Publications by authors named "Elsa Y Pioli"

14 Publications

  • Page 1 of 1

Adenosine AR/AR Antagonists Enabling Additional HR Antagonism for the Treatment of Parkinson's Disease.

J Med Chem 2021 Jun 9;64(12):8246-8262. Epub 2021 Jun 9.

Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Duesseldorf, Universitaets street 1, 40225 Duesseldorf, Germany.

Adenosine A/A receptors (AR/AR) represent targets in nondopaminergic treatment of motor disorders such as Parkinson's disease (PD). As an innovative strategy, multitargeting ligands (MTLs) were developed to achieve comprehensive PD therapies simultaneously addressing comorbid symptoms such as sleep disruption. Recognizing the wake-promoting capacity of histamine H receptor (HR) antagonists in combination with the "caffeine-like effects" of AR/AR antagonists, we designed AR/AR/HR MTLs, where a piperidino-/pyrrolidino(propyloxy)phenyl HR pharmacophore was introduced with overlap into an adenosine antagonist arylindenopyrimidine core. These MTLs showed distinct receptor binding profiles with overall nanomolar HR affinities ( < 55 nM). Compound (, (AR) = 11.5 nM, (AR) = 7.25 nM) and (, (AR) = 11.2 nM, (AR) = 4.01 nM) were evaluated . l-DOPA-induced dyskinesia was improved after administration of compound (1 mg kg, i.p. rats). Compound (2 mg kg, p.o. mice) increased wakefulness representing novel pharmacological tools for PD therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.0c00914DOI Listing
June 2021

Gastrointestinal and metabolic function in the MPTP-treated macaque model of Parkinson's disease.

Heliyon 2020 Dec 23;6(12):e05771. Epub 2020 Dec 23.

Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, 33000, France.

Background: Gastrointestinal (GI) and metabolic function are frequently altered in Parkinson's disease (PD). Although enteric nervous system anatomopathological alterations have previously been reported in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model of PD, the resulting gastric emptying and intestinal permeability functional parameters are unknown. The current exploratory study was, thus, designed to investigate these GI functional factors and insulin resistance in the MPTP-treated monkey.

Methods: Eight rhesus macaque monkeys (4 controls and 4 MPTP-treated) received the oral acetaminophen absorption test to measure gastric emptying, the oral FITC-dextran absorption test to investigate intestinal permeability, and the intravenous glucose tolerance test to assess insulin resistance. Constipation was evaluated using the Bristol stool scale.

Results: None of the tests, acetaminophen absorption, FITC-dextran absorption or glucose tolerance, showed a difference between control and MPTP-treated monkeys. MPTP-treated monkeys did present signs of transit acceleration.

Conclusion: While the MPTP monkey model reliably displays motor and certain non-motor symptoms of PD, the current study did not demonstrate the GI symptoms associated with PD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.heliyon.2020.e05771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772551PMC
December 2020

Vector-mediated l-3,4-dihydroxyphenylalanine delivery reverses motor impairments in a primate model of Parkinson's disease.

Brain 2019 Aug;142(8):2402-2416

Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden.

Ever since its introduction 40 years ago l-3,4-dihydroxyphenylalanine (l-DOPA) therapy has retained its role as the leading standard medication for patients with Parkinson's disease. With time, however, the shortcomings of oral l-DOPA treatment have become apparent, particularly the motor fluctuations and troublesome dyskinetic side effects. These side effects, which are caused by the excessive swings in striatal dopamine caused by intermittent oral delivery, can be avoided by delivering l-DOPA in a more continuous manner. Local gene delivery of the l-DOPA synthesizing enzymes, tyrosine hydroxylase and guanosine-tri-phosphate-cyclohydrolase-1, offers a new approach to a more refined dopaminergic therapy where l-DOPA is delivered continuously at the site where it is needed i.e. the striatum. In this study we have explored the therapeutic efficacy of adeno-associated viral vector-mediated l-DOPA delivery to the putamen in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated rhesus monkeys, the standard non-human primate model of Parkinson's disease. Viral vector delivery of the two enzymes, tyrosine hydroxylase and guanosine-5'-tri-phosphate-cyclohydrolase-1, bilaterally into the dopamine-depleted putamen, induced a significant, dose-dependent improvement of motor behaviour up to a level identical to that obtained with the optimal dose of peripheral l-DOPA. Importantly, this improvement in motor function was obtained without any adverse dyskinetic effects. These results provide proof-of-principle for continuous vector-mediated l-DOPA synthesis as a novel therapeutic strategy for Parkinson's disease. The constant, local supply of l-DOPA obtained with this approach holds promise as an efficient one-time treatment that can provide long-lasting clinical improvement and at the same time prevent the appearance of motor fluctuations and dyskinetic side effects associated with standard oral dopaminergic medication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awz176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658866PMC
August 2019

