Metabotropic Glutamate Receptor 4 (mGlu4) Positive Allosteric Modulators Lack Efficacy in Rat and Marmoset Models of L-DOPA-Induced Dyskinesia.

Background: Increased activity across corticostriatal glutamatergic synapses may contribute to L-DOPA-induced dyskinesia in Parkinson's disease. Given the weak efficacy and side-effect profile of amantadine, alternative strategies to reduce glutamate transmission are being investigated. Metabotropic glutamate receptor 4 (mGlu4) is a promising target since its activation would reduce glutamate release. Objective: We hypothesized that two mGlu4 positive allosteric modulators, Lu AF21934 ((1 S,2 R)-N1-(3,4-dichlorophenyl)cyclohexane-1,2-dicarboxamide) and ADX88178 (5-Methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine), would provide relief in rat and primate models of L-DOPA-induced dyskinesia. Methods: The ability of Lu AF21934 or ADX88178 to reverse pre-established dyskinesia was examined in L-DOPA-primed 6-hydroxydopamine-lesioned rats expressing abnormal involuntary movements (AIMs) or in 1-methyl-4-phenyl,1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets expressing L-DOPA-induced dyskinesia. Additionally, the ability of Lu AF21934 to prevent the development of de novo L-DOPA-induced AIMs was explored in the 6-hydroxydopamine-lesioned rats. Results: Neither Lu AF21934 (10 or 30 mg/kg p.o.) nor ADX88178 (10 or 30 mg/kg p.o.) reduced pre-established AIMs in 6-hydroxydopamine-lesioned rats. Similarly, in L-DOPA-primed common marmosets, no reduction in established dyskinesia was observed with Lu AF21934 (3 or 10 mg/kg p.o.). Conversely, amantadine significantly reduced (>40%) the expression of dyskinesia in both models. Lu AF21934 also failed to suppress the development of AIMs in 6-hydroxydopamine-lesioned rats. Conclusions: This study found no benefit of mGlu4 positive allosteric modulators in tackling L-DOPA-induced dyskinesia. These findings are concordant with the recent failure of foliglurax in phase II clinical trials supporting the predictive validity of these pre-clinical dyskinesia models, while raising further doubt on the anti-dyskinetic potential of mGlu4 positive allosteric modulators.

Effects of muscle strengthening and cardiovascular fitness activities for poliomyelitis survivors: A systematic review and meta-analysis.

OBJECTIVE: To evaluate and assess the effectiveness of muscle strengthening and cardiovascular interventions in improving outcomes in poliomyelitis (polio) survivors. DATA SOURCES: A systematic literature search was conducted in Medline, PubMed, CINAHL, PsychINFO, Web of Science, and Google Scholar for experimental and observational studies. Study selection and extraction: Screening, data-extraction, risk of bias and quality assessment were carried out independently by the authors. The quality appraisal and risk of bias were assessed using the Downs and Black Checklist. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was followed to increase clarity of reporting. DATA SYNTHESIS: A total of 21 studies that met all the inclusion criteria were subjected to statistical analyses according to intervention (muscle strengthening or cardiovascular fitness). A random-effects meta-analysis showed a statistically significant effect for the exercise interventions favouring improvement in outcomes according to the International Classification of Functioning, Disability and Health (ICF). CONCLUSION: This review provides further insight into the effects associated with muscle strengthening and cardiovascular interventions among polio survivors, and helps to further identify the current state of research in this area. Future research is needed, focusing on individualized approaches to exercise with polio survivors and specific exercise prescription recommendations, based on established frameworks, such as the ICF.

Dysregulation of epithelial ion transport and neurochemical changes in the colon of a parkinsonian primate.

