Special Issue on new therapeutic approaches to Parkinson disease.

Parkinson's disease (PD) is a common neurodegenerative disorder. Age is the biggest risk factor, with the prevalence rising from 1% in 45-54 year age group to 2-4% in 85 year or older. Population increases have led some to predict that we are facing a 'PD Pandemic' with the prevalence doubling in the next two decades. There is thus an urgent need for effective therapies to reduce disease burden. In this Special Issue of Neuropharmacology invited authors have reviewed current and emerging targets for pharmacological therapy for PD covering the areas of disease modification, i.e. addressing the underlying disease processes, through to symptomatic therapies, whether for motor or non-motor symptoms of the disease. The articles are from leaders in the field and represent preclinical and clinical stages of therapeutic development. The Special Issue highlights that there is ongoing significant activity across all these potential indications and a vast array of targets have been identified and validated to different extents. PD is, and will remain for the foreseeable future, for the neuropharmacologist a significant area of research, in both the preclinical and clinical space.

The selective 5-HT1A receptor agonist, NLX-112, exerts anti-dyskinetic effects in MPTP-treated macaques.

BACKGROUND: Long-term treatment of Parkinson's disease (PD) with l-DOPA typically leads to development of l-DOPA induced dyskinesia (LID). Amantadine, an NMDA antagonist, attenuates LID, but with limited efficacy and considerable side-effects. NLX-112 (also known as befiradol or F13640), a highly selective and efficacious 5-HT1A receptor agonist, reduced LID when tested in rodent and marmoset models of PD. METHODS: The effects of NLX-112 (0.03, 0.1 and 0.3 mg/kg PO) on established LID evoked by acute challenge with l-DOPA (27.5 ± 3.8 mg/kg PO) were assessed in MPTP-treated cynomolgus macaques. Amantadine (10 mg/kg PO) was tested as a positive control. Plasma exposure of NLX-112 (0.1 mg/kg PO) was determined. RESULTS: NLX-112 significantly and dose-dependently reduced median LID levels by up to 96% during the first hour post-administration (0.3 mg/kg). Moreover, NLX-112 reduced the duration of 'bad on-time' associated with disabling LID by up to 48% (0.3 mg/kg). In contrast, NLX-112 had negligible impact on the anti-parkinsonian benefit of l-DOPA. NLX-112 exposure peaked at ~50 ng/ml at 30 min post-administration but decreased to ~15 ng/ml at 2h. Amantadine reduced by 42% 'bad on-time' associated with l-DOPA, thereby validating the model. CONCLUSION: These data show that, in MPTP-lesioned cynomolgus macaques, NLX-112 exerts robust anti-dyskinetic effects, without reducing the anti-parkinsonian benefit of l-DOPA. These observations complement previous findings and suggest that selective and high efficacy activation of 5-HT1A receptors by NLX-112 may constitute a promising approach to combat LID in PD, providing an alternative for patients in whom amantadine is poorly tolerated or without useful effect.

NYX-458 Improves Cognitive Performance in a Primate Parkinson's Disease Model.

BACKGROUND: NYX-458 is a N-methyl-d-aspartate receptor (NMDAR) modulator that enhances synaptic plasticity. Dopaminergic cell loss in Parkinson's disease (PD) leads to NMDAR dysregulation in the cortico-striato-pallidal-thalmo-cortical network and altered plasticity in brain regions important to cognitive function. We hypothesize that targeting the NMDAR may be an efficacious approach to treating cognitive impairment in PD. OBJECTIVES: NYX-458 was evaluated in 2 nonhuman primate models of PD. The first, a chronic low-dose 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-administration model, was used to assess the effects of NYX-458 on cognitive domains impacted early in PD including attention, working memory, executive function, and visuospatial learning. The second, a high-dose MPTP-administration model, was used to assess potential for NYX-458 induced change in motor symptoms. METHODS: NYX-458 was evaluated in the chronic low-dose MPTP model using the variable delayed response measure to assess attention and working memory and simple discrimination reversal to assess executive function. NYX-458 was also assessed in the high-dose MPTP model as a monotherapy and in combination with low-dose or high-dose levodopa to assess potential impact on motor symptoms. RESULTS: NYX-458 administration resulted in rapid and long-lasting improvement in cognitive function across the domains of attention, working memory, and executive function. Dose levels effective in improving cognitive performance had no effect on PD motor symptoms, the antiparkinsonian benefit of levodopa, or dyskinesia. CONCLUSIONS: NYX-458 provides benefit in specific domains known to be impaired in PD in a dopamine depletion model of PD-like cognitive impairment. These data support the continued evaluation of NYX-458 as a potential therapeutic for cognitive decline in PD. © 2020 International Parkinson and Movement Disorder Society.

