Neuroinflammation in manganese neurotoxicity
| dc.contributor.author | Streifel, Karin Marie, author | |
| dc.contributor.author | Tjalkens, Ronald, advisor | |
| dc.contributor.author | Earley, Scott, committee member | |
| dc.contributor.author | Hanneman, William, committee member | |
| dc.contributor.author | Legare, Marie, committee member | |
| dc.date.accessioned | 2007-01-03T08:21:08Z | |
| dc.date.available | 2007-01-03T08:21:08Z | |
| dc.date.issued | 2011 | |
| dc.description.abstract | Excessive environmental or dietary exposure to the essential nutrient manganese (Mn) causes neuroinflammation, particularly in the striatial-pallidum and substantia nigra pars reticulata of the CNS, concominant in the loss of striatal dopamine and motor features resembling, but distinct from, Parkinson's disease (Newland et al., 1989, Calne et al., 1994, Perl and Olanow, 2007). Previous work in our laboratory and others has identified reactive gliosis associated with an increase expression of inducible Nitric Oxide Synthase (NOS2) inflammatory, and important inflammatory gene. Increases in NOS2 leads to a selective increase in reactive oxygen and nitrogen species that is associated with basal ganglia neuronal injury during the progression of the disease. Recent epidemiological studies have associated childhood Mn exposure with neurological dysfunction, indicating that juveniles may be a susceptible population to Mn neurotoxicity. Furthermore, studies of Mn exposure have generally focused on adult exposures and there is much less information regarding the effects of Mn exposure during juvenile development. Therefore in this research we investigated the role of NOS2 in Mn-induced neuroinflammation in juveniles. Using a NOS2 deficient mouse model we demonstrated that gene deletion of NOS2 attenuates peroxynitrite adduct formation in the striatal-pallidum and substantia nigra pars reticulata protects against changes in neurobehavioral parameters. These findings indicate that Mn-induced production of NO by activicated glial cells contributes to nitrosative and neurobehavioral dysfunction. In addition, I conducted in vitro studies to investigate the effect of acute treatment of basal ganglia neurotoxins on agonist-induced intracellular calcium transients in primary striatal astrocytes. These findings indicate that endogenous and exogenous cationic neurotoxins inhibit physiological calcium signaling in astrocytes through transient receptor potential channel proteins. This suggests a novel mechanism by which Mn and other cationic toxicants of the basal ganglia may inhibit critical trophic functions in astrocytes that depend on calcium signaling, such as metabolism and regulation of cerebral blood flow, that could promote neuronal injury. The overarching objective of this research was to investigate the role of astrocytes in the progression of injury in neurodegenerative disease models, thereby increasing our understanding of how dysfunction within glial cells contributes to pathophysiology in the CNS. | |
| dc.format.medium | born digital | |
| dc.format.medium | doctoral dissertations | |
| dc.identifier | Streifel_colostate_0053A_10848.pdf | |
| dc.identifier | ETDF2011400274ERHS | |
| dc.identifier.uri | http://hdl.handle.net/10217/70655 | |
| dc.language | English | |
| dc.language.iso | eng | |
| dc.publisher | Colorado State University. Libraries | |
| dc.relation.ispartof | 2000-2019 | |
| dc.rights | Copyright and other restrictions may apply. User is responsible for compliance with all applicable laws. For information about copyright law, please see https://libguides.colostate.edu/copyright. | |
| dc.title | Neuroinflammation in manganese neurotoxicity | |
| dc.type | Text | |
| dcterms.rights.dpla | This Item is protected by copyright and/or related rights (https://rightsstatements.org/vocab/InC/1.0/). You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s). | |
| thesis.degree.discipline | Environmental and Radiological Health Sciences | |
| thesis.degree.grantor | Colorado State University | |
| thesis.degree.level | Doctoral | |
| thesis.degree.name | Doctor of Philosophy (Ph.D.) |
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