Parkinson's disease (PD) is a progressive neurodegenerative disorder with evolving layers of complexity. In the present thesis we replicated the PD neurodegenerative pattern using a mouse model characterized by systemic injections of the neurotoxin 1-methyl-4-phenyl1,2,3,6-tethrahydropyridine (MPTP). Firstly, we investigated the role of a pro-inflammatory mediator called high mobility group box 1 (HMGB1), in-vivo and in post-mortem human tissue of PD patients. Our study shows increased protein levels of HMGB1 in substantia nigra of PD patients and MPTP treated mice. Inhibition of HMGB1, using the antagonist glycyrrhizin, and a HMGB1 neutralising antibody, has shown neuroprotection against MPTP neurotoxicity as well as prevented nuclear translocation of the protein in dopaminergic neurons. Secondly, we profiled the expression of two HMGB1 cognate receptors: TLR2 and TLR4. Levels of the receptors were upregulated in mouse ventral midbrain following the acute and sub-acute MPTP regimen. However, TLR4 knock out mice were not protected against MPTP-induced dopaminergic toxicity. Thirdly, we developed a novel method of brain tissue dissociation and isolation of immune cells viable for downstream flow cytometric analyses. The technique allowed us to investigate the effects of low grade chronic systemic inflammation within the CNS of mice. The method has proven to be sensitive enough for the qualitative and quantitative measurement of immune cells isolated from brain parenchyma. Lastly, an extensive behavioural characterization on the three different MPTP mouse models was performed in order to identify translational behavioural paradigms in relation to the nigrostriatal lesion induced by the neurotoxin MPTP. Major gait and balance impairments were identified in acute and chronic MPTP mouse models. The findings on HMGB1, TLR2 and TLR4 proteins are the overarching element between the identification of the behavioural endpoints in the MPTP models and the newly developed method for the isolation of immune cells from the mouse brain parenchyma.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:742368 |
| Date | January 2017 |
| Creators | Santoro, Matteo |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=236467 |
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