Alpha1-adrenoceptors mediate dihydroxyphenylalanine-induced activity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaques.

The mechanisms underlying actions of dihydroxyphenylalanine (L-DOPA) in Parkinson's disease remain to be fully elucidated. Noradrenaline formed from L-DOPA may stimulate alpha(1)-adrenoceptors. We assessed the involvement of alpha(1)-adrenoceptors in actions of L-DOPA in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaques. In each animal, the minimal dose of L-DOPA required to alleviate parkinsonian symptoms was defined (12.5-25 mg/kg p.o.). The effects of coadministration of the alpha(1)-adrenoceptor antagonist prazosin ([4-(4-amino-6,7-dimethoxy-quinazolin-2-yl) piperazin-1-yl]-(2-furyl)methanone) on motor activity, parkinsonism, and dyskinesia were assessed. Antiparkinsonian benefit was accompanied by mild dyskinesia. L-DOPA also elicited hyperactivity, i.e., activity greater than that seen in normal animals. Coadministration of prazosin (0.16-0.63 mg/kg p.o.) with L-DOPA did not significantly affect either its antiparkinsonian actions or dyskinesia. However, prazosin significantly and dose-dependently attenuated L-DOPA-induced activity, reducing it to a level equivalent to that of normal animals. More specifically, during periods of pronounced L-DOPA-induced activity, prazosin attenuated the total and duration of activity by 80 and 76%, respectively. These actions of prazosin were expressed in the absence of sedation. Although activation of alpha(1)-adrenoceptors plays no major role in the antiparkinsonian and dyskinetic effects of L-DOPA per se, it does contribute to the induction of hyperactivity. alpha(1)-Adrenoceptors may be involved in pathological responses to L-DOPA treatment, including the dopamine dysregulation syndrome.

High frequency stimulation or elevated K+ depresses neuronal activity in the rat entopeduncular nucleus.

High frequency stimulation (HFS) is applied to many brain regions to treat a variety of neurological disorders/diseases, yet the mechanism(s) underlying its effects remains unclear. While some studies showed that HFS inhibits the stimulated nucleus, others report excitation. In this in vitro study, we stimulated the rat globus pallidus interna (entopeduncular nucleus, EP), a commonly stimulated area for Parkinson's disease, to investigate the effect of HFS-induced elevation of extracellular potassium (K(+)(e)) on rat EP neuronal activity. Whole-cell patch-clamp recordings and [K(+)](e) measurements were obtained in rat EP brain slices before, during and after HFS. After HFS (150 Hz, 10 s), [K(+)](e) increased from 2.5-9.6+/-1.4 mM, the resting membrane potential of EP neurons depolarized by 11.1+/-2.5 mV, spiking activity was significantly depressed, and input resistance decreased by 25+/-6%. The GABA(A) receptor blocker, gabazine, did not prevent these effects. The bath perfusion of 6 or 10 mM K(+), with or without synaptic blockers, mimicked the HFS-mediated effects: inhibition of spike activity, a 20+/-9% decrease in input resistance and a 17.4+/-3.0 mV depolarization. This depolarization exceeded predicted values of elevated [K(+)](e) on the resting membrane potential. A depolarization block did not fully account for the K(+)-induced inhibition of EP neuronal activity. Taken together, our results show that HFS-induced elevation of [K(+)](e) decreased EP neuronal activity by the activation of an ion conductance resulting in membrane depolarization, independent of synaptic involvement. These findings could explain the inhibitory effects of HFS on neurons of the stimulated nucleus.

