112 results on '"Huot, Philippe"'
Search Results
2. Autoradiographic labelling of metabotropic glutamate type 2/3 receptors in the hemi-parkinsonian rat brain.
- Author
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Kim E, Frouni I, Shaqfah J, Bédard D, and Huot P
- Subjects
- Animals, Rats, Male, Parkinsonian Disorders metabolism, Parkinsonian Disorders chemically induced, Rats, Sprague-Dawley, Dyskinesia, Drug-Induced metabolism, Autoradiography, Receptors, Metabotropic Glutamate metabolism, Brain metabolism, Brain drug effects, Levodopa, Oxidopamine toxicity
- Abstract
L-3,4-dihydroxyphenylalanine (L-DOPA) is the treatment of choice for Parkinson's disease (PD) motor symptoms, but its chronic use is hindered by complications such as dyskinesia. Pre-clinical studies discovered that activation of metabotropic glutamate type 2 and 3 (mGlu
2/3 ) receptors alleviates L-DOPA-induced dyskinesia. To gain mechanistic insight into the anti-dyskinetic activity of mGlu2/3 activation, we performed autoradiographic binding with [3 H]-LY-341,495 in brain sections from L-DOPA-treated 6-hydroxydopamine (6-OHDA)-lesioned rats that developed mild or severe dyskinesia, as well as L-DOPA-untreated 6-OHDA-lesioned and sham-lesioned animals. In the ipsilateral hemisphere, mildly dyskinetic 6-OHDA-lesioned rats showed a decrease in [3 H]-LY-341,495 binding in the entopeduncular nucleus (EPN, 30 % vs sham-lesioned rats, P<0.05), globus pallidus (GP, 28 % vs sham-lesioned rats, P<0.05; 23 % vs L-DOPA-untreated 6-OHDA-lesioned rats, P<0.001), and primary motor cortex (49 % vs sham-lesioned rats, P<0.05; 45 % vs L-DOPA-untreated 6-OHDA-lesioned rats, P<0.001). Severely dyskinetic 6-OHDA-lesioned rats exhibited an increase in binding in the primary motor cortex (43 % vs mildly dyskinetic 6-OHDA-lesioned rats, P<0.05). In the contralateral hemisphere, mildly dyskinetic 6-OHDA-lesioned rats harboured a decrease in binding in the EPN (30 % vs sham-lesioned rats; 24 % vs L-DOPA-untreated 6-OHDA-lesioned rats, both P<0.05), GP (34 % vs sham-lesioned rats, P<0.05; 23 % vs L-DOPA-untreated 6-OHDA-lesioned rats, P<0.001), and primary motor cortex (50 % vs sham-lesioned rats; 44 % vs L-DOPA-untreated 6-OHDA-lesioned rats, both P<0.05). Severely dyskinetic 6-OHDA-lesioned rats presented a decrease in binding in the GP (30 % vs sham-lesioned rats; 19 % vs L-DOPA-untreated 6-OHDA-lesioned rats, both P<0.05). Abnormal involuntary movements scores of 6-OHDA-lesioned animals were positively correlated with [3 H]-LY-341,495 binding in the ipsilateral striatum, ipsilateral EPN, ipsilateral primary motor cortex and contralateral primary motor cortex (all P<0.05). These results suggest that alterations in mGlu2/3 receptor levels may be part of an endogenous compensatory mechanism to alleviate dyskinesia., Competing Interests: Declaration of Competing Interest All other Authors do not have any disclosure to report., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2024
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3. Effect of the mGlu 2 positive allosteric modulator biphenyl-indanone A as a monotherapy and as adjunct to a low dose of L-DOPA in the MPTP-lesioned marmoset.
