Elsevier

The Lancet Neurology

Volume 7, Issue 10, October 2008, Pages 927-938
The Lancet Neurology

Review
Non-dopaminergic treatments in development for Parkinson's disease

https://doi.org/10.1016/S1474-4422(08)70214-XGet rights and content

Summary

Non-dopaminergic treatments are increasingly being recognised as part of the therapeutic armamentarium for Parkinson's disease (PD). Clinical and pathological studies have shown that the disease extends beyond the substantia nigra pars compacta and involves various non-dopaminergic neurotransmitter systems that mediate both motor and non-motor symptoms that characterise PD. To date, several therapeutic strategies have been proposed to treat such symptoms. However, despite the significant morbidity associated with these symptoms, particularly non-motor symptoms, research into and drug development for problems such as mood and autonomic dysfunction remain scarce. Here, we review novel non-dopaminergic approaches that are in at least phase II clinical development for the treatment of PD.

Introduction

Parkinson's disease (PD) is primarily a disorder of the nigrostriatal dopaminergic pathway that results in the cardinal motor symptoms of bradykinesia, tremor, and rigidity. However, the pathological changes in PD also involve various non-dopaminergic neurotransmitter systems, and these are also disturbed as a consequence of long-term levodopa therapy. Thus, cortical and brainstem acetylcholine, noradrenaline, serotonin, and other neurotransmitter systems probably mediate various non-motor symptoms as the disease progresses, including disturbances in cognition, mood, behaviour, sleep, and autonomic function. These symptoms are often resistant to dopamine-replacement therapies and modern surgical treatments, and contribute greatly to the disability of late-stage PD. In addition, glutamate, adenosine, serotonin, and other neurotransmitters are involved in control of motor symptoms and mediate problems such as dyskinesia that occur after long-term levodopa treatment.

Non-dopaminergic neurotransmitter systems within the brainstem might be affected before the onset of classic motor symptoms. Early recognition of pre-motor symptoms, such as sleep disturbances and bowel dysfunction, could provide an opportunity for the use of neuroprotective drugs that target both non-dopaminergic systems and dopaminergic cell death, since, to date, treatments that focus only on the latter have generally been unsuccessful. The need for a shift in focus from developing dopaminergic to non-dopaminergic therapies is important for the future management of PD.1, 2 We discuss potential novel therapeutic approaches to PD symptoms with a focus on non-dopaminergic therapies that are in at least phase II clinical development. Our purpose is not to cover all neurotransmitter systems known to be altered in PD, but only those in which there have been active recent therapeutic advances. For example, although much information is available on the endocannabinoid and opioid systems in PD, to our knowledge there are no new related compounds sufficiently advanced in their clinical development.

Section snippets

Non-dopaminergic therapies for non-motor symptoms

Non-motor symptoms in PD include neuropsychiatric symptoms, sleep disturbances, autonomic dysfunction, and pain or sensory problems.3 Such symptoms are a frequent accompaniment to the motor disability with continuing disease progression.4 Although several non-dopaminergic systems within the brainstem and cortex are involved in PD, specific clinicopathological correlation for such features remains uncertain, and despite the increasing recognition of these problems, specific pharmacological

Non-dopaminergic therapies for motor symptoms

The basal ganglia circuitry that controls movement uses various non-dopaminergic neurotransmitters and neuromodulators that have been implicated in the neural mechanisms that underlie the motor symptoms of PD, as well as the development of motor fluctuations and dyskinesia after long-term levodopa therapy (Figure 1, Figure 2).76, 77 Several drugs targeting these non-dopaminergic systems are in development for PD. There are clear potential advantages to such an approach: non-dopaminergic drugs

Conclusions

Optimisation of symptomatic treatments for many of the motor and non-motor problems of PD requires the targeting of non-dopaminergic neurotransmitter systems. Many such agents are now in development. However, future strategies need to focus on more selective targeting of subtypes of neurotransmitter receptors to reduce side-effects and optimise benefit. Clinical studies need to be done in appropriate study populations, and the translation of preclinical findings into phase II and III trials in

Search strategy and selection criteria

References for this Review were obtained from websites for active clinical trials (currently recruiting), including PDPipeline.org (http://www.pdpipeline.org/) and ClinicalTrials.gov (http://www.clinicaltrials.gov/), with additional references from PubMed searches between 1990 and July, 2008, by use of the search terms “Parkinson's disease” and “clinical trial” in combination with “serotonin”, “5-HT”, “acetylcholine”, “noradrenaline”, “norepinephrine”, “adenosine”, “glutamate”,

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