| Dissertation |
Thesis (Ph.D.) --NUI, 2008 at Department of Anatomy/Neuroscience, UCC. |
| Summary |
Parkinson's disease is characterised by degeneration of dopaminergic neurons within the substantia nigra pars compacta of the midbrain. Inflammation may be associated with the neuropathology of Parkinson's disease, due to evidence of excessive microglial activation and increased levels of pro-inflammatory cytokines within the substantia nigra. Evidence suggests that the mitogen-activated protein kinase p38 is activated upstream of neuronal death in response to inflammatory stress signals. The present study examined the role of inflammation and p38 in a 6-hydroxydopamine-induced rat model of dopaminergic neuronal death in vitro. This study found that 6-hydroxydopamine induced death of dopaminergic neurons in embryonic day 14 rat ventral mesencephalic neuronal-enriched cultures in a dose- and time-dependent manner. Lipopolysaccharide treatment of post-natal day 2 rat glial-enriched cortical cultures resulted in increased production of the pro-inflammatory cytokines, interleukin-1-β and tumour necrosis factor-α. Conditioned medium from the glial-enriched cultures exacerbated the toxic effect of 6-hydroxydopamine on dopaminergic neurons. The interleukin-1-β receptor type 1 was found to co-localise with dopaminergic neurons in the neuronal-enriched cultures. Interleukin-1-β was also found to induce a decrease in the percentage of dopaminergic neurons in these cultures. However, interleukin-1-β did not increase the susceptibility of the dopaminergic neurons to 6-hydroxydopamine. Thus, interleukin-1-β, along with other factors, may contribute to the exacerbation of dopaminergic neuronal death by the conditioned medium. Conditioned medium from the neuronal-enriched cultures did not induce the production of interleukin-1-β or tumour necrosis factor-α from the glial-enriched cultures. Dopamine, which is potentially released during damage to dopaminergic neurons, had no effect on lipopolysaccharide-induced cytokine release from glial-enriched cultures. The p38 inhibitor, SB203580, abrogated 6-hydroxydopamine-induced dopaminergic neuronal death in a dose- and time-dependent manner. The endogenous p38 phosphatase, map kinase phosphatase-1, was found to be present on all cells within the neuronal-enriched cultures (including dopaminergic neurons) and within the glial-enriched cultures. 6-hydroxydopamine treatment of the neuronal-enriched cultures caused a decrease in the intensity of fluorescence of map kinase phosphatase-1, which suggests that 6-hydroxydopamine may affect processing of this phosphatase. The current study suggests that both inflammation and p38 are involved in dopaminergic neuronal death in the 6-hydroxydopamine rat model of Parkinson's disease in vitro, and that manipulation of the p38 pathway may be of potential therapeutic benefit in abrogating the loss of dopaminergic neurons in this disease. |
| Subject |
Parkinson's disease.
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Neurobiology.
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| Collection |
Theses Ph.D.
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Theses Anatomy Department
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Theses Neuroscience Department
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| Description |
349 p. : ill. ; 30 cm. |
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