- Author
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Kang W, Frouni I, Kwan C, Bédard D, Nuara SG, Hamadjida A, Gourdon JC, and Huot P
- Abstract
Activation of metabotropic glutamate 2 (mGlu
2 ) receptors is a potential novel therapeutic approach for the treatment of parkinsonism. Thus, when administered as monotherapy or as adjunct to a low dose of L-3,4-dihydroxyphenylalanine (L-DOPA), the mGlu2 positive allosteric modulator (PAM) LY-487,379 alleviated parkinsonism in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primates. Here, we sought to investigate the effect of biphenyl-indanone A (BINA), a highly selective mGlu2 PAM whose chemical scaffold is unrelated to LY-487,379, to determine if a structurally different mGlu2 PAM would also confer anti-parkinsonian benefit. In monotherapy experiments, MPTP-lesioned marmosets were injected with either vehicle, L-DOPA/benserazide (15/3.75 mg/kg, positive control) or BINA (0.1, 1, 10 mg/kg). In adjunct to a low L-DOPA dose experiments, MPTP-lesioned marmosets were injected with L-DOPA/benserazide (7.5/1.875 mg/kg) in combination with vehicle or BINA (0.1, 1, 10 mg/kg). Parkinsonism, dyskinesia and psychosis-like behaviours (PLBs) were then quantified. When administered alone, BINA 1 and 10 mg/kg decreased parkinsonism severity by ~22% (p < 0.01) and ~47% (p < 0.001), when compared with vehicle, which was comparable with the global effect of a high L-DOPA dose. When administered in combination with a low L-DOPA dose, BINA 1 and 10 mg/kg decreased global parkinsonism by ~38% (p < 0.001) and ~53% (p < 0.001). BINA 10 mg/kg decreased global dyskinesia by ~94% (p < 0.01) and global PLBs by ~92% (p < 0.01). Our results provide additional evidence that mGlu2 positive allosteric modulation elicits anti-parkinsonian effects. That this benefit is not related to a particular chemical scaffold suggests that it may be a class effect rather than the effect of a specific molecule., (© 2024 The Author(s). European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)- Published
- 2024
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4. Effect of mGluR 2 and mGluR 2/3 activators on parkinsonism in the MPTP-lesioned non-human primate.
- Author
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Frouni I, Kwan C, Bédard D, Hamadjida A, Kang W, Belliveau S, Nuara SG, Gourdon JC, and Huot P
- Abstract
We have previously discovered that the selective activation of metabotropic glutamate type 2 receptors (mGluR
2 ) and concurrent stimulation of metabotropic glutamate types 2 and 3 receptors (mGluR2/3 ) enhance the anti-parkinsonian action of L-3,4-dihydroxyphenylalanine (L-DOPA). Here, we sought to determine the effects of the mGluR2/3 orthosteric agonists LY-354,740 and LY-404,039, as well as the effects of the mGluR2 positive allosteric modulators LY-487,379 and CBiPES on the range of movement, bradykinesia, posture and alertness as adjuncts to L-DOPA. Ten 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets entered 4 experimental streams: L-DOPA + LY-354,740 (vehicle, 0.1, 0.3 and 1 mg/kg), L-DOPA + LY-404,039 (vehicle, 0.1, 1 and 10 mg/kg), L-DOPA + LY-487,379 (vehicle, 0.1, 1 and 10 mg/kg), L-DOPA + CBiPES (vehicle, 0.1, 1 and 10 mg/kg). For each molecule, treatments were randomised, and the range of movement, bradykinesia, posture and alertness were assessed by a blinded rater. None of the tested compounds significantly altered the global range of movement. LY-404,039 and CBiPES both reduced global bradykinesia, by up to 46% (both P < 0.05). LY-354,740, LY-404,039 and CBiPES each improved global posture by 35%, 44% and 39% (each P < 0.05), respectively. LY-404,039 and CBiPES both enhanced alertness by 54% (P < 0.05) and 79% (P < 0.01), respectively. LY-487,379 did not improve any of the parameters. Our results suggest that selective mGluR2 positive allosteric modulation and combined mGluR2/3 orthosteric stimulation might benefit bradykinesia, posture and alertness in PD when added to L-DOPA, which potentially represent novel therapeutic indications for molecules acting via these mechanisms., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)- Published
- 2024
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5. Positive allosteric mGluR 2 modulation with BINA alleviates dyskinesia and psychosis-like behaviours in the MPTP-lesioned marmoset.
