Etiopathogenesis and treatment of Parkinson's disease

Parkinson's disease (PD) is a complex neurodegenerative disorder characterised by dopaminergic cell loss in the substantia nigra. In addition, neurodegeneration occurs at a number of extra-nigral locations and involves a variety of non-dopaminergic neurotransmitter systems. Etiopathogenic mechanisms leading to cell death include oxidative stress and free radical generation, mitochondrial dysfunction, glutamate receptor mediated excitotoxicity, inflammation, oligodendrocytic interaction and neurotrophic factors, ubiquitin-proteosome system involvement, autophagy and apoptosis. Each of these is a potential target for novel pharmacotherapies including bioenergetic agents, inhibitors of excitotoxicity, neurotrophic factors, proteosomal enhancers and anti-apoptotic agents. Evidence has also been gained from cell culture and animal models for the potential disease modifying action of currently available dopaminergic therapies. These drugs have undergone clinical evaluation using studies with novel designs including "delayed start" methodology and studies using neuroimaging as a surrogate marker of dopaminergic cell loss. It is estimated from clinical, pathological and imaging studies that at least 50% of dopaminergic neurons are lost before the development of significant motor symptoms with a pre-motor phase of approximately 6-8 years. A number of pre- and post-synaptic neuroplastic homeostatic mechanisms occur during this period to maintain motor function. However these changes have been implicated in the development of motor complications (wearing "off" and dyskinesias). The evidence for treatments of motor complications in PD is discussed as are potential non-dopaminergic therapeutic targets to delay or improve motor complications.