The pathological changes underlying gastrointestinal (GI) dysfunction in Parkinson's disease (PD) are poorly understood and the symptoms remain inadequately treated. In this study we compared the functional and neurochemical changes in the enteric nervous system in the colon of adult, L-DOPA-responsive, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmoset, with naïve controls. Measurement of mucosal vectorial ion transport, spontaneous longitudinal smooth muscle activity and immunohistochemical assessment of intrinsic innervation were each performed in discrete colonic regions of naïve and MPTP-treated marmosets. The basal short circuit current (Isc) was lower in MPTP-treated colonic mucosa while mucosal resistance was unchanged. There was no difference in basal cholinergic tone, however, there was an increased excitatory cholinergic response in MPTP-treated tissues when NOS was blocked with L-Nω-nitroarginine. The amplitude and frequency of spontaneous contractions in longitudinal smooth muscle as well as carbachol-evoked post-junctional contractile responses were unaltered, despite a decrease in choline acetyltransferase and an increase in the vasoactive intestinal polypeptide neuron numbers per ganglion in the proximal colon. There was a low-level inflammation in the proximal but not the distal colon accompanied by a change in α-synuclein immunoreactivity. This study suggests that MPTP treatment produces long-term alterations in colonic mucosal function associated with amplified muscarinic mucosal activity but decreased cholinergic innervation in myenteric plexi and increased nitrergic enteric neurotransmission. This suggests that long-term changes in either central or peripheral dopaminergic neurotransmission may lead to adaptive changes in colonic function resulting in alterations in ion transport across mucosal epithelia that may result in GI dysfunction in PD.

The selective 5-HT1A receptor agonist, NLX-112, exerts anti-dyskinetic and anti-parkinsonian-like effects in MPTP-treated marmosets.

l-DOPA is the gold-standard pharmacotherapy for treatment of Parkinson's disease (PD) but can lead to the appearance of troubling dyskinesia which are attributable to 'false neurotransmitter' release of dopamine by serotonergic neurons. Reducing the activity of these neurons diminishes l-DOPA-induced dyskinesia (LID), but there are currently no clinically approved selective, high efficacy 5-HT1A receptor agonists. Here we describe the effects of NLX-112, a highly selective and efficacious 5-HT1A receptor agonist, on LID in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated marmosets, a non-human primate model of PD. NLX-112 exhibited modest plasma half-life (~2h) and marked plasma protein binding (96%). When administered to parkinsonian marmosets with l-DOPA (7 mg/kg p.o.), NLX-112 (0.025, 0.1 and 0.4 mg/kg p.o.) reduced LID scores at early time-points after administration, whilst only minimally interfering with the l-DOPA-induced reversal of motor disability. In contrast, the prototypical 5-HT1A receptor agonist, (+)8-OH-DPAT (0.6 and 2 mg/kg p. o.), reduced LID but also abolished l-DOPA's anti-disability activity. Administered by itself, NLX-112 (0.1, 0.2 mg/kg p.o.) produced very little dyskinesia or locomotor activity, but reduced motor disability scores by about half the extent elicited by l-DOPA, suggesting that it may have motor facilitation effects of its own. Both NLX-112 and (+)8-OH-DPAT induced unusual and dose-limiting behaviors in marmoset that resembled 'serotonin behavioral syndrome' observed previously in rat. Overall, the present study showed that NLX-112 has anti-LID activity at the doses tested as well as reducing motor disability. The data suggest that additional investigation of NLX-112 is desirable to explore its potential as a treatment for PD and PD-LID.

Contractile dysfunction and nitrergic dysregulation in small intestine of a primate model of Parkinson's disease.

Bowel dysfunction is a common non-motor symptom in Parkinson's disease (PD). The main contractile neurotransmitter in the GI tract is acetylcholine (ACh), while nitric oxide (NO) causes the relaxation of smooth muscle in addition to modulating ACh release. The aim of this study was to characterise functional and neurochemical changes in the isolated ileum of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated marmoset, an established model of PD motor dysfunction. While NO-synthase inhibitor L-NAME concentration dependently augmented the neurogenically-evoked contractions and inhibited the relaxations in normal tissues, it had no effects on the MPTP ileum. Immunohistochemical analyses of the myenteric plexus showed that ChAT-immunoreactivity (-ir) was significantly reduced and the density of the enteric glial cells as shown by SOX-10-ir was increased. However, no change in TH-, 5-HT-, VIP- or nNOS-ir was observed in the MPTP tissues. The enhancement of the neurogenically-evoked contractions and the inhibition of the relaxation phase by L-NAME in the control tissues is in line with NO's direct relaxing effect on smooth muscle and its indirect inhibitory effect on ACh release. The absence of the relaxation and the inefficacy of L-NAME in the MPTP tissues suggests that central dopaminergic loss dopamine may eventually lead to the impairment of NO signal coupling that affects bowel function, and this may be the result of a complex dysregulation at the level of the neuroeffector junction.

