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ItemTherapeutic effects of copper bis(thiosemicarbazone) complexes in Alzheimer’s and Parkinson’s diseasesHUNG, LIN WAI ( 2010)Neurodegeneration is a complex process and one that involves a myriad of physiological changes leading to chronic pathological states. Examples of neurodegenerative disorders include Alzheimer’s disease (AD) and Parkinson’s disease (PD). In this thesis, a group of compounds, CuIIbis(thiosemicarbazones) or CuII(btsc), was investigated for their ability as therapeutic agents in AD and PD. The CuII(btsc) compounds include CuII(atsm) and CuII(gtsm), and have been identified to be good candidates for CNS drugs due to their ability to be bioavailable and cross the blood brain barrier. In addition, they also possess unique properties that help target pathologies in both AD and PD. CuII(gtsm) administration to AD transgenic mice increased intracellular copper bio-availability and inhibited glycogen synthase kinase-3β (GSK-3β) through activation of an Akt signalling pathway. CuII(gtsm) also decreased the abundance of Aβ trimers and phosphorylated tau, and restored performance of AD mice in the Y-maze test to levels expected for cognitively normal animals. Improvements in Y-maze cognition correlated directly with decreased Aβ trimer levels. Therefore, therapeutic ability of CuII(gtsm) in the transgenic mice demonstrated that increasing intracellular copper bio-availability can restore cognitive function by inhibiting the accumulation of neurotoxic Aβ trimers and phosphorylated tau. CuII(atsm), on the other hand, was shown to be therapeutic in PD models by inhibiting nitrosative stress, in particular peroxynitrite (ONOO-) driven α-synuclein aggregation. Treatment of CuII(atsm) in four different PD animal models resulted in significant reductions in α-synuclein nitration and oligomerisation within the substantia nigra. In all models a significant increase in the survival of dopaminergic neurons was observed, indicating treatment was neuroprotective. Motor function was also improved in all models; this was consistent with improved dopamine metabolism as indicated by increased levels of tyrosine hydroxylase within the substantia nigra and vesicular monoamine transporter2 in the striatum. The findings from this thesis establish the therapeutic effects of CuII(btsc) compounds in animal models and suggest that these compounds could be effective disease modifying therapeutic agents for neurodegeneration in clinical studies.