Philippe Huot

The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

l-3,4-Dihydroxyphenylalanine (l-DOPA) remains the most effective symptomatic treatment of Parkinson’s disease (PD). However, long-term administration of l-DOPA is marred by the emergence of abnormal involuntary movements, i.e., l-DOPA-induced dyskinesia (LID). Years of intensive research have yielded significant progress in the quest to elucidate the mechanisms leading to the development and expression of dyskinesia and maintenance of the dyskinetic state, but the search for a complete understanding is still ongoing. Herein, we summarize the current knowledge of the pharmacology of LID in PD. Specifically, we review evidence gathered from postmortem and pharmacological studies, both preclinical and clinical, and discuss the involvement of dopaminergic and nondopaminergic systems, including glutamatergic, opioid, serotonergic, γ-aminobutyric acid (GABA)-ergic, adenosine, cannabinoid, adrenergic, histaminergic, and cholinergic systems. Moreover, we discuss changes occurring in transcription factors, intracellular signaling, and gene expression in the dyskinetic phenotype. Inasmuch as a multitude of neurotransmitters and receptors play a role in the etiology of dyskinesia, we propose that to optimally alleviate this motor complication, it may be necessary to develop combined treatment approaches that will target simultaneously more than one neurotransmitter system. This could be achieved via three ways as follows: 1) by developing compounds that will interact simultaneously to a multitude of receptors with the required agonist/antagonist effect at each target, 2) by targeting intracellular signaling cascades where the signals mediated by multiple receptors converge, and/or 3) to regulate gene expression in a manner that has effects on signaling by multiple pathways

Anatomically Selective Serotonergic Type 1A and Serotonergic Type 2A Therapies for Parkinson's Disease: An Approach to Reducing Dyskinesia without Exacerbating Parkinsonism?

l-DOPA remains the most effective treatment for Parkinsons disease (PD). However, long-term administration of l-DOPA is compromised by complications, particularly dyskinesia. Serotonergic type 1A (5-HT1A) receptor agonists and serotonergic type 2A (5-HT2A) receptor antagonists were, until recently, considered to be promising therapies against dyskinesia. However, there have been some recent high-profile failures in clinical trials, notably with sarizotan, and it seems that these classes of drugs may also impair l-DOPA antiparkinsonian efficacy. A simple explanation for the loss of antiparkinsonian benefit might be lack of good selectivity of these compounds for their respective targets, particularly with respect to off-target actions on dopaminergic receptors or poor dose selection in clinical studies. However, such explanations do not hold broadly when considering the actions of all compounds studied to date, whether in animal models or clinical trials. Here, we review 5-HT1A and 5-HT2A receptor function in PD and provide an anatomically based rationale as to why in some instances 5-HT1A- and 5-HT2A-modulating drugs might worsen parkinsonism, in addition to reducing dyskinesia. We propose that, in addition to selectivity for specific receptor subtypes, to target 5-HT1A and 5-HT2A receptors to alleviate dyskinesia, without worsening parkinsonism, it will be necessary to develop compounds that display anatomical selectivity, targeting corticostriatal transmission, while avoiding 5-HT receptors on ascending serotonergic and dopaminergic inputs from the raphe and substantia nigra, respectively.

Neuropsychiatric behaviors in the MPTP marmoset model of Parkinson's disease.

OBJECTIVESnNeuropsychiatric symptoms are increasingly recognised as a significant problem in patients with Parkinsons disease (PD). These symptoms may be due to sensitisation following repeated levodopa treatment or a direct effect of dopamine on the disease state. The levodopa-treated MPTP-lesioned marmoset was used as a model of neuropsychiatric symptoms in PD patients. Here we compare the time course of levodopa-induced motor fluctuations and neuropsychiatric-like behaviors to determine the relationship between duration of treatment and onset of symptoms.nnnMETHODSnMarmosets were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (2.0 mg/kg s.c.) for five days, resulting in stable parkinsonism. Levodopa (15 mg/kg and benserazide, 3.75 mg/kg) p.o. b.i.d, was administered for 30 days. Animals were evaluated for parkinsonian disability, dyskinesia and on-time (motor fluctuations) and neuropsychiatric-like behaviors on Day 0 (prior to levodopa) and on Days 1, 7, 13, 27 and 30 of treatment using post hoc DVD analysis by a trained rater, blind to the treatment day.nnnRESULTSnThe neuropsychiatric-like behavior rating scale demonstrated high interrater reliability between three trained raters of differing professional backgrounds. As anticipated, animals exhibited a progressive increase in levodopa-induced motor fluctuations, dyskinesia and wearing-off, that correlated with the duration of levodopa therapy. In contrast, levodopa-induced neuropsychiatric-like behaviors were present on Day 1 of levodopa treatment and their severity did not correlate with duration of treatment.nnnCONCLUSIONSnThe data suggest that neuropsychiatric disorders in PD are more likely an interaction between levodopa and the disease state than a consequence of sensitisation to repeated dopaminergic therapy.