- Author
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Kang W, Frouni I, Bédard D, Kwan C, Hamadjida A, Nuara SG, Gourdon JC, and Huot P
- Abstract
There is mounting evidence that positive allosteric modulation of metabotropic glutamate type 2 receptors (mGluR
2 ) is an efficacious approach to reduce the severity of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia, psychosis-like behaviours (PLBs), while conferring additional anti-parkinsonian benefit. However, the mGluR2 positive allosteric modulators (PAMs) tested so far, LY-487,379 and CBiPES, share a similar chemical scaffold. Here, we sought to assess whether similar benefits would be conferred by a structurally-distinct mGluR2 PAM, biphenylindanone A (BINA). Six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets exhibiting dyskinesia and PLBs were administered L-DOPA with either vehicle or BINA (0.1, 1, and 10 mg/kg) in a randomised within-subject design and recorded. Behaviour was analysed by a blinded rater who scored the severity of each of parkinsonism, dyskinesia and PLBs. When added to L-DOPA, BINA 0.1 mg/kg, 1 mg/kg, and 10 mg/kg all significantly reduced the severity of global dyskinesia, by 40%, 52% and 53%, (all P < 0.001) respectively. BINA similarly attenuated the severity of global PLBs by 35%, 48%, and 50%, (all P < 0.001) respectively. Meanwhile, BINA did not alter the effect of L-DOPA on parkinsonism exhibited by the marmosets. The results of this study provide incremental evidence of positive allosteric modulation of mGluR2 as an effective therapeutic strategy for alleviating dyskinesia and PLBs, without hindering the anti-parkinsonian action of L-DOPA. Furthermore, this therapeutic benefit does not appear to be confined to a particular chemical scaffold., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)- Published
- 2024
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6. Activation of mGlu 2/3 receptors with the orthosteric agonist LY-404,039 alleviates dyskinesia in experimental parkinsonism.
- Author
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Kang W, Frouni I, Kwan C, Desbiens L, Hamadjida A, and Huot P
- Subjects
- Animals, Male, Rats, Amino Acids pharmacology, Antiparkinson Agents pharmacology, Bridged Bicyclo Compounds pharmacology, Disease Models, Animal, Dose-Response Relationship, Drug, Excitatory Amino Acid Agonists pharmacology, Levodopa pharmacology, Oxidopamine, Rats, Sprague-Dawley, Rats, Wistar, Dyskinesia, Drug-Induced drug therapy, Parkinsonian Disorders chemically induced, Parkinsonian Disorders drug therapy, Receptors, Metabotropic Glutamate agonists, Receptors, Metabotropic Glutamate metabolism
- Abstract
LY-404,039 is an orthosteric agonist at metabotropic glutamate 2 and 3 (mGlu 2/3 ) receptors, with a possible additional agonist effect at dopamine D 2 receptors. LY-404,039 and its pro-drug, LY-2140023, have previously been tested in clinical trials for psychiatric indications and could therefore be repurposed if they were shown to be efficacious in other conditions. We have recently demonstrated that the mGlu 2/3 orthosteric agonist LY-354,740 alleviated L-3,4-dihydroxyphenylalanine (L-DOPA)-induced abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA)-lesioned rat without hampering the anti-parkinsonian action of L-DOPA. Here, we seek to take advantage of a possible additional D 2 -agonist effect of LY-404,039 and see if an anti-parkinsonian benefit might be achieved in addition to the antidyskinetic effect of mGlu 2/3 activation. To this end, we have administered LY-404,039 (vehicle, 0.1, 1 and 10 mg/kg) to 6-OHDA-lesioned rats, after which the severity of axial, limbs and oro-lingual (ALO) AIMs was assessed. The addition of LY-404,039 10 mg/kg to L-DOPA resulted in a significant reduction of ALO AIMs over 60-100 min (54%, P < 0.05). In addition, LY-404,039 significantly enhanced the antiparkinsonian effect of L-DOPA, assessed through the cylinder test (76%, P < 0.01). These results provide further evidence that mGlu 2/3 orthosteric stimulation may alleviate dyskinesia in PD and, in the specific case of LY-404,039, a possible D 2 -agonist effect might also make it attractive to address motor fluctuations. Because LY-404,039 and its pro-drug have been administered to humans, they could possibly be advanced to Phase IIa trials rapidly for the treatment of motor complications in PD., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2024
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7. Anticonvulsant Agents for Treatment of Restless Legs Syndrome: A Case Report With Lamotrigine and a Review of the Literature.
