ABT‐089 and ABT‐894 reduce levodopa‐induced dyskinesias in a monkey model of Parkinson's disease

Levodopa‐induced dyskinesias (LIDs) are a serious complication of levodopa therapy for Parkinson's disease for which there is little treatment. Accumulating evidence shows that nicotinic acetylcholine receptor (nAChR) drugs decrease LIDs in parkinsonian animals. Here, we examined the effect of two β2 nAChR agonists, ABT‐089 and ABT‐894, that previously were approved for phase 2 clinical trials for other indications. Two sets of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐lesioned monkeys were administered levodopa/carbidopa (10 mg/kg and 2.5 mg/kg, respectively) twice daily 5 days a week until they were stably dyskinetic. Each set had a vehicle‐treated group, an nAChR agonist‐treated group, and a nicotine‐treated group as a positive control. Set A monkeys had previously received other nAChR drugs (nAChR drug‐primed), whereas Set B monkeys were initially nAChR drug‐naive. Both sets were administered the partial agonist ABT‐089 (range, 0.01‐1.0 mg/kg) orally 5 days a week twice daily 30 minutes before levodopa with each dose given for 1 to 5 weeks. ABT‐089 decreased LIDs by 30% to 50% compared with vehicle‐treated monkeys. Nicotine reduced LIDs by 70% in a parallel group. After 4 weeks of washout, the effect of the full agonist ABT‐894 (range, 0.0001‐0.10 mg/kg) was assessed on LIDs in Set A and Set B. ABT‐894 reduced LIDs by 70%, similar to nicotine. Both drugs acted equally well at α4β2* and α6β2* nAChRs; however, ABT‐089 was 30 to 60 times less potent than ABT‐894. Tolerance did not develop for the time periods tested (range, 3‐4 months). The nAChR drugs did not worsen parkinsonism or cognitive ability. Emesis, a common problem with nAChR drugs, was not observed. ABT‐894 and ABT‐089 appear to be good candidate nAChR drugs for the management of LIDs in Parkinson's disease. © 2014 International Parkinson and Movement Disorder Society     

BDNF levels are not related with levodopa‐induced dyskinesias in MPTP monkeys

Levodopa‐induced dyskinesias (LIDs) are frequent in parkinsonian patients and may result from an aberrant plasticity. Brain‐derived neurotrophic factor (BDNF) represents a likely candidate to subserve neuroadaptive processes encountered in LIDs. We compared striatal BDNF levels measured by ELISA in levodopa‐treated 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) monkeys having developed LIDs compared with animals where LIDs were prevented by the addition of CI‐1041 (NR1A/2B NMDA receptor antagonist) or low doses of cabergoline (dopamine D2 receptor agonist). We observed reduced striatal BDNF concentrations in levodopa‐treated MPTP monkeys with or without LIDs, suggesting that levodopa treatment is associated with reduced striatal BDNF levels and is independent of dyskinesias. © 2009 Movement Disorder Society     

Relationship among nigrostriatal denervation, parkinsonism, and dyskinesias in the MPTP primate model.

Presynaptic denervation is likely to play an important role in the pathophysiology of dyskinesias that develop after levodopa administration to patients with Parkinson's disease. In this study, the thresholds of nigrostriatal damage necessary for the occurrence of parkinsonism and levodopa-induced involuntary movements were compared in squirrel monkeys lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Animals treated with a regimen of MPTP that caused parkinsonism displayed > or =95% striatal dopamine depletion, 90% reduction of striatal dopamine uptake sites, and 70% nigral neuronal loss. Levodopa administration ameliorated the parkinsonian signs of these monkeys but also induced dyskinesias. A separate group of animals was treated with a milder MPTP regimen that caused 60%-70% striatal dopamine depletion, a 50% decrease in dopamine transporter, and 40% loss of dopaminergic nigral neurons. While these monkeys displayed no behavioral signs of parkinsonism, they all became dyskinetic after levodopa administration. The priming effect of levodopa, that is, the recurrence of dyskinesias in animals previously exposed to the drug, was compared in severely versus mildly lesioned monkeys. When severely injured parkinsonian animals underwent a second cycle of levodopa treatment, they immediately and consistently developed involuntary movements. In contrast, the recurrence of dyskinesias in primed monkeys with a partial nigrostriatal lesion required several levodopa administrations and remained relatively sporadic. The data indicate that moderate nigrostriatal damage which does not induce clinical parkinsonism predisposes to levodopa-induced dyskinesias. Once dyskinesias have been induced, the severity of denervation may enhance the sensitivity to subsequent levodopa exposures.     