The effect of Banisteriopsis caapi (B. caapi) on the motor deficits in the MPTP-treated common marmoset model of Parkinson's disease.

Banisteriopsis caapi (B. caapi) contains harmine, harmaline, and tetrahydroharmine, has monoamine oxidase inhibitory activity, and has reported antiparkinsonian activity in humans when imbibed as a tea; however, its effects are poorly documented. For this reason, motor function was assessed in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets following administration of B. caapi extract (28.4-113.6 mg/kg; po), harmine (0.1 and 0.3 mg/kg; sc), and selegiline (10 mg/kg; sc), alone or with a submaximal dose of L-3,4-dihydroxyphenylalanine (L-DOPA; 4-7 mg/kg). L-DOPA reversed motor disability, increased locomotor activity, and induced moderate dyskinesia. B. caapi did not increase locomotor activity or induce dyskinesia but at 56.8 and 113.6 mg/kg improved motor disability. The L-DOPA response was unaltered by co-administration of B. caapi. Harmine (0.1 and 0.3 mg/kg) produced a mild improvement in motor disability without affecting locomotor activity or dyskinesia but had no effect on the L-DOPA-induced antiparkinsonian response. Selegiline (10 mg/kg) alone improved motor function to the same extent as L-DOPA, but with only mild dyskinesia, and did not alter the response to L-DOPA, although dyskinesia was reduced. The findings suggest that B. caapi alone has a mild antiparkinsonian effect but does not enhance the L-DOPA response or reduce dyskinesia.

Magnetic resonance imaging and tensor-based morphometry in the MPTP non-human primate model of Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder producing a variety of motor and cognitive deficits with the causes remaining largely unknown. The gradual loss of the nigrostriatal pathway is currently considered the pivotal pathological event. To better understand the progression of PD and improve treatment management, defining the disease on a structural basis and expanding brain analysis to extra-nigral structures is indispensable. The anatomical complexity and the presence of neuromelanin, make the use of non-human primates an essential element in developing putative imaging biomarkers of PD. To this end, ex vivo T2-weighted magnetic resonance images were acquired from control and 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated marmosets. Volume measurements of the caudate, putamen, and substantia nigra indicated significant atrophy and cortical thinning. Tensor-based morphometry provided a more extensive and hypothesis free assessment of widespread changes caused by the toxin insult to the brain, especially highlighting regional cortical atrophy. The results highlight the importance of developing imaging biomarkers of PD in non-human primate models considering their distinct neuroanatomy. It is essential to further develop these biomarkers in vivo to provide non-invasive tools to detect pre-symptomatic PD and to monitor potential disease altering therapeutics.

Altered detrusor contractility in MPTP-treated common marmosets with bladder hyperreflexia.

Bladder hyperreflexia is a common non-motor feature of Parkinson's disease. We now report on the contractility of the isolated primate detrusor strips devoid of nerve input and show that following MPTP, the amplitude and frequency of spontaneous contraction was increased. These responses were unaffected by dopamine D1 and D2 receptor agonists A77636 and ropinirole respectively. Contractions by exogenous carbachol, histamine or ATP were similar and no differences in the magnitude of noradrenaline-induced relaxation were seen in detrusor strip obtained from normal and MPTP-treated common marmosets (Callithrix jacchus). However, the neurogenic contractions following electrical field stimulation of the intrinsic nerves (EFS) were markedly greater in strips obtained from MPTP treated animals. EFS evoked non-cholinergic contractions following atropine were also greater but the contribution of the cholinergic innervation as a proportion of the overall contraction was smaller in the detrusor strips of MPTP treated animals, suggesting a preferential enhancement of the non-cholinergic transmission. Although dopaminergic mechanism has been proposed to underlie bladder hyperreflexia in MPTP-treated animals with intact bladder, the present data indicates that the increased neurogenically mediated contractions where no extrinsic innervation exists might be due to long-term adaptive changes locally as a result of the loss of the nigrostriatal output.

