL-1β and IL-33 cytokines expression. This spinal cord immune modulation was more prominent in the chronic treatment with AS. Thus, nitroxyl limits CCI-induced neuropathic pain by reducing spinal cord glial cells activation.