Striatal delta opioid receptor binding in experimental models of Parkinson's disease and dyskinesia.

Enhanced delta opioid receptor transmission may represent an endogenous compensatory mechanism in parkinsonism to reduce the activity of the indirect striatopallidal pathway following dopamine depletion. Furthermore, increased delta opioid receptor transmission may be causative in the production of dyskinesia following repeated dopaminergic treatment in Parkinson's disease. The present study employed radioligand receptor autoradiography, using [3H]naltrindole, a ligand selective for the delta opioid receptor, to assess delta opioid receptor binding sites in forebrain regions of reserpine-treated rats, and in parkinsonian nondyskinetic, and dyskinetic MPTP-lesioned macaques. In reserpine-treated animals, specific delta opioid binding was increased in premotor cortex (+30%), sensorimotor striatum (+20%), and associative striatum (+17%) rostrally, but was not changed in caudal forebrain. In contrast, delta opioid receptor binding was not significantly altered at any region analyzed, in either nondyskinetic or dyskinetic, MPTP-lesioned macaques, compared to normal. These results suggest that transient changes in delta opioid receptor binding may occur in motor circuits following acute dopamine depletion. However, in the more chronic MPTP-lesioned macaque model, simple changes in delta opioid receptor number or affinity are unlikely to contribute to mechanisms for abnormal opioid transmission in Parkinson's disease and dyskinesia.

Alterations of striatal NMDA receptor subunits associated with the development of dyskinesia in the MPTP-lesioned primate model of Parkinson's disease.

The development of dyskinesias and other motor complications greatly limits the use of levodopa therapy in Parkinson's disease (PD). Studies in rodent models of PD suggest that an important mechanism underlying the development of levodopa-related motor complications is alterations in striatal NMDA receptor function. We examined striatal NMDA receptors in the MPTP-lesioned primate model of PD. Quantitative immunoblotting was used to determine the subcellular abundance of NR1, NR2A and NR2B subunits in striata from unlesioned, MPTP-lesioned (parkinsonian) and MPTP-lesioned, levodopa-treated (dyskinetic) macaques. In parkinsonian macaques, NR1 and NR2B subunits in synaptosomal membranes were decreased to 66 +/- 11% and 51.2 +/- 5% of unlesioned levels respectively, while the abundance of NR2A was unaltered. Levodopa treatment eliciting dyskinesia normalized NR1 and NR2B and increased NR2A subunits to 150 +/- 12% of unlesioned levels. No alterations in receptor subunit tyrosine phosphorylation were detected. These results demonstrate that altered synaptic abundance of NMDA receptors with relative enhancement in the abundance of NR2A occurs in primate as well as rodent models of parkinsonism, and that in the macaque model, NR2A subunit abundance is further increased in dyskinesia. These data support the view that alterations in striatal NMDA receptor systems are responsible for adaptive and maladaptive responses to dopamine depletion and replacement in parkinsonism, and highlight the value of subtype selective NMDA antagonists as novel therapeutic approaches for PD.

Subcellular redistribution of the synapse-associated proteins PSD-95 and SAP97 in animal models of Parkinson's disease and L-DOPA-induced dyskinesia.

