Novel pharmacological targets for the treatment of Parkinson's disease

Parkinson's disease is a neurodegenerative disease that results from a loss of nigrostriatal dopaminergic neurons. Clinical features include bradykinesia, rigidity and tremor. The accompanying loss of non-adrenergic, serotoninergic and cholinergic neurons leads to the progression of 'non-motor' features.Although dopamine-replacement therapies have been highly successful in improving some of the motor features of the disease, their value is limited by the development of other motor complications. Therefore there is a need for novel therapeutics, both for Parkinson's disease, and also for the motor complications that arise from the use of existing drugs.The multiplicity of dopamine receptors in the brain offers a range of potential targets, but exploitation of drugs acting on specific receptor sub-types has been disappointing. 5-hydroxytryptamine (5-HT) receptor modulators — in particular those acting at 5-HT1A, 5-HT1B, 5-HT2A and 5-HT2C receptors — could be useful, particularly with respect to levodopa-induced dyskinesia.Since the vast majority of pathways in the basal ganglia utilize glutamate and γ-amino butyric acid, these systems are obvious drug candidates, but targeting these receptor systems is fraughtwith potential complications. Recognition of the enhanced opioid peptide transmission in Parkinson's disease patients with levodopa-induced motor complications has raised the possibility of controlling these by targeting opioid transmission in the basal ganglia.Central adenosine A2A receptors are relatively selectively expressed in the striatum, which is innervated by the dopaminergic nigrostriatal neurons lost in Parkinson's disease. Therefore, its antagonism has emerged as a leading candidate strategy for the improved treatment of Parkinson's disease.Although no drug has yet been shown to be neuroprotective in Parkinson's disease, several including dopamine agonists and monoamine oxidase type B inhibitors, have been tested in clinical trials.