Parkinson’s disease (PD) is an increasingly prevalent neurodegenerative disorder primarily found in the elderly. James Parkinson first described the cardinal motor symptoms of the disorder – bradykinesia, resting tremor, rigidity and postural instability – in 1817 in ‘An Essay on the Shaking Palsy’. The cause of PD remains unknown but its progression is associated with the degeneration of the dopaminergic system altering the activity of neuronal circuits controlling movement.

Levodopa (L-dopa) was first introduced in 1968¹ and remains the most effective pharmacotherapy for PD, targeting the DA deficiency. Prolonged L-dopa therapy is associated with unwanted motor complications such as wearing off, dyskinesia and the ‘on-off’ phenomenon. 

Although effective, several other possible pharmacotherapies are now being investigated to both improve drug regimens and create new therapies with alternative sites of action. This review focuses on both current and emerging strategies for the treatment of the motor complications of PD as well as surgical interventions and alternative therapies.

Drugs affecting DA function

Natural sources of L-dopa

It is well known that natural products provide inspiration for drug discovery and design and even with advances in biotechnology a number of natural pharmacotherapies remain the most long-standing and effective. 

Ayurveda is an ancient Indian healing system combining herbal remedies with changes in lifestyle, diet, exercise and meditation. There is evidence that Mucuna pruriens, a naturally occurring L-dopa preparation, produces an onset of effect of up to twice as fast as the standard co-careldopa treatment. 

In one study the mean ‘on’ time was 37 minutes longer and tolerability and dyskinesia were similar to that of the standard treatment.² M. pruriens provides a naturally derived alternative treatment option for PD and further study is needed on both its long-term effects and tolerability.

L-dopa formulations

L-dopa is an orally administered drug, co-administered with a peripheral dopa decarboxylase inhibitor. L-dopa must pass through the stomach and into the duodenum to exert its therapeutic effect.  In a large number of PD patients gastric emptying is erratic and so absorption reduced. This, combined with the short plasma half-life of L-dopa, results in pulsatile stimulation of DA receptors leading to motor complications seen in advanced PD. 

More rapid and efficient absorption can be obtained using liquid formulations. A methyl ester form of levodopa, known as melevodopa, is an effervescent prodrug with a higher water solubility than the current tablet form of L-dopa. With oral administration it quickly reaches the small intestine and allows faster absorption and a more rapid onset of action.³

The downside of these esterified compounds is that although ‘time to on’ is quicker, the total ‘on time’ is shortened.⁴ Melevodopa is a very promising treatment option for advanced PD patients and is available in Italy but remains in phase II trials in the US. 

Alternative L-dopa formulations present an attractive target for symptomatic relief of PD. XP21279 is a L-dopa prodrug currently in phase I trials designed for absorption throughout the gastrointestinal tract and not solely the duodenum.⁵ IPX066 is currently in phase III trials and is an extended release carbidopa-L-dopa formulation. It has proven to be superior to immediate-release L-dopa in a study of 27 patients with at least three hours of daily ‘off’ time.⁵ This sustained action of the drug may reduce dosing frequency and improve compliance.

Dopamine agonists

Dopamine agonists provide clinicians with an alternative to L-dopa therapy. Comparatively, dopamine agonists provide modest symptomatic benefit and are less prone to producing unwanted motor fluctuations but are associated with a higher incidence of hallucinations, oedema, sudden sleep attacks and impulse control disorders. 

Dopamine agonists include ergot derivatives  such as bromocriptine, cabergoline, lisuride and pergolide. Apomorphine is a non-ergot dopamine agonist and is useful in patients experiencing ‘off-periods’ with levodopa and/or other dopamine agonists. It is a potent stimulator of D1 and D2 receptors. It is administered sub-cutaneously.

Both ropinirole (D2 agonist) and pramipexole  (D2/D3 agonist) have been approved as once-daily prolonged-release formulations providing an important addition to the treatment options for PD. Despite improving overall compliance though, neuropsychiatric side-effects remain a central limiting factor.

Despite the downfalls of dopamine agonists, in vitro and animal model studies have suggested their neuroprotective role.⁶ In clinical trials it has been shown that both pramipexole and ropinirole modulate the production of neuroprotective endogenous brain-derived and glial cell-derived neurotrophic factor (GDNF), causing a disease-modifying effect.⁷

Monoamine oxidase (MAO) is responsible for the degradation of DA, and MAO-b inhibitors are clinically used and effective in the treatment of PD. Interest in MAO-b inhibitors has recently been renewed with research suggesting the neuroprotective effects of rasagiline in animal models of PD.⁸ Notably, the Attenuation of Disease Progression with Rasagiline Once-daily (ADAGIO) study showed that rasagiline delays the need for other anti-Parkinsonian drugs in previously untreated early PD patients.⁹

Enhanced DA synthesis

In 2007 a multicentre, randomised, double-blind trial showed that zonisamide, an anti-epileptic drug, was effective as an adjunctive therapy in patients showing insufficient response to L-dopa, reporting significant improvements in motor fluctuations, dyskinesias and tremor.¹⁰ It has been proposed that zonisamide exerts an effect on tyrosine hydroxylase activity, resulting in increased DA synthesis. 