Docosahexaenoic acid reduces levodopa-induced dyskinesias in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine monkeys

OBJECTIVE: The objective of the present study was to investigate the effect of docosahexaenoic acid (DHA), a polyunsaturated fatty acid (omega-3), on levodopa-induced dyskinesias (LIDs) in parkinsonian 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. METHODS: We explored the effect of DHA in two paradigms. First, a group of MPTP monkeys was primed with levodopa for several months before introducing DHA. A second group of MPTP monkeys (de novo) was exposed to DHA before levodopa therapy. RESULTS: DHA administration reduced LIDs in both paradigms without alteration of the anti-parkinsonian effect of levodopa indicating that DHA can reduce the severity or delay the development of LIDs in a nonhuman primate model of Parkinson's disease. INTERPRETATION: These results suggest that DHA can reduce the severity or delay the development of LIDs in a nonhuman primate model of Parkinson's disease. DHA may represent a new approach to improve the quality of life of Parkinson's disease patients.     

Development of levodopa-induced dyskinesias in parkinsonian monkeys may depend upon rate of symptom onset and/or duration of symptoms

Levodopa-induced dyskinesias (LIDs) present a major problem for the long-term management of Parkinson's disease (PD) patients. Due to the interdependence of risk factors in clinical populations, it is difficult to independently examine factors that may influence the development of LIDs. Using macaque monkeys with different types of MPTP-induced parkinsonism, the current study evaluated the degree to which rate of symptom progression, symptom severity, and response to and duration of levodopa therapy may be involved in the development of LIDs. Monkeys with acute (short-term) MPTP exposure, rapid symptom onset and short symptom duration prior to initiation of levodopa therapy developed dyskinesia between 11 and 24 days of daily levodopa administration. In contrast, monkeys with long-term MPTP exposure, slow symptom progression and/or long symptom duration prior to initiation of levodopa therapy were more resistant to developing LIDs (e.g., dyskinesia developed no sooner than 146 days of chronic levodopa administration). All animals were similarly symptomatic at the start of levodopa treatment and had similar therapeutic responses to the drug. These data suggest distinct differences in the propensity to develop LIDs in monkeys with different rates of symptom progression or symptom durations prior to levodopa and demonstrate the value of these models for further studying the pathophysiology of LIDs.     

Brain 5-HT(2A) receptors in MPTP monkeys and levodopa-induced dyskinesias

Levodopa‐induced dyskinesias (LIDs) are abnormal involuntary movements induced by the chronic use of levodopa (l ‐Dopa) limiting the quality of life of Parkinson’s disease (PD) patients. We evaluated changes of the serotonin 5‐HT_2A receptors in control monkeys, in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐lesioned monkeys and in l ‐Dopa‐treated MPTP monkeys, without or with adjunct treatments to inhibit the expression of LID: CI‐1041, a selective NR1A/2B subunit antagonist of glutamate N‐methyl‐d ‐aspartic acid (NMDA) receptor, or Cabergoline, a long‐acting dopamine D₂ receptor agonist. All treatments were administered for 1 month and animals were killed 24 h after the last dose of l ‐Dopa. Striatal concentrations of serotonin were decreased in all MPTP monkeys investigated, as measured by high‐performance liquid chromatography. [³H]Ketanserin‐specific binding to 5‐HT_2A receptors was measured by autoradiography. l ‐Dopa treatment that induced dyskinesias increased 5‐HT_2A receptor‐specific binding in the caudate nucleus and the anterior cingulate gyrus (AcgG) compared with control monkeys. Moreover, [³H]Ketanserin‐specific binding was increased in the dorsomedial caudate nucleus in l ‐Dopa‐treated MPTP monkeys compared with saline‐treated MPTP monkeys. Nondyskinetic monkeys treated with CI‐1041 or Cabergoline showed low 5‐HT_2A‐specific binding in the posterior dorsomedial caudate nucleus and the anterior AcgG compared with dyskinetic monkeys. No significant difference in 5‐HT_2A receptor binding was observed in any brain regions examined in saline‐treated MPTP monkeys compared with control monkeys. These results confirm the involvement of serotonergic pathways and the glutamate/serotonin interactions in LID. They also support targeting 5‐HT_2A receptors as a potential treatment for LID.     