L-745,870 Reduces l-DOPA-Induced Dyskinesia in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Lesioned Macaque Model of Parkinson's Disease

l-DOPA-induced dyskinesia remains an unmet challenge in the treatment of Parkinsons disease (PD). Here, we investigate the potential antidyskinetic efficacy of 3-([4-(4-chlorophenyl)piperazin-1-yl]methyl)-1H-pyrrolo[2,3-b]pyridine (l-745,870), a potent and selective dopamine D4 receptor antagonist with a good toxicology profile and an excellent safety and tolerability record in phase I/II clinical studies, for non-PD indications. Six macaques were rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration. After induction of stable and marked dyskinesia, animals were administered acute challenges of l-745,870 in combination with l-DOPA. To guarantee D4 selectivity at the doses used in the study, we determined the plasma, cerebrospinal fluid, and brain levels of l-745,870. Coadministration of l-745,870 (1 mg/kg) and l-DOPA significantly reduced the severity of dyskinesia, by up to 59%, in comparison with l-DOPA alone (P < 0.01). l-745,870 had no effect on the duration of antiparkinsonian benefit (ON-time) (P > 0.05). However, l-745,870 (1 mg/kg) significantly increased the duration of ON-time without disabling dyskinesia (+204%; P < 0.001) and decreased duration of ON-time with disabling dyskinesia compared with l-DOPA alone (−56%; P < 0.01). Brain levels of l-745,870 (∼600 ng/g) were within the range at which l-745,870 provides selective D4 receptor antagonism. Plasma levels were comparable with those demonstrated to be well tolerated in human studies. These data suggest that selective D4 receptor antagonists represent a potential therapeutic approach for l-DOPA-induced dyskinesia. It is noteworthy that l-745,870 has already undergone significant clinical development, has an excellent profile for a therapeutic candidate, and could be advanced rapidly to phase IIa clinical studies for dyskinesia in PD.

Monoamine Reuptake Inhibitors in Parkinson’s Disease

The motor manifestations of Parkinsons disease (PD) are secondary to a dopamine deficiency in the striatum. However, the degenerative process in PD is not limited to the dopaminergic system and also affects serotonergic and noradrenergic neurons. Because they can increase monoamine levels throughout the brain, monoamine reuptake inhibitors (MAUIs) represent potential therapeutic agents in PD. However, they are seldom used in clinical practice other than as antidepressants and wake-promoting agents. This review article summarises all of the available literature on use of 50 MAUIs in PD. The compounds are divided according to their relative potency for each of the monoamine transporters. Despite wide discrepancy in the methodology of the studies reviewed, the following conclusions can be drawn: (1) selective serotonin transporter (SERT), selective noradrenaline transporter (NET), and dual SERT/NET inhibitors are effective against PD depression; (2) selective dopamine transporter (DAT) and dual DAT/NET inhibitors exert an anti-Parkinsonian effect when administered as monotherapy but do not enhance the anti-Parkinsonian actions of L-3,4-dihydroxyphenylalanine (L-DOPA); (3) dual DAT/SERT inhibitors might enhance the anti-Parkinsonian actions of L-DOPA without worsening dyskinesia; (4) triple DAT/NET/SERT inhibitors might exert an anti-Parkinsonian action as monotherapy and might enhance the anti-Parkinsonian effects of L-DOPA, though at the expense of worsening dyskinesia.