- Author
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Al-Kassmy J, Alsalmi M, Kang W, and Huot P
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- Humans, Female, Middle Aged, Restless Legs Syndrome drug therapy, Lamotrigine therapeutic use, Lamotrigine adverse effects, Anticonvulsants therapeutic use, Anticonvulsants adverse effects, Triazines therapeutic use, Triazines adverse effects
- Abstract
Introduction: Restless Legs Syndrome (RLS) is a neurological disorder primarily treated with pregabalin and gabapentin, followed by dopamine agonists later in the process due to the risk of augmenting RLS symptoms. In addition, clinical reports have disclosed varying degrees of success employing other agents in patients unresponsive to traditional agents. Here, we present a patient who had success in the reduction of RLS symptoms with lamotrigine, a broad-spectrum anticonvulsant. Previously, lamotrigine had been used in 2 trials with successful treatment of RLS., Case Report: We present a 58-year-old right-handed lady with long-standing history of smoking, hypertension, dyslipidaemia, prediabetes, gastro-esophageal reflux disease, asthma, strabismus, uterine cancer, severe and debilitating course of RLS accompanied by unexplained deterioration. The patient initially demonstrated abnormal sensation in all her limbs, which worsened with radiotherapy treatment, and was eventually diagnosed with RLS based on the diagnostic criteria. Subsequent examinations were unremarkable and revealed no further explanation for the deterioration of the RLS symptoms. While the complexity of the patient's medical history had exposed her to a variety of medications, she reported that only lamotrigine, in addition to her original regimen of methadone and pramipexole, offered significant symptomatic relief. It must be noted that no adverse side effects, including impulse-control disorder, were reported by the patient., Conclusions: We present a case of a woman whose deteriorating symptoms of RLS were successfully alleviated by the administration of lamotrigine. This is only the third case in the literature to have successfully utilized lamotrigine as a treatment option for RLS., Competing Interests: P.H. has received payments from Abbvie, adMare BioInnovations, ConSynance Therapeutics, Neurodiem, Sanford Burnham Prebys, Sunovion, and Througline Strategy. The remaining authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2024
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8. [ 3 H]-NFPS binding to the glycine transporter 1 in the hemi-parkinsonian rat brain.
- Author
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Frouni I, Kim E, Shaqfah J, Bédard D, Kwan C, Belliveau S, and Huot P
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- Animals, Rats, Male, Parkinsonian Disorders metabolism, Rats, Sprague-Dawley, Disease Models, Animal, Tritium, Functional Laterality physiology, Glycine Plasma Membrane Transport Proteins metabolism, Glycine Plasma Membrane Transport Proteins antagonists & inhibitors, Oxidopamine pharmacology, Brain metabolism, Brain drug effects, Sarcosine analogs & derivatives
- Abstract
L-3,4-dihydroxyphenylalanine (L-DOPA) is the main treatment for Parkinson's disease (PD) but with long term administration, motor complications such as dyskinesia are induced. Glycine transporter 1 (GlyT1) inhibition was shown to produce an anti-dyskinetic effect in parkinsonian rats and primates, coupled with an improvement in the anti-parkinsonian action of L-DOPA. The expression of GlyT1 in the brain in the dyskinetic state remains to be investigated. Here, we quantified the levels of GlyT1 across different brain regions using [
3 H]-NFPS in the presence of Org-25,935. Brain sections were chosen from sham-lesioned rats, L-DOPA-naïve 6-hydroxydopamine (6-OHDA)-lesioned rats and 6-OHDA-lesioned rats exhibiting mild or severe abnormal involuntary movements (AIMs). [3 H]-NFPS binding decreased in the ipsilateral and contralateral thalamus, by 28% and 41%, in 6-OHDA-lesioned rats with severe AIMs compared to sham-lesioned animals (P < 0.01 and 0.001). [3 H]-NFPS binding increased by 21% in the ipsilateral substantia nigra of 6-OHDA-lesioned rats with severe AIMs compared to 6-OHDA-lesioned rats with mild AIMs (P < 0.05). [3 H]-NFPS binding was lower by 19% in the contralateral primary motor cortex and by 20% in the contralateral subthalamic nucleus of 6-OHDA-lesioned rats with mild AIMs animals compared to rats with severe AIMs (both P < 0.05). The severity of AIMs scores positively correlated with [3 H]-NFPS binding in the ipsilateral substantia nigra (P < 0.05), ipsilateral entopeduncular nucleus (P < 0.05) and contralateral primary motor cortex (P < 0.05). These data provide an anatomical basis to explain the efficacy of GlyT1 inhibitors in dyskinesia in PD., (© 2024. The Author(s).)- Published
- 2024
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9. The 5-HT 2A/2C inverse agonist nelotanserin alleviates L-DOPA-induced dyskinesia in the MPTP-lesioned marmoset.