Dyskinesias in Parkinson's disease: views from positron emission tomography studies

Levodopa‐induced dyskinesias (LIDs) and graft‐induced dyskinesias (GIDs) are serious and common complications of Parkinson's disease (PD) management following chronic treatment with levodopa or intrastriatal transplantation with dopamine‐rich foetal ventral mesencephalic tissue, respectively. Positron emission tomography (PET) molecular imaging provides a powerful in vivo tool that has been employed over the past 20 years for the elucidation of mechanisms underlying the development of LIDs and GIDs in PD patients. PET used together with radioligands tagging molecular targets has allowed the functional investigation of several systems in the brain including the dopaminergic, serotonergic, glutamatergic, opioid, endocannabinoid, noradrenergic and cholinergic systems. In this article the role of PET imaging in unveiling pathophysiological mechanisms underlying the development of LIDs and GIDs in PD patients is reviewed.     

Neurotoxicity of MPTP

After the discovery of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP), we acquired a good animal model of Parkinson's disease. The extraordinary recent growth in knowledge using MPTP parkinsonism has fostered increased understanding of Parkinson's disease. In the present paper, the discovery of MPTP and the biochemical, pathological, and clinical findings of MPTP parkinsonism are first reviewed briefly. Next, using MPTP parkinsonism, unresolved issuses such as the apoptosis of MPTP, levodopa toxicity, and neuroprotective effects of monoamine oxidase inhibitors or dopamine agonists are discussed. Finally, environmental factors such as the etiology of Parkinson's disease are examined. Some genetic factors that lead to familial Parkinson's disease have recently been reported, but most cases of Parkinson's disease are sporadic. Recent epidemiological evidence emphasizes an etiological relation of 18th and 19th century industrialization to Parkinson's disease. Man‐made toxins, such as industrial chemicals and herbicides/pesticides, have been suggested to increase the risk of developing Parkinson's disease. I would like to highlight the significance of re‐examination of environmental factors in the etiology of Parkinson's disease.     

Nicotine and Parkinson's disease: Implications for therapy

Accumulating evidence suggests that nicotine, a drug that stimulates nicotinic acetylcholine receptors, may be of therapeutic value in Parkinson's disease. Beneficial effects may be several‐fold. One of these is a protective action against nigrostriatal damage. This possibility stems from the results of epidemiological studies that consistently demonstrate an inverse correlation between tobacco use and Parkinson's disease. This reduced incidence of Parkinson's disease has been attributed to the nicotine in tobacco products, at least in part, based on experimental work showing a protective effect of nicotine against toxic insults. Second, several studies suggest a symptomatic effect of nicotine in Parkinson's disease, although effects are small and somewhat variable. Third, recent data in nonhuman primates show that nicotine attenuates levodopa‐induced dyskinesias, a debilitating side effect that develops in the majority of patients on levodopa therapy. Collectively, these observations suggest that nicotine or CNS selective nicotinic receptor ligands hold promise for Parkinson's disease therapy to reduce disease progression, improve symptoms, and/or decrease levodopa‐induced dyskinesias. © 2007 Movement Disorder Society     

Metabolic activity of the subthalamic nucleus in a primate model of L-Dopa-unresponsive parkinsonism

Abstract

Increased activity of the subthalamic nucleus (STN) is critical in mediating motor symptoms of Parkinson's disease. To determine if altered STN activity also occurs in levodopa (L-Dopa)-unresponsive parkinsonism due to a combined nigral and striatal degeneration, metabolic activity of the STN was assessed using cytochrome oxidase (CO) histochemistry in monkeys with nigral, striatal, or nigral+striatal degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and/or 3-nitropropionic acid (3NP). MPTP- and MPTP+3NP-treated monkeys had a similar parkinsonian score and were clinically indistinguishable. However, CO activity in the STN was significantly increased in MPTP-induced parkinsonism but not in MPTP+3NP-induced striatonigral degeneration. These results indicate that metabolic activity of the STN is normal following a combined nigral+striatal degeneration and may help to understand the lack of effect of STN stimulation in L-Dopa-unresponsive parkinsonism.     

Targeting metabotropic glutamate receptors as a new strategy against levodopa‐induced dyskinesia in Parkinson's disease?