A novel MDMA analogue, UWA-101, that lacks psychoactivity and cytotoxicity, enhances l-DOPA benefit in parkinsonian primates

Treatment of Parkinsons disease with dopaminergic agents, such as l‐DOPA, is frequently compromised by disabling side effects, particularly dyskinesia and a shortening in duration of antiparkinsonian action. Studies in animal models and anecdotal evidence from a patient with Parkinsons disease show that the illicit drug ecstasy (MDMA) can alleviate these side effects, though with many drawbacks (e.g., psychoactivity). MDMA itself thus has little therapeutic potential. On the basis of known structure‐psychoactivity relationships, we designed a series of α‐substituted MDMA analogues, one of which, bearing an α‐cyclopropyl substituent (UWA‐101), enhanced the quality of l‐DOPA actions in animal models. Indeed, UWA‐101 was more effective than MDMA. Unlike MDMA, UWA‐101 did not reduce viability of serotonergic cells, exhibit psychoactive properties, or reduce food intake, and did not substitute for MDMA in drug discrimination assays. UWA‐101 displayed a unique receptor/transporter binding profile relative to MDMA, with a > 5‐fold decrease in affinity for NET and 5‐HT2A receptors and a 10‐fold increase in affinity for DAT. Furthermore, in a functional reuptake assay, UWA‐101 inhibited both 5‐HT and dopamine reuptake, while having no effect on the reuptake of noradrenaline. UWA‐101 is the first selective DAT/SERT inhibitor described with comparable affinities for these two sites. These data identify a new class of therapeutic in Parkinsons disease and highlight the potential benefits of studying illicit drugs that in themselves would never be considered safe for long‐term therapy.—Johnston, T. H., Millar, Z., Huot, P., Wagg, K., Thiele, S., Salomonczyk, D., Yong‐Kee, C. J., Gandy, M. N., McIldowie, M., Lewis, K. D., Gomez‐Ramirez, J., Lee, J., Fox, S. H., Martin‐Iverson, M., Nash, J. E., Piggott, M. J., Brotchie, J. M. A novel MDMA analogue, UWA‐101, that lacks psychoactivity and cytotoxicity, enhances l‐DOPA benefit in parkinsonian primates. FASEB J. 26, 2154‐2163 (2012). www.fasebj.org

L-745,870 reduces the expression of abnormal involuntary movements in the 6-OHDA-lesioned rat.

L-3,4-Dihydroxyphenylalanine (L-DOPA) is the most effective treatment for Parkinsons disease, but chronic administration is complicated by the development of dyskinesia. We have previously demonstrated that the dopamine D4 receptor antagonist L-745,870 reduces the severity of L-DOPA-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned macaque without compromising L-DOPA antiparkinsonian benefits. In the current study, we have addressed the effects of L-745,870 on the expression of L-DOPA-induced abnormal involuntary movements (AIMs) in the 6-hydroxydopamine-lesioned rat. Rats were primed with repeated L-DOPA administration, after which acute challenges of L-DOPA/L-745,870 (vehicle, 0.1, 0.3 and 1u2009mg/kg) were administered, and AIMs were assessed. Rotarod performance and AIMs were assessed. In L-DOPA-primed rats, L-745,870 (1u2009mg/kg, but not lower doses) alleviated previously established AIMs (by 84%, P<0.001). Whereas rotarod performance was significantly improved by L-DOPA/vehicle treatment, L-DOPA/L-745,870 failed to improve rotarod performance (P>0.05), suggesting that, in contrast to the MPTP-lesioned macaque, L-745,870 reduces L-DOPA antiparkinsonian benefit in the rat model. Overall, these data suggest that L-745,870 may have a narrow therapeutic window as an antidyskinetic agent in advanced Parkinsons disease.

RGFP109, a histone deacetylase inhibitor attenuates l-DOPA-induced dyskinesia in the MPTP-lesioned marmoset: A proof-of-concept study

