Treatment of Parkinson's disease: what's in the non-dopaminergic pipeline?

Abstract

Dopamine depletion resulting from degeneration of nigrostriatal dopaminergic neurons is the primary neurochemical basis of the motor symptoms of Parkinson's disease (PD). While dopaminergic replacement strategies are effective in ameliorating these symptoms early in the disease process, more advanced stages of PD are associated with the development of treatment-related motor complications and dopamine-resistant symptoms. Other neurotransmitter and neuromodulator systems are expressed in the basal ganglia and contribute to the extrapyramidal refinement of motor function. Furthermore, neuropathological studies suggest that they are also affected by the neurodegenerative process. These non-dopaminergic systems provide potential targets for treatment of motor fluctuations, levodopa-induced dyskinesias, and difficulty with gait and balance. This review summarizes recent advances in the clinical development of novel pharmacological approaches for treatment of PD motor symptoms. Although the non-dopaminergic pipeline has been slow to yield new drugs, further development will likely result in improved treatments for PD symptoms that are induced by or resistant to dopamine replacement.

Fig. 1

Neurotransmitter systems involved in basal ganglia circuitry. Excitatory glutamatergic efferents (green) from cortex project to gamma-aminobutyric acid (GABA)ergic (red) striatal neurons. In the direct pathway (left), striatal neurons receive excitatory dopaminergic inputs (blue) from substantia nigra and project directly to globus pallidus interna (GPi). In the indirect pathway (right), dopamine inhibits striatal GABAergic output to the globus pallidus externa (GPe), which then projects to GPi. Adenosine A_2A receptors (yellow) are localized to dopamine D2 receptor-containing cells in the indirect pathway. Noradrenergic and cholinergic efferents from the locus coeruleus (orange) and pedunculopontine nucleus (purple), respectively, project widely to multiple brain regions, including cortex and basal ganglia. The coronal brain image is adapted with permission from http://www.brains.rad.msu.edu and http://brainmuseum.org, supported by the US National Science Foundation

Fig. 2

Expression patterns of neurotransmitter systems in the rodent brain. Dopamine D1 and D2 receptors and adenosine A_2A receptors are localized and highly expressed in the striatum, while glutamic acid decarboxylase [GAD, present in gamma-aminobutryic acid (GABA)ergic neurons], N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA), and metabotropic glutamate receptor (mGlu5) subunits, and serotonin (5-HT) receptor subtypes are not concentrated in specific brain regions. In situ hybridization images are obtained from the Allen brain atlas (www.brain-map.org)