Levodopa‐induced dyskinesias (LIDs) represent one major motor disability of Parkinson's disease (PD) therapy. Thus, research effort is still devoted to finding agents that may improve parkinsonism and concomitantly reduce or avoid dyskinesia. Rodent and nonhuman primate models provide useful tools to study the molecular and neuronal bases of LIDs. Among the various strategies investigated recently, the use of drugs targeting metabotropic glutamate receptors has received large attention. In particular, use of antagonists of the subtype 5 of metabotropic glutamate receptors revealed promising preclinical and clinical results. © 2014 International Parkinson and Movement Disorder Society     

Pramipexole combined with levodopa improves motor function but reduces dyskinesia in MPTP‐treated common marmosets

Reduced expression of dyskinesia is observed in levodopa‐primed MPTP‐treated common marmosets when dopamine agonists are used to replace levodopa. We now investigate whether a combination of the D‐2/D‐3 agonist pramipexole and levodopa also reduces dyskinesia intensity while maintaining the reversal of motor disability. Drug naïve, non‐dyskinetic MPTP‐treated common marmosets were treated daily for up to 62 days with levodopa (12.5 mg/kg plus carbidopa 12.5 mg/kg p.o. BID) or pramipexole (0.04–0.3 mg/kg BID) producing equivalent reversal of motor disability and increases in locomotor activity. Levodopa alone resulted in marked dyskinesia induction but little or no dyskinesia resulted from the administration of pramipexole. From day 36, some animals were treated with a combination of levodopa (3.125–6.25 mg/kg plus carbidopa 12.5 mg/kg p.o. BID) and pramipexole (0.1–0.2 mg/kg p.o. SID). This improved motor disability to a greater extent than occurred with levodopa alone. Importantly, while dyskinesia was greater than that produced by pramipexole alone, the combination resulted in less intense dyskinesia than produced by levodopa alone. These results suggest that pramipexole could be administered with a reduced dose of levodopa to minimize dyskinesia in Parkinson's disease while maintaining therapeutic efficacy. © 2010 Movement Disorder Society     

Striatal Akt/GSK3 signaling pathway in the development of L-Dopa-induced dyskinesias in MPTP monkeys

L-Dopa treatment, the gold standard therapy for Parkinson's disease, is hampered by motor complications such as dyskinesias. Recently, impairment of striatal Akt/GSK3 signaling was proposed to play a role in the mechanisms implicated in development of L-Dopa-induced dyskinesias in a rodent model of Parkinson's disease. The present experiment investigated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys, the effects on Akt/GSK3 of chronic L-Dopa treatment inducing dyskinesias compared to L-Dopa with CI-1041 (NMDA receptor antagonist) or a low dose of cabergoline (dopamine D2 receptor agonist) preventing dyskinesias. The extensive dopamine denervation induced by MPTP was associated with a decrease by about half of phosphorylated Akt(Ser473) levels in posterior caudate nucleus, anterior and posterior putamen; smaller changes were observed for phosphorylated Akt(Thr308) levels that did not reach statistical significance. Dopamine depletion reduced phosphorylated GSK3β(Ser9) levels, mainly in posterior putamen whereas pGSK3β(Tyr216) and pGSK3α(Ser21) were unchanged. In posterior caudate nucleus, anterior and posterior putamen of dyskinetic L-Dopa-treated MPTP monkeys, pAkt(Ser473) and pGSK3β(Ser9) were elevated whereas L-Dopa+cabergoline treated MPTP monkeys without dyskinesias had lower values in posterior striatum as vehicle-treated MPTP monkeys. In non-dyskinetic MPTP monkeys treated with L-Dopa+CI-1041, putamen pAkt(Ser473) and pGSK3β(Ser9) levels remained elevated as in dyskinetic monkeys while in posterior caudate nucleus, these levels were low as vehicle-treated and lower than L-Dopa treated MPTP monkeys. Extent of phosphorylation of Akt and GSK3β in putamen correlated positively with dyskinesias scores of MPTP monkeys; these correlations were higher with dopaminergic drugs (L-Dopa, cabergoline) suggesting implication of additional mechanisms and/or signaling molecules in the NMDA antagonist antidyskinetic effect. In conclusion, our results showed that in MPTP monkeys, loss of striatal dopamine decreased Akt/GSK3 signaling and that increased phosphorylation of Akt and GSK3β was associated with L-Dopa-induced dyskinesias.     

