Nitric oxide (NO) is an atypical signaling molecule in both the peripheral and central nervous system, which is produced by three isoforms of nitric oxide synthase (NOS). In the brain, NO has been shown to possess various neurophysiological roles, including its involvement in cognitive functioning. NO can also be neurotoxic and has been implicated in neurodegenerative processes. / The present thesis examined the effects of aging on the NO producing systems in the brain and the putative associations between NO, cognitive impairments, aging, and Alzheimer's disease (AD). In situ hybridization experiments demonstrated that neuronal NOS (nNOS) mRNA expression was significantly increased in aged rats, and that cognitively impaired aged rats showed higher nNOS mRNA expression than aged animals without cognitive deficits. Moreover, mRNA expression of heme oxygenase 2 (HO-2) also showed age-related changes. Western blotting experiments and NOS assays showed that cortical and hippocampal nNOS expressions and activities were decreased in aged animals. In a primary rat cortical mixed neuronal and glial culture model, amyloid (Abeta) peptide increased NO production by nNOS and inducible NOS (iNOS) significantly. Furthermore, NO was neurotoxic in this model, and specific iNOS inhibitors, a NO scavenger, as well as an antioxidant were able to prevent and reverse NO and peroxynitrite toxicity. Western blotting and NOS assay experiments on the brains of patients with AD revealed significant decline in hippocampal nNOS expression along with increased hippocampal and frontal cortical iNOS expressions, as well as the predominance of iNOS activity. / Taken together, the studies presented here have indicated the existence of complex relationships between aging, cognitive impairments, and NOS. Moreover, iNOS could be a significant "intermediate" element in AD pathogenesis.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.37651 |
| Date | January 2002 |
| Creators | Law, Andrew C.-K. |
| Contributors | Gauthier, Serge (advisor), Quirion, Remi (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Division of Neuroscience.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001864223, proquestno: NQ78710, Theses scanned by UMI/ProQuest. |
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