Abnormalities in subcellular localization and interaction between receptors and their signaling molecules occur within the striatum in Parkinson's disease (PD) and L-DOPA-induced dyskinesia (LID). Synapse-associated proteins (SAPs), for example, PSD-95 and SAP97 organize the molecular architecture of synapses and regulate interactions between receptors and downstream-signaling molecules. Here, we show that expression and subcellular distribution of PSD-95 and SAP97 are altered in the striatum of unilateral 6-OHDA-lesioned rats following repeated vehicle (a model of PD) or L-DOPA administration (a model of L-DOPA-induced dyskinesia). Furthermore, following dopamine-depletion and development of behavioral deficits in Rotorod performance, indicative of parkinsonism, we observed a dramatic decrease in total striatal levels of PSD-95 and SAP97 (to 25.6 +/- 9.9% and 19.0 +/- 5.0% of control, respectively). The remaining proteins were redistributed from the synapse into vesicular compartments. L-DOPA (6.5mg/kg twice a day, 21 days) induced a rotational response, which became markedly enhanced with repeated treatment (day 1: -15.8+/-7.3 rotations cf day 21: 758.2+/-114.0 rotations). Post L-DOPA treatment, PSD-95 and SAP97 levels increased (367.4 +/- 43.2% and 159.9 +/- 9.5% from control values, respectively), with both being redistributed toward synaptic membranes from vesicular compartments. In situ hybridization showed that changes in total levels of PSD-95, but not SAP97, were accompanied by qualitatively similar changes in mRNA. These data highlight the potential role of abnormalities in the subcellular distribution of SAPs in the pathophysiology of a neurological disease.

Topiramate reduces levodopa-induced dyskinesia in the MPTP-lesioned marmoset model of Parkinson's disease.

Overactive AMPA receptor-mediated transmission may be involved in the pathogenesis of levodopa-induced dyskinesia. The mechanism of action of the anticonvulsant drug topiramate involves attenuation of AMPA receptor-mediated transmission. In this study, the potential antidyskinetic action of topiramate was examined in the MPTP-lesioned marmoset model of Parkinson's disease and levodopa-induced dyskinesia. Topiramate significantly reduced levodopa-induced dyskinesia, without affecting the antiparkinsonian action of levodopa. Topiramate represents an exciting potential novel therapeutic approach to levodopa-induced dyskinesia in patients with Parkinson's disease.

Levodopa-induced dyskinesia in Parkinson's disease.

Levodopa-induced dyskinesias (LID) are abnormal involuntary movements that develop progressively with repeated dopamine replacement therapy in Parkinson's disease (PD). The pathophysiology of LID comprises many functionally-related abnormalities in neurotransmission which lead to abnormalities in the rate, pattern and synchronisation of neuronal activity within and outside the basal ganglia. In this review, we discuss the significance of the problem of LID, options currently available for avoiding and treating LID, recent advances in understanding the mechanisms responsible for the generation of LID once it has been established. In particular the discussion relates to the mechanisms underlying LID seen while levodopa is exerting its peak anti-parkinsonian actions, as it is this component of LID that is best modelled in animals and, to date, best understood. We do not aim to discuss the mechanisms by which LID is established and evolves, often termed priming, with repeated treatment, though this is an important area that has also witnessed significant advances recently (for recent review, see Blanchet et al., 2004). Finally, we define, where possible, the rationale for multiple novel therapeutic approaches that might help resolve the problem of LID.

The NR2B-selective NMDA receptor antagonist CP-101,606 exacerbates L-DOPA-induced dyskinesia and provides mild potentiation of anti-parkinsonian effects of L-DOPA in the MPTP-lesioned marmoset model of Parkinson's disease.