- Author
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Kwan C, Frouni I, Bédard D, Hamadjida A, Nuara SG, Gourdon JC, and Huot P
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- Animals, Female, Male, Antiparkinson Agents adverse effects, Callithrix, Drug Inverse Agonism, Levodopa adverse effects, Serotonin, Dyskinesia, Drug-Induced drug therapy, Dyskinesia, Drug-Induced etiology, Parkinsonian Disorders drug therapy, Parkinsonian Disorders chemically induced, Phenylurea Compounds, Pyrazoles
- Abstract
Nelotanserin is a serotonin 2A and 2C (5-HT
2A/2C ) inverse agonist that was previously tested in the clinic for rapid-eye movement sleep behaviour disorder and psychosis in patients with Parkinson's disease (PD) dementia. Its effect on L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia has however not been investigated. As 5-HT2A antagonism/inverse agonism is a validated approach to alleviate dyskinesia, we undertook the current study to evaluate the anti-dyskinetic potential of nelotanserin in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Parkinsonism was induced in six common marmosets (Callithrix jacchus, three females and three males) that were then chronically treated with L-DOPA to induce dyskinesia. On experimental days, they were administered L-DOPA in combination with vehicle or nelotanserin (0.1, 0.3 and 1 mg/kg) subcutaneously, in a randomised fashion. Dyskinesia and parkinsonism were rated post hoc by a blinded observer. In comparison to vehicle, the addition of nelotanserin 0.3 and 1 mg/kg to L-DOPA diminished peak dose dyskinesia by 47% (P < 0.05) and 69% (P < 0.001). Nelotanserin 0.3 and 1 mg/kg also reduced the severity of global dyskinesia, by 40% (P < 0.01) and 55% (P < 0.001), when compared to vehicle. Nelotanserin 0.1 mg/kg did not alleviate peak dose or global dyskinesia severity. Nelotanserin had no impact on the anti-parkinsonian action of L-DOPA. Our results highlight that nelotanserin may represent an efficacious anti-dyskinetic drug and provide incremental evidence of the potential benefit of 5-HT2A/2C antagonism/inverse agonism for drug-induced dyskinesia in PD., (© 2023 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)- Published
- 2024
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10. Levodopa-induced dyskinesia: do current clinical trials hold hope for future treatment?
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Alsalmi M, Al-Kassmy J, Kang W, Palayew M, and Huot P
- Subjects
- Humans, Levodopa adverse effects, Antiparkinson Agents adverse effects, Parkinson Disease drug therapy, Dyskinesias drug therapy
- Published
- 2024
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11. Glycine and clozapine: potential relevance for the treatment of Parkinson's disease.
- Author
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Maddaford S and Huot P
- Subjects
- Humans, Antipsychotic Agents therapeutic use, Antiparkinson Agents therapeutic use, Clozapine therapeutic use, Parkinson Disease drug therapy, Glycine therapeutic use, Glycine pharmacology
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- 2024
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12. Metronidazole-induced encephalopathy in a patient with cirrhosis.
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Ji X, Li KX, Freitas LF, and Huot P
- Abstract
Metronidazole is a commonly used antibiotic with anaerobic bacterial, protozoal, and microaerophilic bacterial coverage. Encephalopathy and peripheral neurotoxicity are rare but known adverse events with prolonged metronidazole use, which can be difficult to distinguish from other causes of delirium in acutely ill patients. Definitive diagnosis can be made by brain magnetic resonance imaging (MRI), which often reveals symmetric bilateral hypersignal demyelination lesions typically involving the dentate nuclei, splenium of the corpus collosum, midbrain, dorsal medulla, and pons. This case report describes a 72-year-old male presenting with altered mental status and neurological deficits after prolonged metronidazole use for bacteremia with spondylodiscitis, with full clinical and neuroradiological resolution upon appropriate diagnosis and drug cessation. Neuroradiologists play an indispensable role in recognizing this rare and poorly understood manifestation., (© 2023 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)
- Published
- 2023
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13. Effect of the mGlu 4 positive allosteric modulator ADX-88178 on parkinsonism, psychosis-like behaviours and dyskinesia in the MPTP-lesioned marmoset.