Drugs affecting non-DA pathways

The role of neurotransmitters in the modulation of the DA pathway in the basal ganglia is poorly understood and has led to the development of a number of compounds that target non-DA receptors and pathways. 

Neurotransmitters that may potentially modify or prevent dyskinesia include serotonin, noradrenaline and γ-aminobutyric acid (GABA), and remain a focus for novel therapeutic strategies.

α2-adrenergic receptor antagonists

The α2-adrenergic (α2a) receptor antagonist fipamezole acts on receptors found on pre-synaptic noradrenergic terminals and post-synaptic GABAergic medium spiny neurons modulating both the direct and indirect pathways.¹¹

Fipamezole prolongs the duration of action of L-dopa and reduces the severity of disease in animal models of PD.⁶ These benefits have been replicated in a study carried out on patients with advanced PD but a series of adverse effects has been noted, including pallor, nausea, sweating and dizziness.⁶ The use of fipamezole in clinical practice now has to be further evaluated.

Adenosine α2a receptor antagonists

The adenosine α2a receptor is densely localised on the basal ganglia and in particular the medium spiny neurons of the indirect pathway that projects from the striatum to the globus pallidus externa.  As these neurons are GABAergic, antagonism results in a decrease of the excessive activation of the output pathway, restoring the fine balance in the basal ganglia thalamocortical circuit.¹² Istradefylline (KW-6002) is the drug in this class that has generated the most interest from researchers. 

In animal models of PD, istradefylline improves motor function without causing dyskinesia when used in conjunction with L-dopa or a selective D1 or D2 agonist.¹³ With mounting evidence of animal model efficacy, a number of human clinical trials are currently being undertaken on istradefylline. 

One trial reported a measurable prolongation of ‘on’ time without exacerbation of dyskinesias when administered as an adjunct to low-dose L-dopa therapy.¹⁴

A subsequent trial reported a reduction in ‘off’ time in L-dopa treated patients with advanced PD with motor fluctuations and peak-dose dyskinesia but with a measurable increase in ‘on’ time with dyskinesia.¹⁵

This same group then carried out phase III trials on istradefylline, where patients showed a 0.7hr reduction in daily ‘off’ time when compared to the placebo group but these results were not replicated in other trials.

Other therapies

Gene therapy

Gene therapy involves the introduction of specific genes into patients which serve to take over the role of defective genes, induce specific processes that prevent cell death or promote regeneration.  

Gene therapy has proven effective in the treatment of single-gene heritable diseases and is now being investigated as a potential therapeutic option for many other disorders of the brain, including PD.¹⁶ Packaging the novel genes into viral vectors (AAV) has become the most commonly utilised method of transport and induces only a very mild immune response. 

Most of the research into gene therapy in PD is centred on GDNF, which has been shown to have potent neuroprotective effects on midbrain dopaminergic neurons.¹⁷ Intraputaminal infusion of GDNF has been subjected to a number of clinical trials, and produces substantial improvement in motor function and activities of daily living.¹⁸

There have also been successful phase I trials of AAV-GAD gene therapy which causes locally released GABA, providing homeostatic physiological control and ameliorating signs of advanced PD.¹⁹

Stem cells

Stem cells are undifferentiated cells that have the ability to differentiate into specific cells with particular roles. If these cells can be induced to become DA-producing cells and implanted into the area of the brain replete of these cells, neuronal circuits involved in movement can be re-established. 

Much research into stem cell therapy of this kind as a potential treatment for PD is underway. In 2011 a group of US scientists published reports of human pluripotent stem cells that had been differentiated effectively into midbrain DA neurons and successfully grafted into primate PD models.²⁰

This is a very promising step forward in the potential for stem cell treatment and potentially even a cure of PD.

Deep brain stimulation

Deep brain stimulation (DBS) is a surgical procedure used to treat advanced PD patients. It involves applying an electrical current to a targeted area in the brain and is effective in treating motor disability associated with the disease. 

Most commonly, DBS is targeted at the subthalamic nucleus but can also target the globus pallidus interna and pedunculopontine nucleus depending on the disability of the patient.²¹

There is emerging evidence that DBS may have a neuroprotective effect in rodent and primate PD models^22,23 but it is not yet known the mechanism behind this neuroprotection. 

Stemming from this evidence, there is growing interest in the potential for early DBS in improving quality-adjusted life expectancy. There are currently two studies underway evaluating these claims⁵ and results are expected to be released shortly. 

Conclusion

PD is now known to cause a broad spectrum of motor and non-motor signs and symptoms. Current therapies remain focused on the symptomatic treatment of the disease rather than curing the disease itself. As our understanding of the pathophysiology of PD increases, research has moved towards targeting alternative receptor sites, neurotransmitters, as well as improving current pharmacotherapies. There are also other areas of research driven by the need to repair damage exerted on the brain by this condition and to protect the brain from damage in the first instance.

It is clear that the problem of PD is being approached from many different angles and with the increasing prevalence of the disease there is a huge desire to make a major breakthrough. Pharmacotherapy strategies are becoming more advanced and effective and it is only a matter of time until this disease can be effectively managed and potentially cured.  

References

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