BACKGROUNDnl-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID) are a complication of chronic dopamine replacement therapy in Parkinsons disease (PD). Recent studies have suggested that the mechanisms underlying development and expression of LID in PD may involve epigenetic changes that include deacetylation of striatal histone proteins. We hypothesised that inhibition of histone deacetylase, the enzyme responsible of histone deacetylation, would alleviate LID.nnnMETHODSnFour female common marmoset (Callithrix jacchus) were rendered parkinsonian by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Following stabilisation of the parkinsonian phenotype, marmosets were primed to exhibit dyskinesia with chronic administration of L-DOPA. We then investigated the effects of the brain-penetrant histone deacetylase inhibitor, RGFP109 (30 mg/kg p.o. once daily for 6 days), on LID and L-DOPA anti-parkinsonian efficacy.nnnRESULTSnRGFP109 had no acute effects on dyskinesia after single or 6 days once-daily treatment (both P > 0.05). However, one week following cessation of RGFP109, dyskinesia and duration of ON-time with disabling dyskinesia were reduced by 37% and 50%, respectively (both P < 0.05), compared to that seen previously with L-DOPA alone. There was no change in anti-parkinsonian actions of, or ON-time duration afforded by, L-DOPA (P > 0.05).nnnCONCLUSIONSnHistone deacetylation inhibition may represent a novel approach to reverse established LID in PD and improve quality of the anti-parkinsonian benefit provided by L-DOPA.

Serotonergic Approaches in Parkinson’s Disease: Translational Perspectives, an Update

Parkinsons disease (PD) has long been seen as a disorder caused by degeneration of the dopaminergic system, leading to the classic motor manifestations of the disease. However, there is now overwhelming evidence that PD is more than a disease merely caused by dopamine depletion. It is well-known that a myriad of other neurotransmitters are affected by the disease process. One such neurotransmitter is serotonin (5-HT). 5-HT has been shown to play a role in several motor and nonmotor manifestations of PD, including tremor, cognition, depression and psychosis. 5-HT also seems to play a critical role in L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia. A breadth of preclinical studies and clinical trials have been conducted that aimed at modulating the 5-HT system in order to alleviate depression, cognitive deficits, psychosis, and dyskinesia. In this Review, we summarize recent advances in the 5-HT field in PD, but with a translational emphasis. We start by presenting a novel nonhuman primate model of PD that presents with dual dopamine and 5-HT lesions. We then present preclinical and clinical data that introduce new concepts, such as the use of biased and partial agonists, as well as molecules recently introduced to the field of PD, such as eltoprazine, pimavanserin, nelotanserin, and SYN-120, to enhance therapeutic benefit while minimizing adverse events, notably on parkinsonian disability.

Use of catechol-O-methyltransferase inhibition to minimize L-3,4-dihydroxyphenylalanine-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque

L‐3,4‐dihydroxyphenylalanine (L‐DOPA)‐induced dyskinesia is a complication of dopaminergic treatment in Parkinsons disease. Lowering the L‐DOPA dose reduces dyskinesia but also reduces the antiparkinsonian benefit. A therapy that could enhance the antiparkinsonian action of low‐dose L‐DOPA (LDl) without exacerbating dyskinesia would thus be of considerable therapeutic benefit. This study assessed whether catechol‐O‐methyltransferase (COMT) inhibition, as an add‐on to LDl, might be a means to achieve this goal. Cynomolgus macaques were administered 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine. Dyskinesia was established by chronic treatment with L‐DOPA. Two doses of L‐DOPA were identified – high‐dose L‐DOPA (LDh), which provided good antiparkinsonian benefit but was compromised by disabling dyskinesia, and LDl, which was sub‐threshold for providing significant antiparkinsonian benefit, without dyskinesia. LDh and LDl were administered in acute challenges in combination with vehicle and, for LDl, with the COMT inhibitor entacapone (5, 15 and 45 mg/kg). The duration of antiparkinsonian benefit (ON‐time), parkinsonism and dyskinesia were determined. The ON‐time after LDh was ∼170 min and the ON‐time after LDl alone (∼98 min) was not significantly different to vehicle (∼37 min). In combination with LDl, entacapone significantly increased the ON‐time (5, 15 and 45 mg/kg being ∼123, ∼148 and ∼180 min, respectively). The ON‐time after LDl/entacapone 45 mg/kg was not different to that after LDh. However, whereas the percentage ON‐time that was compromised by disabling dyskinesia was ∼56% with LDh, it was only ∼31% with LDl/entacapone 45 mg/kg. In addition to the well‐recognized action of COMT inhibition to reduce wearing‐OFF, the data presented suggest that COMT inhibition in combination with low doses of L‐DOPA has potential as a strategy to alleviate dyskinesia.