Oral r-(-)-11-o-valeryl-n-n-propylnoraporphine reverses motor deficits in mptp-treated marmosets.

BACKGROUND: The D1/D2 dopamine agonist apomorphine has poor oral bioavailability, necessitating subcutaneous administration in the treatment of Parkinson's disease (PD). Acute subcutaneous injection is used as rescue therapy from "off" periods, whereas continuous subcutaneous infusion is used to increase "on" periods and to reduce dyskinesia when oral treatment fails. An orally active derivative of apomorphine would avoid the need for parenteral administration. We now describe the effects of the orally active compound R-(-)-11-O-valeryl-N-n-propylnoraporphine (11-OH-NPa valerate) on reversal of motor disability and expression of dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated, l-dopa-primed dyskinetic common marmosets. METHODS: Locomotor activity, motor disability, and dyskinesia were assessed in MPTP-treated marmosets following the administration of apomorphine (0.075 mg/kg, subcutaneous and 0.28 to 1.12 mg/kg, oral) and 11-OH-NPa valerate (0.19, 0.38, and 0.75mg/kg, oral). RESULTS: Subcutaneous administration of apomorphine (0.075 mg/kg) produced a short-lasting reversal of motor disability and the expression of established dyskinesia, but when administered orally (0.28-1.12 mg/kg) it had no effect. In contrast, oral treatment with 11-OH-NPa valerate (0.19 and 0.75 mg/kg) induced a dose-related reversal of motor disability and increased locomotor activity with only mild to moderate dyskinesia. Only at the highest dose (0.75 mg/kg) was marked dyskinesia seen accompanying an extended period of motor disability reversal and increased locomotor activity. CONCLUSION: Oral administration of 11-OH-NPa valerate produced a rapid reversal of motor disability and, at effective dose levels, had a limited propensity to induce dyskinesia. 11-OH-NPa valerate is the first orally active derivative of apomorphine with potential for use in PD. © 2016 International Parkinson and Movement Disorder Society.

Proteomic analysis of striatum from MPTP-treated marmosets (Callithrix jacchus) with L-DOPA-induced dyskinesia of differing severity.

Marmosets rendered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and treated with L-3,4-dihydroxyphenylalanine (L-DOPA) develop dyskinesia, but with differing degrees of severity. To provide insight into the molecular mechanisms responsible for the different level of dyskinesia to manifest in individual animals, proteins in striatum from MPTP-treated marmosets with different levels of L-DOPA-induced dyskinesia were separated by 2-dimensional (2-D) protein electrophoresis. Thirty-five differentially expressed proteins were identified by mass spectrometry and peptide mass fingerprinting, and comparative analysis found 10 were significantly increased and 3 had significantly reduced expression in animals with a high level of dyskinesia when compared to animals with a low incidence of dyskinesia. These proteins belonged to a range of functional classes, for example, molecular chaperones, metabolic enzymes and synaptic structural proteins. The findings of this study provide clues about the molecular mechanisms that cause dyskinesia to manifest and point towards potential novel targets for the development of therapeutic agents to prevent or treat established dyskinesia.

Evidence for abundant isolated magnetic nanoparticles at the Paleocene-Eocene boundary.

