Investigating the role of neuroinflammation in a mouse model of L-Dopa induced dyskinesia and exploring the anti-dyskinetic potential of a cannabinoid receptor agonist

Neuroinflammation has long been recognized as one of the pathophysiological hallmarks of Parkinson’s disease (PD). More recently, PD-related neuroinflammation has also been implicated in the development of L-Dopa induced dyskinesia (LID), a PD side effect that arises with chronic L-Dopa treatment. This thesis had two major aims; First, we aimed to characterize the neuroinflammatory phenotype present in a mouse model of PD and LID. Second, we aimed to determine whether anti-inflammatory treatments are anti-dyskinetic, or if a known anti-dyskinetic treatment (amantadine) is capable of reducing neuroinflammation. To achieve these aims we utilized the 6-hydroxydopamine (6-OHDA) mouse model that recapitulated the cardinal behavioral and pathological features of both PD and LID. We first conducted a time course of neurodegeneration following the injection of the neurotoxicant 6-OHDA into the medial forebrain bundle (MFB) of mice. By quantifying the loss of neuronal populations in the midbrain and fibers in the striatum, we confirmed that a 3-week 6-OHDA lesion protocol is sufficient to generate a consistent lesion of the nigrostriatal tract. Next, we assessed the neuroinflammatory profile in this mouse model, finding that mice with a dyskinetic phenotype displayed exacerbated neuroinflammatory responses when compared to naive and PD mice. In particular, dyskinetic mice had increased numbers of microglia and astrocytes in the striatum, increased expression of pro-inflammatory cytokines and upregulated activity of the transcription factor NF-κB. Interestingly, this exacerbated neuroinflammatory phenotype was found in dyskinetic mice, but not non-dyskinetic mice (a subset of 6-OHDA lesioned mice that do not develop LID despite repeated L-Dopa injections and a complete lesion of the nigrostriatal tract). This suggests exacerbated neuroinflammation could be linked to the development or onset of LID. Finally, we investigated the anti-dyskinetic effect of a cannabinoid receptor agonist, comparing its efficacy to both the well-established anti-dyskinetic agent amantadine and the anti-inflammatory treatment regime of minocycline/indomethacin. Strikingly, all treatment regimes were anti-dyskinetic and concomitantly reduced neuroinflammatory alterations. In summary this thesis was able to show a correlation between neuroinflammatory processes and a dyskinetic phenotype.

Grantor dc:publisher

UNSW, Sydney

Year dc:date

2019

Author dc:creator

• Rentsch, Peggy

• Parkinson’s disease
• Neuroinflammation
• Cannabinoid receptor agonist
• Anti-dyskinetic

Statement dc:rights

• open access
• CC BY-NC-ND 3.0
• free_to_read

Licence

• https://purl.org/coar/access_right/c_abf2
• https://creativecommons.org/licenses/by-nc-nd/3.0/au/

Language dc:language

EN

Identifier

https://doi.org/10.26190/unsworks/3844

OAI identifier oai:identifier

oai:unsworks.library.unsw.edu.au:1959.4/64260