Motac Neuroscience Ltd

Manchester, United Kingdom

Motac Neuroscience Ltd

Manchester, United Kingdom
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Bezard E.,Institut Universitaire de France | Bezard E.,French National Center for Scientific Research | Bezard E.,China Academy of Medical science | Munoz A.,University of Santiago de Compostela | And 7 more authors.
Neuroscience Research | Year: 2013

The serotonin system has emerged as a potential target for anti-dyskinetic therapy in Parkinson's disease. In fact, serotonin neurons can convert L-DOPA into dopamine, and mediate its synaptic release. However, they lack a feedback control mechanism able to regulate synaptic dopamine levels, which leads to un-physiological stimulation of post-synaptic striatal dopamine receptors. Accordingly, drugs able to dampen the activity of serotonin neurons can suppress L-DOPA-induced dyskinesia in animal models of Parkinson's disease.Here, we investigated the ability of the 5-HT1A/1B receptor agonist anpirtoline to counteract L-DOPA-induced dyskinesia in L-DOPA-primed 6-OHDA-lesioned rats and MPTP-treated macaques. Results suggest that anpirtoline dose-dependently reduced dyskinesia both in rats and monkeys; however, the effect in MPTP-treated macaques was accompanied by a worsening of the Parkinson's disease score at significantly effective doses (1.5 and 2.0. mg/kg). At a lower dose (0.75. mg/kg), anpirtoline markedly reduced dyskinesia in 4 out of 5 subjects, but statistical significance was prevented by the presence of a non-responsive subject.These results provide further evidence that the serotonin neurons contribute both to the pro-dyskinetic effect of L-DOPA and to its therapeutic efficacy in the rat and monkey models of Parkinson's disease. © 2013 Elsevier Ireland Ltd and the Japan Neuroscience Society.


Camus S.M.J.,Institut Universitaire de France | Rochais C.,French National Center for Scientific Research | Blois-Heulin C.,French National Center for Scientific Research | Li Q.,Motac Neuroscience Ltd | And 5 more authors.
Frontiers in Behavioral Neuroscience | Year: 2014

Background: To unravel the causes of major depressive disorder (MDD), the third leading cause of disease burden around the world, ethological animal models have recently been proposed. Our previous studies highlighted a depressive-like profile among single- and socially-housed farm-bred cynomolgus macaques. Although phylogenetically close, cynomolgus and rhesus macaques, the two most commonly used macaque species in biomedical research, differ on several levels such as patterns of aggression, reconciliation, temperament, or dominance styles. The question of whether one captive macaque species was more vulnerable than another in the development of a pathological profile reminiscent of MDD symptoms was explored. Methods: Behavioral data (including body postures, orientations, gaze directions, inter-individual distances, and locations in the cage) were collected in farming conditions. Using an unbiased validated ethological scan-sampling method, followed by multiple correspondence and hierarchical clustering analyses, 40 single- and 35 socially-housed rhesus macaques were assessed. Independently, for each housing condition, inter-species comparisons were made with previously acquired data on farm-bred cynomolgus monkeys. Results: Consistent with our previous studies, we found depressive-like characteristics (e.g., inactivity, low level of investigation and maintenance, long time spent inactive while facing the wall) among single- and socially-housed rhesus macaques. Species-specificities were reported in non-depressive time budgets and in the prevalence of the pathological profiles. Conclusions: Our results suggest that rhesus may be more vulnerable to developing a despair-like state than cynomolgus macaques, both in single- and in social-housing conditions. Therefore, rhesus macaques are more suitable for use as a "spontaneous" model of depressive disorders. © 2014 Camus, Rochais, Blois-Heulin, Li, Hausberger and Bezard.


Iderberg H.,Lund University | Francardo V.,Lund University | Pioli E.Y.,Motac Neuroscience Ltd
Neuroscience | Year: 2012

Major limitations to the pharmacotherapy of Parkinson's disease (PD) are the motor complications resulting from . l-DOPA treatment. Abnormal involuntary movements (dyskinesia) affect a majority of the patients after a few years of . l-DOPA treatment and can become troublesome and debilitating. Once dyskinesia has debuted, an irreversible process seems to have occurred, and the movement disorder becomes almost impossible to eliminate with adjustments in peroral pharmacotherapy. There is a great need to find new pharmacological interventions for PD that will alleviate parkinsonian symptoms without inducing dyskinesia. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned non-human primate model is an excellent symptomatic model of PD and was the first model used to reproduce . l-DOPA-induced dyskinesia experimentally. As it recapitulates the motor features of human dyskinesia, that is, chorea and dystonia, it is considered a reliable animal model to define novel therapies. Over the last decade, rodent models of . l-DOPA-induced dyskinesia have been developed, having both face validity and predictive validity. These models have now become the first-line experimental tool for therapeutic screening purposes. The application of classical 6-hydroxydopamine (6-OHDA) lesion procedures to produce rodent models of dyskinesia has provided the field with more dynamic tools, since the versatility of toxin doses and injection coordinates allows for mimicking different stages of PD. This article will review models developed in non-human primate and rodents to reproduce motor complications induced by dopamine replacement therapy. The recent breakthroughs represented by mouse models and the relevance of rodents in relation to non-human primate models will be discussed.This article is part of a Special Issue entitled: Neuroscience Disease Models. © 2012 IBRO.