In Parkinson's disease (PD), degeneration of the dopaminergic nigrostriatal pathway leads to enhanced transmission at NMDA receptors containing NR2B subunits. Previous studies have shown that some, but not all, NR2B-containing NMDA receptor antagonists alleviate parkinsonian symptoms in animal models of PD. Furthermore, enhanced NMDA receptor-mediated transmission underlies the generation of L-DOPA-induced dyskinesia (LID). The subunit content of NMDA receptors responsible for LID is not clear. Here, we assess the actions of the NMDA antagonist CP-101,606 in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset model of Parkinson's disease. CP-101,606 is selective for NMDA receptors containing NR2B subunits, with higher affinity for NR1/NR2B complexes compared to ternary NR1/NR2A/NR2B complexes. CP-101,606 had no significant effect on parkinsonian symptoms when administered as monotherapy over a range of doses (0.1-10 mg/kg). CP-101,606 provided a modest potentiation of the anti-parkinsonian actions of L-DOPA (8 mg/kg), although, at doses of 1 and 3 mg/kg, CP-101,606 exacerbated LID. Results of this study provide further evidence of differences in the anti-parkinsonian activity and effects on LID of the NR2B subunit selective NMDA receptor antagonists. These distinctions may reflect disparities in action on NR1/NR2B as opposed to NR1/NR2A/NR2B receptors.

Selective blockade of D(3) dopamine receptors enhances the anti-parkinsonian properties of ropinirole and levodopa in the MPTP-lesioned primate.

To date, the lack of highly selective antagonists at the dopamine D(3) receptor has hampered clarification of their involvement in the actions of currently used therapies in Parkinson's disease. However, the novel benzopyranopyrrole, S33084, displays greater than 100-fold selectivity as an antagonist for D(3) versus D(2) receptors and all other sites tested. S33084 was administered to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets previously primed with levodopa to elicit dyskinesia. Administered alone, S33084 exerted a modest, but significant, anti-parkinsonian effect without provoking dyskinesia. At low D(3)-selective doses (0.16 and 0.64 mg/kg), S33084 potentiated, though to different extents and in qualitatively different ways, the anti-parkinsonian actions of both ropinirole and levodopa. At these doses, S33084 did not significantly modify levodopa-induced or ropinirole-induced dyskinesia. These data suggest that ropinirole and levodopa do not exert their anti-parkinsonian or pro-dyskinetic actions via D(3) receptor stimulation. Indeed, stimulation of D(3) receptors may be detrimental to the anti-parkinsonian properties of D(2)/D(3) agonists. Selectivity for stimulation of D(2), over D(3), receptors may therefore be a beneficial property of dopamine receptor agonists in management of motor symptoms of Parkinson's disease patients with established dyskinesia.

5-hydroxytryptamine (5-HT, serotonin) and Parkinson's disease - opportunities for novel therapeutics to reduce the problems of levodopa therapy.

While Parkinson's disease is undoubtedly a disorder with a primary pathology of dopamine neuronal loss, that loss of dopamine and subsequent dopamine replacement therapy leads to imbalances in many non-dopaminergic transmitter systems, including 5-hydroxytryptamine (5-HT). Recent advances in understanding the role of 5-HT in parkinsonism and the generation of side-effects of dopamine replacement therapy (e.g. wearing-off and levodopa-induced dyskinesia) have identified 5-HT1A, 5-HT1B and 5-HT2C receptors as potential therapeutic targets in Parkinson's disease.

Striatal AMPA receptor binding is unaltered in the MPTP-lesioned macaque model of Parkinson's disease and dyskinesia.

Long-term levodopa or dopamine agonist treatment in the MPTP-lesioned primate model of Parkinson's disease elicits dyskinesia, which is phenotypically similar to levodopa-induced dyskinesia in patients with Parkinson's disease. AMPA receptor antagonists have previously been shown to have both anti-parkinsonian and anti-dyskinetic actions in MPTP-lesioned primates, suggesting that AMPA receptor transmission is functionally overactive under these conditions. In this study, we investigated the level of striatal AMPA receptor binding in the MPTP lesioned primate using the selective AMPA ligand (3)H-(S)-5-fluorowillardiine. AMPA receptor binding was studied in non-parkinsonian, non-dyskinetic parkinsonian, and dyskinetic macaques. Striatal AMPA receptor binding was not different in any of the treatment groups (P > 0.05). Although AMPA receptor-mediated transmission is functionally overactive in Parkinson's disease and dyskinesia, changes in striatal AMPA receptor levels are not likely to be the cause of such movement disorders.