New rock magnetic results (thermal fluctuation tomography, high-resolution first-order reversal curves and low temperature measurements) for samples from the Paleocene-Eocene thermal maximum and carbon isotope excursion in cored sections at Ancora and Wilson Lake on the Atlantic Coastal Plain of New Jersey indicate the presence of predominantly isolated, near-equidimensional single-domain magnetic particles rather than the chain patterns observed in a cultured magnetotactic bacteria sample or magnetofossils in extracts. The various published results can be reconciled with the recognition that chain magnetosomes tend to be preferentially extracted in the magnetic separation process but, as we show, may represent only a small fraction of the overall magnetic assemblage that accounts for the greatly enhanced magnetization of the carbon isotope excursion sediment but whose origin is thus unclear.

Benserazide dosing regimen affects the response to L-3,4-dihydroxyphenylalanine in the 6-hydroxydopamine-lesioned rat.

Peripheral aromatic amino acid decarboxylase (AADC) inhibitors, such as benserazide, are routinely used to potentiate the effects of L-3,4-dihydroxyphenylalanine (L-DOPA) in Parkinson's disease (PD) and in experimental models of PD. However, there is little information available on the optimal dose or the timing of administration relative to L-DOPA treatment. We now assess the effect of dose, timing, and supplemental administration of benserazide on the rotational response induced by L-DOPA in unilateral 6-hydroxydopamine-lesioned rats. L-DOPA (12.5 mg/kg, p.o.) concomitant with benserazide (3.125-15 mg/kg, p.o.) produced a dose-dependent increase in contraversive rotation compared with the effects of L-DOPA alone. The optimal L-DOPA response was achieved with 10 mg/kg of benserazide and this dose was used in subsequent experiments. When L-DOPA treatment was delayed for 1, 2, or 3 h after benserazide, the rotational response declined suggesting loss of AADC inhibition. Unexpectedly, there was also a progressive decline in response when benserazide and L-DOPA were given together but at increasingly later time points of 08.00, 09.00, 10.00, and 11.00 h. To assess supplemental administration of benserazide, an additional dose was given 2 h after the initial benserazide/L-DOPA treatment. This produced a further increase in the number of contralateral rotations indicating that the effect of benserazide declines while plasma levels of L-DOPA are maintained. Therefore, optimization of the dose and timing of benserazide administration is essential to achieve a consistent L-DOPA response in 6-hydroxydopamine-lesioned rats. These findings may have implications for the way in which peripheral AADC inhibitors are used in the treatment of PD.

An evaluation of the effectiveness of a commercial mechanical trap to reduce abundance of adult nuisance mosquito populations.

In this study, we explore the potential of a commercially available mechanical mosquito control device, the Liberty Plus Mosquito Magnet (hereafter referred to as Mosquito Magnet), to reduce the abundance of adult nuisance mosquito populations in public recreational areas. Mosquitoes were trapped on 2 replicate sites close to a campground at Brae Island Regional Park near Fort Langley, British Columbia, Canada. Each site comprised a treatment (Mosquito Magnets used) and control subsection (Mosquito Magnets not used). Mosquito numbers were assessed before and after the treatment period in both subsections at each site with Centers for Disease Control and Prevention (CDC) black light traps. Although nearly 200,000 mosquitoes from 14 different species were collected over 366 trap-nights from May 31 to July 31, 2008, the majority of those identified were Aedes sticticus (68%) and Ae. vexans (22%)-2 of the most notorious nuisance mosquito species in British Columbia. The number of mosquitoes captured by CDC black light traps increased overall during the study period due to natural seasonal variation. Nevertheless, a significant treatment effect (P = 0.0389) was associated with an average decrease of about 32% in the average number of adult mosquitoes collected per day. These results strongly suggest that Mosquito Magnets can reduce the abundance of nuisance mosquitoes, potentially reducing the biting pressure on the public, and providing another tool in mosquito control operations.

A major metabolite of bupropion reverses motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets.