Ko W.K.D.,Motac Neuroscience Ltd | Bezard E.,Motac Neuroscience Ltd | Bezard E.,Institut Universitaire de France | Bezard E.,French National Center for Scientific Research
Experimental Neurology | Year: 2017

With the understanding that α-synuclein plays a major role in the pathogenesis of Parkinson's disease (PD), novel animal models have been developed for conducting preclinical research in screening novel disease modifying therapies. Advancements in research techniques in α-synuclein targeted disease modification have utilised methods such as viral mediated expression of human α-synuclein, as well as the inoculation of pathogenic α-synuclein species from Lewy Bodies of PD patients, for accurately modelling progressive self-propagating neurodegeneration. In applying these cutting-edge research tools with sophisticated trial designs in preclinical drug trials, a useful platform has emerged for developing candidate agents with disease modifying actions, promising a greater chance of success for clinical translation. In this article, we describe the transition of well-established animal models of PD symptomatology to newly developed models of PD pathogenesis, with specific focus on methods of viral-mediated and inoculation of pathogenic α-synuclein, that aim to aid scientific translation of neuroprotective strategies. © 2017 Elsevier Inc.


Ko W.K.D.,Motac Neuroscience Ltd | Ko W.K.D.,Institut Universitaire de France | Ko W.K.D.,French National Center for Scientific Research | Pioli E.,Motac Neuroscience Ltd | And 8 more authors.
Movement Disorders | Year: 2014

Amantadine, an N-methyl-D-aspartate glutamate receptor antagonist, is currently the only pharmacological treatment for levodopa-induced dyskinesia (LID) in Parkinson's disease (PD), but causes adverse effects on the central nervous system at therapeutic doses. Fenobam, a negative modulator of metabotropic glutamate receptor subtype 5, has recently been reported to attenuate LID in MPTP-treated macaques. The aim of the current study was to investigate the treatment interactions of fenobam and amantadine on LID in the MPTP-treated macaque model of PD. The antidyskinetic and -parkinsonian effects were measured after administration of fenobam (10-30 mg/kg) and amantadine (10-30 mg/kg) alone and in combination. Fenobam (30 mg/kg) and amantadine (30 mg/kg) alone reduced LID, whereas lower doses of either drug did not cause any significant effects. A combined treatment of fenobam and amantadine at subthreshold doses (10 and 20 mg/kg) significantly reduced LID without worsening PD disability. These data suggest that a low-dose combination of fenobam and amantadine can be used for alleviating dyskinesia without causing adverse motor effects. Such combined therapies may offer a new therapeutic strategy for treatment of LID in PD patients. © 2014 International Parkinson and Movement Disorder Society.


Schneider J.S.,Thomas Jefferson University | Pioli E.Y.,Motac Cognition Inc | Pioli E.Y.,Motac Neuroscience Ltd | Jianzhong Y.,Motac Cognition Inc | And 6 more authors.
Movement Disorders | Year: 2013

Background: Levodopa effectively relieves motor symptoms in Parkinson's disease (PD), but has had inconsistent effects on cognition, even worsening some aspects of cognitive functioning. Therefore, remediation of PD cognitive deficits is a major unmet need. However, drug development efforts have been hampered by lack of an animal model in which motor and cognitive deficits can be examined simultaneously. Methods: Cynomolgus monkeys were trained to perform cognitive tasks and then chronically exposed to MPTP to slowly produce cognitive and motor deficits of parkinsonism. Results: Administration of L-dopa to these animals dose dependently improved motor functioning, but did not significantly improve cognitive performance. At doses that maximally improved motor function, additional cognitive deficits were observed. The present model of MPTP-induced parkinsonism recapitulates important motor and cognitive aspects of PD. Results with L-dopa mirror data derived from PD patients. Conclusion: This model should allow more efficient testing of potential PD therapeutics to evaluate motor and cognitive functions simultaneously. © 2012 Movement Disorders Society.