Cannabinoids reduce levodopa-induced dyskinesia in Parkinson's disease: a pilot study.

The lateral segment of the globus pallidus (GPl) is thought to be overactive in levodopa-induced dyskinesia in PD. Stimulation of cannabinoid receptors in the GPl reduces gamma-aminobutyric acid (GABA) reuptake and enhances GABA transmission and may thus alleviate dyskinesia. In a randomized, double-blind, placebo-controlled, crossover trial (n = 7), the authors demonstrate that the cannabinoid receptor agonist nabilone significantly reduces levodopa-induced dyskinesia in PD.

Antiparkinsonian action of a delta opioid agonist in rodent and primate models of Parkinson's disease.

The opioid peptides localized in striatal projection neurons are of great relevance to Parkinson's disease, not only as a consequence of their distribution, but also due to the pronounced changes in expression seen in Parkinson's disease. It has long been suspected that increased expression of enkephalin may represent one of the many mechanisms that compensate for dopamine (DA) depletion in Parkinson's disease. Here we demonstrate that a systemically delivered, selective delta opioid agonist (SNC80) has potent antiparkinsonian actions in both rat and primate models of Parkinson's disease. In rats treated with either the D2-preferring DA antagonist haloperidol (1 mg/kg) or the selective D1 antagonist SCH23390 (1 mg/kg), but not a combination of D1 and D2 antagonists, SNC80 (10 mg/kg) completely reversed the catalepsy induced by DA antagonists. In rats rendered immobile by treatment with reserpine, SNC80 dose-dependently reversed akinesia (EC(50) 7.49 mg/kg). These effects were dose-dependently inhibited (IC(50) 1.05 mg/kg) by a selective delta opioid antagonist (naltrindole) and by SCH23390 (1 mg/kg), but not by haloperidol (1 mg/kg). SNC80 also reversed parkinsonian symptoms in the MPTP-treated marmoset. At 10 mg/kg (ip), scores measuring bradykinesia and posture were significantly reduced and motor activity increased to levels comparable with pre-MPTP-treatment scores. Any treatment that serves to increase delta opioid receptor activation may be a useful therapeutic strategy for the treatment of Parkinson's disease, either in the early stages or as an adjunct to dopamine replacement therapy. Furthermore, enhanced enkephalin expression observed in Parkinson's disease may serve to potentiate dopamine acting preferentially at D1 receptors.

Relationship between the appearance of symptoms and the level of nigrostriatal degeneration in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson's disease.

The concept of a threshold of dopamine (DA) depletion for onset of Parkinson's disease symptoms, although widely accepted, has, to date, not been determined experimentally in nonhuman primates in which a more rigorous definition of the mechanisms responsible for the threshold effect might be obtained. The present study was thus designed to determine (1) the relationship between Parkinsonian symptom appearance and level of degeneration of the nigrostriatal pathway and (2) the concomitant presynaptic and postsynaptic striatal response to the denervation, in monkeys treated chronically with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine according to a regimen that produces a progressive Parkinsonian state. The kinetics of the nigrostriatal degeneration described allow the determination of the critical thresholds associated to symptom appearance, these were a loss of 43.2% of tyrosine hydroxylase-immunopositive neurons at the nigral level and losses of 80.3 and 81.6% DA transporter binding and DA content, respectively, at the striatal level. Our data argue against the concept that an increase in DA metabolism could act as an efficient adaptive mechanism early in the disease progress. Surprisingly, the D(2)-like DA receptor binding showed a biphasic regulation in relation to the level of striatal dopaminergic denervation, i.e., an initial decrease in the presymptomatic period was followed by an upregulation of postsynaptic receptors commencing when striatal dopaminergic homeostasis is broken. Further in vivo follow-up of the kinetics of striatal denervation in this, and similar, experimental models is now needed with a view to developing early diagnosis tools and symptomatic therapies that might enhance endogenous compensatory mechanisms.