Effects of fibroblast transplantation into the internal pallidum on levodopa-induced dyskinesias in parkinsonian non-human primates

Recent studies have shown that fibroblast transplantation can modify the activity of basal ganglia networks in models of Parkinson's disease.To determine its effects on parkinsonian motor symptoms,we performed autologous dermal fibroblast transplantation into the internal pallidum(GPi) in two parkinsonian rhesus monkeys with stable levodopainduced dyskinesias(LIDs).Levodopa responses were assessed every week after transplantation for three months.A reduction of between 58%and 64%in total LIDs on the contralateral side was observed in both animals.No clear LID changes were observed on the ipsilateral side.These effects lasted the entire3-month period in one monkey,but declined after6-8 weeks in the other.The antiparkinsonian effects of levodopa did not diminish.The results of this pilot study indicate that fibroblast transplantation into the GPi may have beneficial effects on LIDs and warrant further investigation for potential therapeutic use.     

Implication of NMDA Receptors in the Antidyskinetic Activity of Cabergoline,CI-1041, and Ro 61-8048 in MPTP Monkeys with Levodopa-induced Dyskinesias

This study assessed striatal N-methyl-D-aspartate (NMDA) glutamate receptors of 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys with levodopa (L-DOPA)-induced dyskinesias (LID). In a first experiment, four MPTP monkeys receiving L-DOPA/Benserazide alone developed dyskinesias. Four MPTP monkeys received L-DOPA/Benserazide plus CI-1041 an NMDA antagonist selective for NR1/NR2B and four were treated with L-DOPA/Benserazide plus a small dose of cabergoline; one monkey of each group developed mild dyskinesias at the end of treatment. In a second experiment, a kynurenine 3-hydroxylase inhibitor Ro 61-8048, combined with L-DOPA/Benserazide, reduced dyskinesias in MPTP monkeys. Drug-treated MPTP monkeys were compared to intact monkeys and saline-treated MPTP monkeys. Glutamate receptors were investigated by autoradiography using [³H]CGP-39653 (NR1/NR2A antagonist) and [³H]Ro25-6981 (NR1/NR2B antagonist). In general, striatal [³H]CGP-39653 specific binding was unaltered in all experimental groups. MPTP lesion decreased striatal [³H]Ro25-6981 specific binding; these levels were enhanced in the L-DOPA-alone-treated MPTP monkeys and decreased in antidyskinetic drugs treated monkeys. Maximal dyskinesias scores of the MPTP monkeys correlated significantly with [³H]Ro25-6981 specific binding in the rostral and caudal striatum. Hence, MPTP lesion, L-DOPA treatment and prevention of LID with CI-1041 and cabergoline, or reduction with Ro 61-8048 were associated with modulation of NR2B/NMDA glutamate receptors.     

Focal striatal dopamine may potentiate dyskinesias in parkinsonian monkeys

Striatal neurons convert L-dopa to dopamine (DA) following gene transfer of aromatic L-amino acid decarboxylase (AADC) via adeno-associated virus (AAV) in parkinsonian monkeys. We investigated whether AAV-AADC could reduce or eliminate L-dopa-induced dyskinesias (LIDs) and side effects in MPTP-treated monkeys. Five monkeys were made parkinsonian by bilateral MPTP lesions. The optimal therapeutic dose of L-dopa was determined using an acute dose response regimen. After 3 weeks of chronic L-dopa treatment, AAV-AADC or control vector was bilaterally injected into the striatum. Animals were assessed for 6 months with the same L-dopa dosing as presurgery as well as chronic oral L-dopa treatment. Presurgery LID was observed at doses greater than 5 mg/kg. The AAV-AADC-treated animals displayed an average 7.3-fold decrease in the therapeutic dose of L-dopa throughout the 6-month follow-up period. Only AAV-AADC-treated monkeys were susceptible to dyskinesias even at sub-clinical doses. Immunohistochemical analysis revealed well-delineated foci of AADC within the striatum. These results suggest that high levels of focal DA were generated in response to L-dopa administration and may be responsible for the exacerbation of dyskinesias. This may be similar to focal dopaminergic activity in PD patients that developed off-drug or "runaway" dyskinesias following fetal mesencephalic grafts.     

