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  • Review Article
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Novel pharmacological targets for the treatment of Parkinson's disease

Key Points

  • 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.

Abstract

Dopamine deficiency, caused by the degeneration of nigrostriatal dopaminergic neurons, is the cause of the major clinical motor symptoms of Parkinson's disease. These symptoms can be treated successfully with a range of drugs that include levodopa, inhibitors of the enzymatic breakdown of levodopa and dopamine agonists delivered by oral, subcutaneous, transcutaneous, intravenous or intra-duodenal routes. However, Parkinson's disease involves degeneration of non-dopaminergic neurons and the treatment of the resulting predominantly non-motor features remains a challenge. This review describes the important recent advances that underlie the development of novel dopaminergic and non-dopaminergic drugs for Parkinson's disease, and also for the motor complications that arise from the use of existing therapies.

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Figure 1: A single-photon emission computerized tomographic (SPECT) scan of dopamine transporter density in a Parkinson's disease patient shortly after diagnosis and serially for 46 months.
Figure 2: Schematic representation of the neurodegenerative changes in the central nervous system in Parkinson's disease.
Figure 3: Data from imaging studies in dopamine agonist neuroprotection trials showing a slowing of progression in Parkinson's patients in comparison to L-DOPA.
Figure 4: Delayed start TVP-1012 Early Monotherapy for Parkinson's disease Outpatients (TEMPO) study with rasagiline, 371 subjects.

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Correspondence to Anthony H. V. Schapira.

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This manuscript was prepared by the authors following a workshop sponsored by Boehringer-Ingelheim.

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DATABASES

OMIM

Parkinson's disease

FURTHER INFORMATION

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Glossary

Bradykinesia

Abnormally slow voluntary movements.

Lewy body

Abnormal aggregates of protein (predominately α-synuclein) that develop inside nerve cells and displace other cell components.

Dyskinesia

Involuntary writhing movements affecting head, trunk and limbs.

Depotentiation

The reversal of long-term potentiation back to baseline levels.

Indirect motor pathway

Globus pallidus-mediated control of motor activity.

Microglial reaction

Inflammatory-mediated reaction.

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Schapira, A., Bezard, E., Brotchie, J. et al. Novel pharmacological targets for the treatment of Parkinson's disease. Nat Rev Drug Discov 5, 845–854 (2006). https://doi.org/10.1038/nrd2087

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