Towards therapies for Parkinson’s Disease: treatment-related complications and animal models
Bibliographic record
Abstract
Parkinson’s disease (PD) is an increasingly prevalent neurodegenerative disorder with the global burden of disease expected to double in the next few decades. L-3,4-dihydroxyphenylanaline (L-DOPA) remains the mainstay symptomatic treatment for motor features. Despite its benefit in early disease, long-term L-DOPA therapy is accompanied by side effects, with most patients eventually developing L-DOPA induced dyskinesia. Our lab has focussed on the investigation of new therapeutic targets for treatment-related complications in neurotoxin-based animal models of PD. Preclinical and clinical studies have implicated an aetiological role for the dysregulated release of striatal dopamine in dyskinesia. Evidence from in vitro and in vivo studies has found that blockade of the serotonin type 3 (5-HT3) receptor dampens the release of striatal dopamine, which may provide anti-dyskinetic benefit. Recent behavioural studies suggest that the 5-HT3 antagonist ondansetron alleviates dyskinesia in the hemi-parkinsonian rat model. The objective of the current thesis was to examine the efficacy of 5-HT3 blockade and its mechanism of action in treatment-related complications in PD, as well as to develop the methodology to construct a new animal model of PD to evaluate disease-modifying therapies. Neurotoxin-based experimental models of PD have led to the failure of several high-profile clinical trials that examined the effect of therapeutics at slowing disease progression, in part because they do not replicate the processes at play in the human disease, e.g., the abnormal propagation of alpha-synuclein within the brain. Chapter 1 describes brain and plasma levels of ondansetron associated with doses that provide therapeutic effects in the rat, contextualising the literature over a range of indications. Chapter 2 expands the profile of 5-HT3 blockade in dyskinesia with granisetron, another 5-HT3 antagonist, which also significantly improved dyskinesia in the hemi-parkinsonian rat without impairing the therapeutic efficacy of L-DOPA. Chapter 3 extends the anti-dyskinetic findings of ondansetron obtained in the rat to the parkinsonian non-human primate, while also demonstrating an improvement in global parkinsonism and psychosis-like behaviours severity. In Chapter 4, novel psychosis-like behaviours are described in L-DOPA treated parkinsonian marmosets, enriching the existing behavioural paradigm to characterise the anti-psychotic potential of experimental drugs. Chapter 5 provides the first investigation into the mechanism underlying the anti-dyskinetic efficacy of 5-HT3 antagonists. Compared to sham-lesioned animals, there was a regional selective upregulation of 5-HT3 receptors in L-DOPA treated hemi-parkinsonian rats, predominantly in the subthalamic nucleus, and to a lesser extent in the globus pallidus and ventral anterior/ventral lateral thalamus. Moving away from symptomatic therapies in toxin-based models and towards models that permit the evaluation of disease-modifying therapies, Chapter 6 describes the methodology that couples subject-specific registration with frameless stereotaxic neuronavigation to localise and inject alpha-synuclein fibrils in the putamen of two marmosets. Evidence of nigrostriatal denervation suggestive of accurate targeting was obtained, with a novel procedure that enhanced the accuracy of stereotaxic neurosurgeries in marmosets. Taken together, these results provide support for the therapeutic potential of 5-HT3 antagonism in L-DOPA induced dyskinesia and PD psychosis, providing compelling data to move such drugs to clinical trials. Moreover, the development of a new alpha-synuclein based model in the marmoset represents an important step towards the testing of experimental molecules with disease-modifying potential in PD with higher chance of success upon translation to the clinic
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.007 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".