The atypical antidepressant, bupropion, causes a partial reversal of motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates. However, its monoamine uptake blocking actions are believed to be mediated by the major metabolites, racemic (-)-(2R,3R)-2-(3-chlorophenyl-3,5,5-trimethyl-2-morphinol) (R,R-hydroxybupropion) and (+)-(2S,3S)-2-(3-chlorophenyl-3,5,5-trimethyl-2-morphinol) (S,S-hydroxybupropion). Therefore, we have evaluated the ability of enantiomers to improve locomotor activity and motor disability in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets. Bupropion produced a little increase in locomotor activity and a more pronounced improvement in motor disability. The S,S-hydroxybupropion, but not the R,R-hydroxybupropion, enantiomer dose-dependently increased both locomotor activity and reversed motor disability. Combined administration of S,S-hydroxybupropion and R,R-hydroxybupropion at the same dose (analogous to the racemate) again improved motor function and to the same extent as produced by S,S-hydroxybupropion alone. The data suggest that the S,S-enantiomer of hydroxybupropion may possess potential antiparkinsonian activity.

Morphological changes in serotoninergic neurites in the striatum and globus pallidus in levodopa primed MPTP treated common marmosets with dyskinesia.

Hyperinnervation of the striatum by serotoninergic (5-HT) terminals occurs after destruction of the dopaminergic nigro-striatal pathway. Recent studies have suggested that non-physiological release of dopamine (DA) formed from levodopa in these serotoninergic terminals underlies abnormal involuntary movement (AIMs) induction in 6-OHDA lesioned rats. In the present study, we used tryptophan hydroxylase (TPH) immunohistochemistry to determine whether 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) treatment and the induction of dyskinesia by levodopa alter the morphology of 5-HT fibres in the striatum of common marmosets. The caudate-putamen of normal monkeys contained numerous fine and smooth TPH positive fibres and numerous varicose fibres, but a marked hyperinnervation of TPH positive fibres characterised by a significant increase in the number and diameter of TPH positive axon varicosities was noted in the dorsal caudate and putamen of MPTP-intoxicated monkeys but not the globus pallidus. In MPTP-intoxicated marmosets that had received chronic levodopa treatment to induce dyskinesia, a further increase in the number and enlargement of TPH positive axonal varicosities in both caudate nucleus and putamen was evident. Following LID induction, a similar pattern of increase was also observed in the external segment of the globus pallidus, but only a significant varicosity enlargement was seen in the internal pallidal segment. These results confirm that striatal 5-HT hyperinnervation follows nigro-striatal pathway loss and provide the first evidence in primates that chronic levodopa treatment and the onset of dyskinesia are associated with a marked hypertrophy of striatal 5-HT axonal varicosities. These findings support the concept that altered 5-HT function may contribute to the genesis or expression of LID.

The timing of administration, dose dependence and efficacy of dopa decarboxylase inhibitors on the reversal of motor disability produced by L-DOPA in the MPTP-treated common marmoset.

Dopa decarboxylase inhibitors are routinely used to potentiate the effects of L-DOPA in the treatment of Parkinson's disease. However, neither in clinical use nor in experimental models of Parkinson's disease have the timing and dose of dopa decarboxylase inhibitors been thoroughly explored. We now report on the choice of dopa decarboxylase inhibitors, dose and the time of dosing relationships of carbidopa, benserazide and L-alpha-methyl dopa (L-AMD) in potentiating the effects of L-DOPA in the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-treated common marmoset. Pre-treatment with benserazide for up to 3h did not alter the motor response to L-DOPA compared to simultaneous administration with L-DOPA. There was some evidence of a relationship between carbidopa and benserazide dose and increased locomotor activity and the reversal of motor disability. But in general, commonly used dose levels of dopa decarboxylase inhibitors appeared to produce a maximal motor response to L-DOPA. In contrast, dyskinesia intensity and duration continued to increase with both carbidopa and benserazide dose. The novel dopa decarboxylase inhibitor, L-AMD, increased locomotor activity and improved motor disability to the same extent as carbidopa or benserazide but importantly this was accompanied by significantly less dyskinesia. This study shows that currently, dopa decarboxylase inhibitors may be routinely employed in the MPTP-treated primate at doses which are higher than those necessary to produce a maximal potentiation of the anti-parkinsonian effect of L-DOPA. This may lead to excessive expression of dyskinesia in this model of Parkinson's disease and attention should be given to the dose regimens currently employed.

