Potential therapeutic targets for Parkinson's disease

Abstract

Background: Parkinson's disease is a common disorder that becomes more prevalent with advanced age. The cardinal features are related to dopamine deficiency, arising from loss of neurons projecting from the substantia nigra in the midbrain to the striatum. Therapies based on dopamine replacement are well established but while highly effective, leave a number of currently unmet needs. These include features of disease that are probably not related to dopamine deficiency and are unresponsive to dopamine-replacement therapy, as well as complications of long-term dopaminergic therapy itself. The most important gap is the availability of treatments that modify the inexorable progression of disease or that could prevent its onset in subjects at risk. Objective: To identify needs that are unmet or only partially addressed by currently available therapies for Parkinson's and select approaches that may be helpful for their management. Methods: Discussion of the mechanisms that may contribute to currently unmet needs in Parkinson's disease. Based on consideration of pathogenic mechanisms and a review of recent and previous relevant literature, identification of possible approaches that are in development, including pharmacological strategies and potential targets for gene therapy. Conclusions: Better treatments for levodopa-unresponsive aspects of Parkinson's will depend upon improved understanding of the pathophysiology of these complications. Dopamine-based therapies have been extensively developed and further improvements in treatment of established disease are likely to be based on modification of other neurotransmitter systems, including 5-hydroxytryptamine, adenosine receptors, amino acid receptors and possibly neuropeptides. The failure of neuroprotective and neurorescue strategies to keep pace with expectations probably reflects a combination of inadequate models of disease pathogenesis and poor biomarkers to assess the impact of these interventions. The development of novel therapies will be heavily dependent on improvements in these arenas. Most gene therapies under development will address the symptoms of Parkinson's disease but will at best only partially address the underlying disease.

Keywords::

• 5-hydroxytryptamine
• adenosine receptors
• animal models
• apoptosis
• biomarkers
• dementia
• dopamine
• dyskinesias
• excitatory amino acids
• gene therapy
• glutamic acid decarboxylase
• kinase
• mitochondria
• neuroprotection
• neurotrophins
• Parkinson's
• protein aggregation
• ubiquitin-proteasome system