The neurotoxin 6-hydroxydopamine (6-OHDA) is widely used to produce a neurochemically selective and progressive destruction of dopamine pathways. The resulting motoric deficits and histopathology reproduces several key features of Parkinson's disease, a neurodegenerative disorder for which there is no known cure. The objective of the present thesis was to characterize the in vivo neurotoxicity of 6-OHDA in dopamine pathways, and to examine the mechanisms underlying dopamine cell death. / Infusion of 6-OHDA into different dopamine pathways revealed that the nigrostriatal projection was more vulnerable than the mesolimbic dopamine pathway. In addition, a considerable portion of cell bodies was preserved despite significant losses of dopamine markers in nigrostriatal and mesolimbic nerve terminal regions. The partial sparing of cell bodies was enhanced by hypothermia associated with surgical anesthesia. This neuroprotective effect was localized to a specific subregion within the mesolimbic dopamine cell body area. The preservation of dopamine cell bodies following 6-OHDA administration may have functional significance since somatodendritic dopamine release has been demonstrated in this brain area. / The studies in Chapter 3 examined the contribution of two proteases, calpain and caspase-3, in mediating the degeneration resulting from 6-OHDA administration. Calpain activation occurred early and remained elevated in nigrostriatal cell body and terminal field subregions, whereas caspase-3 activation was only transient. Adenoviral delivery of the calpain inhibitor, calpastatin, completely prevented the elevation in calpain activity following 6-OHDA administration. Moreover, calpastatin delivery significantly improved motor deficits associated with nigrostriatal dysfunction. The behavioural protection was not, however, accompanied by a sparing of nigrostriatal dopamine markers, but was unexpectedly associated with a preservation of mesolimbic dopamine markers. These findings suggest that calpain activation contributes to dopamine cell death, but this effect may be brain region dependent. / Collectively, our findings highlight differential vulnerability amongst midbrain dopamine neurons, of possible relevance to Parkinson's disease. In addition, our work suggests that calpains may represent a future therapeutic target for the treatment of Parkinson's disease. However, present drawbacks associated with this approach indicate that additional studies are necessary before such neuroprotective compounds can be employed to treat Parkinson's disease.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.85071 |
| Date | January 2004 |
| Creators | Grant, Rebecca J. |
| 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 (Department of Pharmacology and Therapeutics.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002166532, proquestno: AAINR06302, Theses scanned by UMI/ProQuest. |
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