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.

The administration of entacapone prevents L-dopa-induced dyskinesia when added to dopamine agonist therapy in MPTP-treated primates.

More continuous delivery of l-3,4-dihydroxyphenylalanine (l-dopa) achieved by combination with the catechol-O-methyl transfer (COMT) inhibitor entacapone reduces the onset of dyskinesia in MPTP-treated common marmosets compared with pulsatile l-dopa regimens. We now investigate whether l-dopa delivery also influences dyskinesia induction when added to dopamine agonist treatment. Drug-naive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-treated common marmosets were treated with ropinirole twice daily (BID) for 14 days which reversed motor disability and increased locomotor activity with minimal dyskinesia. Ropinirole treatment was continued but some animals also received l-dopa BID or four times daily (QID) with and without entacapone or vehicle for a further 16 days. Continuing ropinirole treatment alone maintained a similar reversal of motor deficits and low levels of dyskinesia for the first 14 days and the second 16 days. The addition of l-dopa BID or QID without entacapone produced only a minor further reversal of motor deficits, but significantly increased the intensity of dyskinesia. In contrast, the addition of l-dopa BID or QID with entacapone also produced some further improvement in motor function with the combination of entacapone and l-dopa BID significantly improving motor disability compared to l-dopa alone, but no further increase in dyskinesia intensity was observed compared with ropinirole alone treatment. The results show that combined treatment with l-dopa and entacapone has a marked effect on dyskinesia induction even when therapy has been introduced with a dopamine agonist.

Antiparkinsonian activity of L-propyl-L-leucyl-glycinamide or melanocyte-inhibiting factor in MPTP-treated common marmosets.

The neuropeptide melanocyte-inhibiting factor (MIF) or L-propyl-L-leucyl-glycinamide (PLG) has been reported in some studies to improve the motor signs of Parkinson's disease (PD) and in rodent models of PD. In this study of oral and intravenous MIF in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets, a wide range of doses of MIF administered alone (0.25, 1, 2, 5, 10, 20 mg/kg orally) did not increase locomotor activity, relieve motor disability, or induce dyskinesias. When MIF (1.0 and 5.0 mg/kg orally or 10 and 20 mg/kg intravenously) was administered concomitantly with levodopa/benserazide, no significant differences in motor function or dyskinesias were observed compared with levodopa/benserazide alone. The results of this first study of MIF in the marmoset MPTP model provide no encouragement for the reinvestigation of MIF in the clinical management of the motor signs of PD.

Decreased expression of l-dopa-induced dyskinesia by switching to ropinirole in MPTP-treated common marmosets.

Current concepts suggest that pulsatile stimulation of dopamine receptors following L-dopa administration leads to priming for dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-treated primates, while continuous dopaminergic stimulation with long-acting dopamine agonists does not. We investigated whether L-dopa-induced dyskinesia is reduced by switching to a dopamine agonist. MPTP-treated marmosets received chronic treatment with L-dopa or ropinirole in doses producing equivalent motor activity and reversal of motor deficits. Administration of L-dopa led to the rapid onset of moderate to severe dyskinesia, whereas ropinirole produced only mild dyskinesia. Animals initially treated with L-dopa were switched to an equivalent dose of ropinirole and those treated with ropinirole were switched to an equivalent dose of L-dopa for 56 days. L-dopa-primed animals that were switched to ropinirole showed a trend towards a reduction of dyskinesia intensity, whereas animals initially treated with ropinirole and switched to L-dopa showed a trend toward increased dyskinesia intensity. A subsequent, acute L-dopa challenge reversed motor deficits and induced intense dyskinesia in both groups. This suggests that L-dopa leads to the priming and expression of dyskinesia, but that expression is not maintained when switching to a long-acting dopamine agonist. In contrast, dopamine agonists may prime for dyskinesia, but do not lead to its full expression.