Meta-analysis of amantadine efficacy for improving preclinical research reliability.

Mov Disord 2018 10 4;33(10):1555-1557. Epub 2018 Oct 4.

Motac Neuroscience, Manchester, United Kingdom.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mds.27486DOI Listing
October 2018

An evaluation of istradefylline treatment on Parkinsonian motor and cognitive deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaque models.

Neuropharmacology 2016 11 14;110(Pt A):48-58. Epub 2016 Jul 14.

Motac Neuroscience Ltd, Manchester, United Kingdom; Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.

Istradefylline (KW-6002), an adenosine A2A receptor antagonist, is used adjunct with optimal doses of L-3,4-dihydroxyphenylalanine (l-DOPA) to extend on-time in Parkinson's disease (PD) patients experiencing motor fluctuations. Clinical application of istradefylline for the management of other l-DOPA-induced complications, both motor and non-motor related (i.e. dyskinesia and cognitive impairments), remains to be determined. In this study, acute effects of istradefylline (60-100 mg/kg) alone, or with optimal and sub-optimal doses of l-DOPA, were evaluated in two monkey models of PD (i) the gold-standard 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaque model of parkinsonian and dyskinetic motor symptoms and (ii) the chronic low dose (CLD) MPTP-treated macaque model of cognitive (working memory and attentional) deficits. Behavioural analyses in l-DOPA-primed MPTP-treated macaques showed that istradefylline alone specifically alleviated postural deficits. When combined with an optimal l-DOPA treatment dose, istradefylline increased on-time, enhanced therapeutic effects on bradykinesia and locomotion, but exacerbated dyskinesia. Istradefylline treatment at specific doses with sub-optimal l-DOPA specifically alleviated bradykinesia. Cognitive assessments in CLD MPTP-treated macaques showed that the attentional and working memory deficits caused by l-DOPA were lowered after istradefylline administration. Taken together, these data support a broader clinical use of istradefylline as an adjunct treatment in PD, where specific treatment combinations can be utilised to manage various l-DOPA-induced complications, which importantly, maintain a desired anti-parkinsonian response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuropharm.2016.07.012DOI Listing
November 2016

The mGluR5 negative allosteric modulator dipraglurant reduces dyskinesia in the MPTP macaque model.

Mov Disord 2014 Jul 27;29(8):1074-9. Epub 2014 May 27.

Motac neuroscience, Manchester, UK; Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France; Service de Neurologie, CHU de Bordeaux, Pessac, France; Institute of Laboratory Animal Sciences, China Academy of Medical Sciences, Beijing, China.

Background: Blocking metabotropic glutamate receptor type 5 (mGluR5) has been proposed as a target for levodopa-induced dyskinesias (LID) in Parkinson's disease (PD). We assessed the effect on LID of dipraglurant, a potent selective mGluR5 receptor negative allosteric modulator in the gold-standard LID macaque model.

Methods: Dipraglurant (3, 10, and 30 mg/kg, by mouth) was tested in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) macaque model of LID in a four-way crossover, single-dose, controlled study (n = 8).

Results: Dipraglurant inhibited dyskinesias in the LID macaque model, with best effect reached at 30 mg/kg dose with no alteration of levodopa efficacy.