Camus S.M.J.,Institut Universitaire de France | Blois-Heulin C.,French National Center for Scientific Research | Li Q.,China Academy of Medical science | Li Q.,Motac Neuroscience Ltd | And 4 more authors.
PLoS ONE | Year: 2013

Background:To date, experimental and preclinical studies on neuropsychiatric conditions have almost exclusively been performed in experimentally-induced animal models and have only rarely relied upon an ethological approach where animals have been observed in more naturalistic settings. The laboratory species of choice has been the rodent while the potential of more closely-related non-human primates have remained largely underexplored.Methods:The present study, therefore, aimed at investigating the possible existence of spontaneous atypical/abnormal behaviours displayed by 40 cynomolgus macaques in captive conditions using an unbiased ethological scan-sampling analysis followed by multifactorial correspondence analysis and a hierarchical clustering.Results:The study identified five distinct profiles (groups A to E) that significantly differed on several behaviours, body postures, body orientations, gaze directions and locations in the cage environment. We suggest that animals from the low n groups (D and E) present depressive-like and anxious-like symptoms, reminiscent of depressive and generalized anxiety disorders. Inter-individual differences were highlighted through unbiased ethological observations of spontaneous behaviours and associated parameters, although these were not associated with differences in plasma or cerebrospinal fluid levels of either stress-related hormones or monoamines, i.e. in accordance with the human situation.Conclusions:No interventional behavioural testing was required to discriminate between 3 typical and 2 atypical ethologically-defined behavioural profiles, reminiscent of certain depressive-like and anxiety-like symptoms. The use of unbiased behavioural observations might, thus, allow the identification of animal models of human mental/behavioural disorders and their most appropriate control groups. © 2013 Camus et al.


Camus S.,Motac Neuroscience Ltd | Ko W.K.D.,Motac Neuroscience Ltd | Pioli E.,Motac Neuroscience Ltd | Bezard E.,Motac Neuroscience Ltd | And 2 more authors.
Neurobiology of Learning and Memory | Year: 2015

Although everyone would agree that successful translation of therapeutic candidates for central nervous disorders should involve non-human primate (nhp) models of cognitive disorders, we are left with the paucity of publications reporting either the target validation or the actual preclinical testing in heuristic nhp models. In this review, we discuss the importance of nhps in translational research, highlighting the advances in technological/methodological approaches for 'bridging the gap' between preclinical and clinical experiments. In this process, we acknowledge that nhps remain a vital tool for the investigation of complex cognitive functions, given their resemblance to humans in aspects of behaviour, anatomy and physiology. The recent improvements made for a suitable nhp model in cognitive research, including new surrogates of disease and application of innovative methodological approaches, are continuous strides for reaching efficient translation for human benefit. This will ultimately aid the development of innovative treatments against the current and future threat of neurological and psychiatric disorders to the global population. © 2015 Elsevier Inc.


Bezard E.,Institut Universitaire de France | Bezard E.,Institute for Neurodegenerative Diseases | Bezard E.,China Academy of Medical science | Tronci E.,University of Cagliari | And 8 more authors.
Movement Disorders | Year: 2013

The serotonin (5-hydroxytryptamine [5HT]) system has recently emerged as an important player in the appearance of l-3,4-dihydroxyphenylalanine (levodopa [l-dopa])-induced dyskinesia in animal models of Parkinson's disease. In fact, dopamine released as a false transmitter from serotonin neurons appears to contribute to the pulsatile stimulation of dopamine receptors, leading to the appearance of the abnormal involuntary movements. Thus, drugs able to dampen the activity of serotonin neurons hold promise for the treatment of dyskinesia. The authors investigated the ability of the mixed 5-HT 1A/1B receptor agonist eltoprazine to counteract l-dopa-induced dyskinesia in 6-hydroxydopamine-lesioned rats and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaques. The data demonstrated that eltoprazine is extremely effective in suppressing dyskinesia in experimental models, although this effect was accompanied by a partial worsening of the therapeutic effect of l-dopa. Interestingly, eltoprazine was found to (synergistically) potentiate the antidyskinetic effect of amantadine. The current data indicated that eltoprazine is highly effective in counteracting dyskinesia in preclinical models. However, the partial worsening of the l-dopa effect observed after eltoprazine administration represents a concern; whether this side effect is due to a limitation of the animal models or to an intrinsic property of eltoprazine needs to be addressed in ongoing clinical trials. The data also suggest that the combination of low doses of eltoprazine with amantadine may represent a valid strategy to increase the antidyskinetic effect and reduce the eltoprazine-induced worsening of l-dopa therapeutic effects. © 2012 Movement Disorder Society.


Patent
MOTAC NEUROSCIENCE Ltd | Date: 2011-03-31

The invention relates to the use of compounds that enhance 5-hydroxytryptamine 1a receptor activity, or activation (e.g. a selective 5-hydroxytryptamine 1a receptor agonists) for preventing or reducing motor fluctuations associated with dopamine replacement therapy.

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