Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

Smith, Yoland; Wichmann, Thomas; Factor, Stewart A.; DeLong, Mahlon R.

doi:10.1038/npp.2011.212

Cited by 194 publications

(144 citation statements)

References 502 publications

(469 reference statements)

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“…59 Their wide distribution in the basal ganglia has generated interest to use them as a potential therapeutic target for treating PD and LID. 78 Lesion of the nigrostriatal pathway via MPTP treatment has been reported to increase mGlu5 receptor-specific binding, measured by autoradiography, in the striatum, 45,56,70 whereas other studies 55 and also the present one showed no significant increase in mGlu5 receptors in the striatum.…”

Section: Mglu2/3 Receptor Bindingcontrasting

confidence: 45%

Changes in glutamate receptors in dyskinetic parkinsonian monkeys after unilateral subthalamotomy

Jourdain

Morin

Grégoire

et al. 2015

JNS

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abbreviatioNs AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GP = globus pallidus; GPe = GP externus; GPi = GP internus; LID = levodopa-induced dyskinesia; mGlu = metabotropic glutamate; MPTP = 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NMDA = N-methyl-d-aspartate; PD = Parkinson disease; STN = subthalamic nucleus; 6-OHDA = 6-hydroxydopamine. obJect Unilateral subthalamotomy is a surgical procedure that may be used to alleviate disabling levodopa-induced dyskinesias (LIDs) in patients with Parkinson disease (PD). However, the mechanisms involved in LID remain largely unknown. The subthalamic nucleus (STN) is the sole glutamatergic nucleus within the basal ganglia, and its lesion may produce changes in glutamate receptors in various areas of the basal ganglia. The authors aimed to investigate the biochemical changes in glutamate receptors in striatal and pallidal regions of the basal ganglia after lesion of the STN in parkinsonian macaque monkeys. methods The authors treated 12 female ovariectomized monkeys with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce PD-like symptoms, treated 8 of these animals with 3,4-dihydroxy-l-phenylalanine (L-DOPA; levodopa) to induce LID, and performed unilateral subthalamotomy in 4 of these 8 monkeys. Four additional monkeys were treated with saline only and were used as controls. The MPTP monkeys had previously been shown to respond behaviorally to lower doses of levodopa after the STN lesion. Autoradiography of slices from postmortem brain tissues was used to visualize changes in the specific binding of striatal and pallidal ionotropic glutamate receptors (that is, of the α-amino-3-hydroxy 5-methyl-4-isoxazole propionate [AMPA] and N-methyl-d-aspartate [NMDA] NR1/NR2B subunit receptors) and of metabotropic glutamate (mGlu) receptors (that is, mGlu2/3 and mGlu5 receptors). The specific binding and distribution of glutamate receptors in the basal ganglia of the levodopa-treated, STN-lesioned MPTP monkeys were compared with those in the saline-treated control monkeys and in the saline-treated and levodopa-treated MPTP monkeys. results The autoradiographic results indicated that none of the pharmacological and surgical treatments produced changes in the specific binding of AMPA receptors in the basal ganglia. Levodopa treatment increased the specific binding of NMDA receptors in the basal ganglia. Subthalamotomy reversed these increases in the striatum, but in the globus pallidus (GP), the subthalamotomy reversed these increases only contralaterally. Levodopa treatment reversed MPTPinduced increases in mGlu2/3 receptors only in the GP. mGlu2/3 receptor-specific binding in the striatum and GP decreased bilaterally in the levodopa-treated, STN-lesioned MPTP monkeys compared with the other 3 groups. Compared with mGlu5 receptor-specific binding in the control monkeys, that of the levodopa-treated MPTP monkeys increased in the dorsal putamen and remained unchanged in the caudate nucleus and in the GP. coNclusioNs These results implicate glutamate recepto...

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Section: Mglu2/3 Receptor Bindingcontrasting

confidence: 45%

Changes in glutamate receptors in dyskinetic parkinsonian monkeys after unilateral subthalamotomy

Jourdain

Morin

Grégoire

et al. 2015

JNS

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“…There are several reported nonmotor side effects that can result from DBS therapy in PD patients (targeting either the STN or the GPi) including varying degrees of cognitive changes and changes in mood, 14 symptoms of mania or hypomania, 15 depression, 15 and even suicide. 3 Postoperative symptoms of psychosis have also been reported in PD patients receiving DBS treatment.…”

mentioning

confidence: 99%

Postoperative symptoms of psychosis after deep brain stimulation in patients with Parkinson’s disease

Qureshi

Cheng

Sunshine

et al. 2015

FOC

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OBJECT Cases of postoperative psychosis in Parkinson’s disease patients receiving deep brain stimulation (DBS) treatment have previously been published. However, the magnitude of symptom incidence and the clinical risk factors are currently unknown. This retrospective study sheds light on these issues by investigating psychosis in a group of 128 Parkinson’s disease patients who received DBS implants. METHODS A retrospective chart review was performed to obtain surgery dates, follow-up clinic visit dates, and associated stimulation parameter settings (contacts in use and the polarity of each along with stimulation voltage, frequency, and pulse width) for each patient. Unified Parkinson’s Disease Rating Scale II Thought Disorder scores, used as a clinical assessment tool to evaluate the presence of psychosis at each visit, were also collected. The data were compiled into a database and analyzed. RESULTS The lifetime incidence of psychosis in this cohort of patients was 28.1%. The data suggest that risk of psychosis remains fairly constant throughout the first 5 years after implantation of a DBS system and that patients older at the time of receiving the first DBS implant are not only more likely to develop psychosis, but also to develop symptoms sooner than their younger counterparts. Further analysis provides evidence that psychosis is largely independent of the clinically used electrode contact and of stimulation parameters prior to psychosis onset. CONCLUSIONS Although symptoms of psychosis are widely seen in patients with Parkinson’s disease in the years following stimulator placement, results of the present suggest that most psychoses occurring postoperatively are likely independent of implantation and stimulation settings.

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“…The development of adenosine A2A selective antagonists, which have biological plausibility since these receptors occupy the striatum and colocalize with D2 and MGluR5 receptors, lead to great anticipation that these drugs would provide similar if not better efficacy than caffeine on a background of superior safety and tolerance. Preclinical studies of two such agents, istradefylline and preladenant, demonstrated antiparkinsonian effects and dyskinesia prevention [52][53][54][55]. However, istradefylline was the subject of four phase 3 trials in~1500 advanced PD patients and demonstrated only modest decrease in off times with an increase in dyskinesia.…”

Section: Pharmacogenomicsmentioning

confidence: 99%

Promise of Pharmacogenomics for Drug Discovery, Treatment and Prevention of Parkinson's Disease. A Perspective

Payami

Factor

2014

Neurotherapeutics

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Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

Cited by 194 publications

References 502 publications

Changes in glutamate receptors in dyskinetic parkinsonian monkeys after unilateral subthalamotomy

Changes in glutamate receptors in dyskinetic parkinsonian monkeys after unilateral subthalamotomy

Postoperative symptoms of psychosis after deep brain stimulation in patients with Parkinson’s disease

Promise of Pharmacogenomics for Drug Discovery, Treatment and Prevention of Parkinson's Disease. A Perspective

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