Conclusion: Acute challenges of dipraglurant were efficacious on choreic and dystonic LID in the MPTP-macaque model. Dipraglurant pharmacokinetic variables were similar to those of levodopa, suggesting that both drugs can be co-administered simultaneously in further studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mds.25920DOI Listing
July 2014

An automated maze task for assessing hippocampus-sensitive memory in mice.

Behav Brain Res 2014 Mar 12;261:249-57. Epub 2013 Dec 12.

Department of Comparative Medicine, (and by courtesy) Department of Psychiatry and Behavioral Sciences, Stanford University, 287 Campus Drive, Stanford, CA 94305-5410, USA.

Memory deficits associated with hippocampal dysfunction are a key feature of a number of neurodegenerative and psychiatric disorders. The discrete-trial rewarded alternation T-maze task is highly sensitive to hippocampal dysfunction. Normal mice have spontaneously high levels of alternation, whereas hippocampal-lesioned mice are dramatically impaired. However, this is a hand-run task and handling has been shown to impact crucially on behavioural responses, as well as being labour-intensive and therefore unsuitable for high-throughput studies. To overcome this, a fully automated maze was designed. The maze was attached to the mouse's home cage and the subject earned all of its food by running through the maze. In this study the hippocampal dependence of rewarded alternation in the automated maze was assessed. Bilateral hippocampal-lesioned mice were assessed in the standard, hand-run, discrete-trial rewarded alternation paradigm and in the automated paradigm, according to a cross-over design. A similarly robust lesion effect on alternation performance was found in both mazes, confirming the sensitivity of the automated maze to hippocampal lesions. Moreover, the performance of the animals in the automated maze was not affected by their handling history whereas performance in the hand-run maze was affected by prior testing history. By having more stable performance and by decreasing human contact the automated maze may offer opportunities to reduce extraneous experimental variation and therefore increase the reproducibility within and/or between laboratories. Furthermore, automation potentially allows for greater experimental throughput and hence suitability for use in assessment of cognitive function in drug discovery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbr.2013.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3923974PMC
March 2014

Anti-dyskinetic effect of anpirtoline in animal models of L-DOPA-induced dyskinesia.

Neurosci Res 2013 Dec 14;77(4):242-6. Epub 2013 Oct 14.

Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China.

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 2.0mg/kg). At a lower dose (0.75mg/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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neures.2013.10.002DOI Listing
December 2013

Study of the antidyskinetic effect of eltoprazine in animal models of levodopa-induced dyskinesia.

Mov Disord 2013 Jul 6;28(8):1088-96. Epub 2013 Feb 6.

Institute for Neurodegenerative Diseases, Bordeaux University, Bordeaux, France.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mds.25366DOI Listing
July 2013

Levodopa improves motor deficits but can further disrupt cognition in a macaque Parkinson model.

Mov Disord 2013 May 12;28(5):663-7. Epub 2012 Dec 12.

Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.

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 Disorder Society.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mds.25258DOI Listing
May 2013

Effects of memantine and galantamine on cognitive performance in aged rhesus macaques.

Neurobiol Aging 2013 Apr 15;34(4):1126-32. Epub 2012 Nov 15.

Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA19107, USA.

Current pharmacotherapies for Alzheimer's disease (AD) are focused on improving performance of daily activities, personal care, and management of problematic behaviors. Both memantine, a noncompetitive N-methyl-D-aspartate channel blocker and galantamine, a selective acetylcholinesterase inhibitor, are currently prescribed as symptomatic therapies for AD. However, drugs that progressed directly from testing in rodent models to testing in AD patients in clinical trials failed to demonstrate consistent effects on cognitive symptoms. Considering the lack of nonhuman primate data on the effects of memantine and galantamine alone or in combination on cognitive dysfunction in aged nonhuman primates, the present study examined how closely data derived from aged nonhuman primates reflects data obtained in humans. Mild beneficial effects on aspects of cognitive performance in aged primates were found, in general agreement with the human clinical experience with these drugs but in contrast to the more positive effects reported in the rodent literature. These data suggest that the nonhuman primate might have more predictive validity for drug development in this area than comparable rodent assays.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2012.10.020DOI Listing
April 2013

Diverse and often opposite behavioural effects of NMDA receptor antagonists in rats: implications for "NMDA antagonist modelling" of schizophrenia.

