The effect of L-dopa and neuroprotective agents on cell replacement therapy for Parkinson's disease

Parkinson disease PD is the second most common neurodegenerative disease affecting 1.8% of population aged over 65 years. The current medications that control the symptoms of the disease are associated with limited efficacy and induction of side effects (dyskinesia) at later stages of the disease. One promising future therapy in PD is cell replacement therapy, however clinical trials declared inconsistent outcomes and developing dyskinesia related to the graft. Studies later suggested suboptimal conditions contributed on these outcomes. This thesis builds on this knowledge endeavouring to support cell transplantian therapy in Parkinson disease in models that are more closely aligned to the clinic thorough considering anti-parkinsonian medications in the model. It is addressed the low survival and efficacy problem of the transplanted cells examining neuroprotective agents that have previously shown the ability to protect nigrostriatal dopaminergic neurons against toxic challenges. In addition, this thesis characterises stem cell transplantation, the potential cell source for transplantation that can overcome the many practical and ethical issues surrounding foetal tissue. In the first part of the thesis, the investigations on finding neuroprotective agents to support graft survival and efficacy was achieved in the unilateral 6-OHDA lesioned rat model, treated with chronic L-dopa, (the gold standard anti- Parkinson medication), prior to, and following, cell transplantation. The results revealed for the first time that Glucagon Like Peptide-1 (GLP- 1) receptor agonists (exendin-4 and liraglutide) were capable of improving graft size and the motor and behaviour recovery results from peripheral administration. Importantly, this protection was affected by the presence or absence of L-dopa treatment, as exendin-4 supported the graft only in absence of L-dopa while liraglutide supported the graft only in the presence of L-dopa. While other neuroprotective agents (ghrelin and ghrelin receptor agonist) failed to support graft survival or efficacy in the same animal model. In the second part of the thesis, the characterisation of different source of stem cells derived dopaminergic neurons revealed for the first time that these cells can survive and function in the striatum of 6-OHDA rat model primed with chronic L-dopa treatment and exposed to L-dopa treatment for 16 weeks after transplantation. I show, for the first time, that these cells are capable of ameliorating L-dopa induced dyskinesia.