An Update on Nondopaminergic Treatments for Motor and Non-motor Symptoms of Parkinson's Disease

Abstract

Nondopaminergic neurotransmitters such as adenosine, norepinephrine, serotonin, glutamate, and acetylcholine are all involved in Parkinson's disease (PD) and promote its symptoms. Therefore, nondopaminergic receptors are key targets for developing novel preparations for the management of motor and non-motor symptoms in PD, without the potential adverse events of dopamine replacement therapy. We reviewed English-written articles and ongoing clinical trials of nondopaminergic treatments for PD patients till 2014 to summarize the recent findings on nondopaminergic preparations for the treatment of PD patients. The most promising research area of nondopaminergic targets is to reduce motor complications caused by traditional dopamine replacement therapy, including motor fluctuations and levodopa-induced dyskinesia. Istradefylline, Safinamide, and Zonisamide were licensed for the management of motor fluctuations in PD patients, while novel serotonergic and glutamatergic agents to improve motor fluctuations are still under research. Sustained- release agents of Amantadine were approved for treating levodopa induced dyskinesia (LID), and serotonin 5HT1B receptor agonist also showed clinical benefits to LID. Nondopaminergic targets were also being explored for the treatment of non-motor symptoms of PD. Pimavanserin was approved globally for the management of hallucinations and delusions related to PD psychosis. Istradefylline revealed beneficial effect on daytime sleepiness, apathy, depression, and lower urinary tract symptoms in PD subjects. Droxidopa may benefit orthostatic hypotension in PD patients. Safinamide and Zonisamide also showed clinical efficacy on certain non-motor symptoms of PD patients. Nondopaminergic drugs are not expected to replace dopaminergic strategies, but further development of these drugs may lead to new approaches with positive clinical implications.

Keywords: Parkinson’s disease; motor symptoms; nondopaminergic neurotransmitters; nondopaminergic treatments; nonmotor symptoms; update.

Fig. (1)

Nondopaminergic neurotransmitters including GABA, Glutamate, Acetylcholine, Histamine, Serotonin and Adenosine are distributed throughout the basal ganglia or related structures and play an important role in the motor and non-motor symptoms of PD patients. Nondopaminergic agents targeting on Histamine, Glutamate, Acetylcholine, Serotonin or Noradrenaline systems appear to regulate the direct pathway through the globus pallidus internus (left). While those targeting on GABA and adenosine systems mainly influence the indirect pathway reaching the globus pallidus externus and subthalamic nucleus before the globus pallidus internus (right). GPi: globus pallidus internus. SN: substantia nigra. PPN: pedunculopontine nucleus. GPe: globus pallidus externus. LC: locus coeruleus. Th: thalamus. STN: subthalamic nucleus. Str: striatum.

Fig. (2)

Schematic diagram of direct and indirect pathway in basal ganglia, regulation of serotonergic and noradrenergic projections, and receptors associated with non-dopaminergic treatments. GPi: globus pallidus internus. SNpc: substantia nigra pars compacta. pedunculopontine nucleus. GPe: globus pallidus externus. STN: subthalamic nucleus. LC: locus coeruleus. SNpr substantia nigra pars reticulata. MRN: median raphe nucleus.

Fig. (3)

Nondopaminergic preparations for the management of Levodopa-induced dyskenia in PD patients.

Fig. (4)

Nondopaminergic preparations for the management of motor fluctuations and gait disorder.

Fig. (5)

Nondopaminergic preparations for the management of non-motor symptoms in PD patients.