Psychopharmacology (Berl) 2009 Aug 7;205(2):203-16. Epub 2009 May 7.

Lilly Centre for Cognitive Neuroscience, Lilly Research Laboratories, Eli Lilly & Co. Ltd, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey GU206PH, England, UK.

Rationale: Little attention has been paid to the relative equivalence of behavioural effects of NMDA receptor antagonists in rodents, with different compounds often used interchangeably to "model" aspects of schizophrenia in preclinical studies.

Objectives: To further resolve such conjecture, the present study systematically compared eight different NMDA receptor antagonists: MK-801, PCP, ketamine, memantine, SDZ 220,581, Ro 25-6981, CP 101-606 and NVP-AAM077, in a series of variable interval (VI) schedules of reinforcement. Aspects of motivation as indexed in these tasks may well be impaired in schizophrenia and undoubtedly impact on the capacity to perform more complex, explicit tasks of cognition.

Methods And Results: An initial locomotor activity assessment demonstrated that all antagonists tested, except the NR2A-subunit preferring antagonist NVP-AAM077, induced hyperactivity, albeit of greatly differing magnitudes, qualities and temporal profiles. Three distinct patterns of antagonist effect were evident from the VI assays used: a uniform decrease in responding produced by (S)-(+)-ketamine, memantine and NVP-AAM077, a uniform increase in responding caused by the NR2B-subunit preferring antagonists Ro 25-6981 and CP 101-606, and variable bidirectional effects of PCP, SDZ 220,581 and MK-801.

Conclusion: Despite nominally common mechanisms of action and often presumed biological equivalence, the NMDA antagonists tested produced very diverse effects on the expression of instrumental action. Other aspects of responding were left intact, including switching and matching behaviours, and the ability to respond to conditional stimuli. The implications of such findings with regard to animal modelling of schizophrenic psychotic symptoms are manifold.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00213-009-1530-7DOI Listing
August 2009

Asymmetrically lesioned mesencephalon in healthy rodents: call for caution.

Brain Res 2004 Oct;1022(1-2):251-3

Basal Gang, Laboratoire de Physiologie et Physiopathologie de la Signalisation Cellulaire, CNRS UMR 5543, Université Victor Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France.

Stereological counting of tyrosine-hydroxylase immunoreactive (TH-IR) neurons in the mesencephalon is a pivotal parameter in assessing the extent of lesioning in animal models of Parkinson's disease. We here show that the number of TH-IR neurons often appears abnormally decreased in healthy--commercially available--mice and rats, although both the number of Nissl-stained cells and the striatal dopaminergic innervation are unaffected. This potential bias in assessing extent of neurotoxin-induced lesion and subsequent protection by pharmacological manipulation prompts us to call for caution in setting up experimental designs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.brainres.2004.07.014DOI Listing
October 2004

The deafferented nonhuman primate is not a reliable model of intractable pain.

Neurol Res 2003 Mar;25(2):127-9

Basal Gang, Laboratoire de Neurophysiologie, CNRS UMR, 5543, Université Victor Segalen, 146 rue Léo Saignat, 33076 Bordeaux, France.

Before extending the application of motor cortex stimulation it is important to investigate the intimate mechanisms by which it alleviates intractable pain and to consider possible side effects. Self-mutilation in animals following extensive neurectomy or posterior rhizotomy of a limb is thought to reveal severe dysesthesias in the deafferented zone suggesting its usefulness as an animal model of chronic pain in humans. We here show in deafferented nonhuman primates that the autotomy behavior immediately follows the surgery and disappears after 28 days. In keeping with the experience of Y. Lamarre, the simple but careful care of all wounds is sufficient to abolish this behavior. Our results do not exclude the possibility that the deafferentiation is still painful for the monkeys, but they definitely rule out that autotomy is a consistent response to deafferentation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1179/016164103101201274DOI Listing
March 2003
-->