Parkinsonian monkeys with prior levodopa‐induced dyskinesias followed by fetal dopamine precursor grafts do not display graft‐induced dyskinesias

Clinical trials testing the hypothesis that fetal dopamine grafts would provide antiparkinsonian benefit in patients who had already developed side effects from their long‐term use of L‐dopa revealed, in some cases, the presence of dyskinesias even in the absence of L‐dopa. The form, intensity, and frequency of these dyskinesias were quite variable, but their manifestation slowed the clinical development of cell replacement therapies. Rodent models of graft‐induced dyskinesias (GIDs) have been proposed, but their accuracy in modeling GIDs has been questioned because they usually require amphetamine for their presentation. The present study attempted to model GIDs in parkinsonian monkeys and, for the first time, to test the effect of grafts on previously dyskinetic monkeys. Toward this end, monkeys were rendered parkinsonian with n‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) and dyskinetic with levodopa. They then received intraputamenal grafts of fetal dopaminergic cells, control cerebellar cells, or vehicle bilaterally and were studied for 18 months. Dopaminergic cells were grafted in a manner designed to produce either “hot spot” or “widespread” striatal innervation. Although levodopa‐induced dyskinesias could be elicited postoperatively, GIDs were never observed in any animal at any time after grafting. Grafted monkeys were also challenged with levodopa but did not show any greater responses to these challenges than before grafting. These studies support the development of future dopamine neuron cell transplantation therapy‐based approaches, indicating that in relevant primate models with appropriate cell preparation methodology, with successful graft survival and putamenal dopamine innervation, there is no evidence of graft‐induced dyskinesias. J. Comp. Neurol. 525:498–512, 2017. © 2016 Wiley Periodicals, Inc.     

Prevention of levodopa-induced dyskinesias by a selective NR1A/2B N-methyl-D-aspartate receptor antagonist in parkinsonian monkeys: implication of preproenkephalin.

Enkephalin is reported to play an important role in the pathophysiology of levodopa (LD) -induced dyskinesias. The present study investigated the effect of chronic treatment with a selective NR1A/2B N-methyl-D-aspartate (NMDA) receptor antagonist, CI-1041, on the expression of preproenkephalin-A (PPE-A) in brains of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) -treated monkeys in relation to the development of LD-induced dyskinesias. Four MPTP-monkeys received LD/benserazide alone; they all developed dyskinesias. Four other MPTP-monkeys received LD/benserazide plus CI-1041; only one of them developed mild dyskinesias at the end of the fourth week of treatment. Four normal monkeys and four saline-treated MPTP monkeys were also included. MPTP-treated monkeys had extensive and similar striatal dopamine denervation. An increase of PPE-A mRNA levels assayed by in situ hybridization was observed in the lateral putamen (rostral and caudal) and caudate nucleus (rostral) of saline-treated MPTP monkeys compared to controls, whereas no change or a small increase was observed in their medial parts. Striatal PPE-A mRNA levels remained elevated in LD-treated MPTP monkeys, whereas cotreatment with CI-1041 brought them back to control values. These findings suggest that chronic blockade of striatal NR1A/2B NMDA receptors with CI-1041 normalizes PPE-A mRNA expression and prevents the development of LD-induced dyskinesias in an animal model of Parkinson disease.     

Levodopa-induced dyskinesias in Parkinson's disease: is sensitization reversible?

Levodopa-induced dyskinesias (LIDs) in patients with Parkinson's disease are considered to result from the severity of dopaminergic denervation in the striatum, which is an irrevocable phenomenon, and sensitization induced by long-term intermittent administration of levodopa. Taking advantage of the 64% reduction of levodopa treatment allowed in 12 Parkinson's disease patients by continuous high-frequency stimulation of the subthalamic nucleus, we evaluated the severity of parkinsonian motor disability and LIDs during two levodopa challenges performed before the surgical implantation of the stimulation electrodes and after 8.8 months of continuous bilateral subthalamic nucleus stimulation that was interrupted 2 hours before the levodopa test. Motor disability during the "off" and "on" drug periods was unchanged. The severity of LIDs during the "on" period and dystonia during the "off" period decreased by 54% and 62%, respectively. The reduced severity of LIDs in the absence of subthalamic nucleus stimulation demonstrates that the sensitization phenomenon resulting from long-term intermittent levodopa administration is partially reversible.