- Author
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Frouni I, Kwan C, Bédard D, Kang W, Hamadjida A, Nuara SG, Gourdon JC, and Huot P
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- Rats, Animals, Levodopa adverse effects, Callithrix, Antiparkinson Agents pharmacology, Behavior, Animal, Dyskinesia, Drug-Induced drug therapy, Parkinsonian Disorders chemically induced, Parkinsonian Disorders drug therapy, Parkinson Disease drug therapy, Psychotic Disorders drug therapy
- Abstract
Rationale: Positive allosteric modulation of metabotropic glutamate type 4 (mGlu
4 ) receptors is a promising strategy to alleviate parkinsonian disability and L-3,4-dihydroxyphenylalanine (L-DOPA) induced dyskinesia. ADX-88178 is a highly selective mGlu4 positive allosteric modulator (PAM) that previously enhanced the anti-parkinsonian action of L-DOPA in the 6-hydroxydopamine-lesioned rat model of Parkinson's disease (PD)., Objectives: We sought to explore the effects of ADX-88178 on psychosis-like behaviours (PLBs) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. We also aimed to determine the effect of ADX-88178 on parkinsonism and dyskinesia., Methods: Six MPTP-lesioned marmosets were administered L-DOPA chronically to induce stable PLBs and dyskinesias. They were then administered ADX-88178 (0.01, 0.1 and 1 mg/kg) or vehicle, in combination with L-DOPA/benserazide (15/3.75 mg/kg), both sub-cutaneously, in a randomised fashion. PLBs, parkinsonism and dyskinesia were then measured., Results: ADX-88178 mildly worsened global PLBs at the dose of 1 mg/kg (by 13%, P = 0.020). L-DOPA alone conferred 158 min of on-time, while the duration of on-time was 212 min (34% increase, P = 0.011), after adding ADX-88178 1 mg/kg to L-DOPA. Accordingly, ADX-88178 1 mg/kg reduced global parkinsonian disability, by 38% (P = 0.0096). ADX-88178 1 mg/kg diminished peak dose dyskinesia by 34% (P = 0.015). Minimal effects were provided by lower doses., Conclusions: Whereas these results provide additional evidence of the anti-parkinsonian and anti-dyskinetic effects of mGlu4 positive allosteric modulation as an adjunct to L-DOPA, they also suggest that ADX-88178 may exacerbate dopaminergic psychosis. Further studies are needed to evaluate this possible adverse effect of mGlu4 PAMs on PD psychosis., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)- Published
- 2023
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14. The mGluR 2/3 orthosteric agonist LY-404,039 reduces dyskinesia, psychosis-like behaviours and parkinsonism in the MPTP-lesioned marmoset.
- Author
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Kang W, Nuara SG, Bédard D, Frouni I, Kwan C, Hamadjida A, Gourdon JC, Gaudette F, Beaudry F, and Huot P
- Subjects
- Animals, Levodopa pharmacology, Antiparkinson Agents pharmacology, Antiparkinson Agents therapeutic use, Callithrix, Dopamine, Behavior, Animal, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Dyskinesia, Drug-Induced drug therapy, Dyskinesia, Drug-Induced etiology, Parkinsonian Disorders drug therapy, Parkinsonian Disorders chemically induced, Parkinson Disease drug therapy, Psychotic Disorders drug therapy
- Abstract
LY-404,039 is an orthosteric agonist of metabotropic glutamate 2 and 3 receptors (mGluR
2/3 ) that may harbour additional agonist effect at dopamine D2 receptors. LY-404,039 and its pro-drug, LY-2140023, have previously entered clinical trials as treatment options for schizophrenia. They could therefore be repurposed, if proven efficacious, for other conditions, notably Parkinson's disease (PD). We have previously shown that the mGluR2/3 orthosteric agonist LY-354,740 alleviated L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia and psychosis-like behaviours (PLBs) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Unlike LY-404,039, LY-354,740 does not stimulate dopamine D2 receptors, suggesting that LY-404,039 may elicit broader therapeutic effects in PD. Here, we sought to investigate the effect of this possible additional dopamine D2 -agonist action of LY-404,039 by assessing its efficacy on dyskinesia, PLBs and parkinsonism in the MPTP-lesioned marmoset. We first determined the pharmacokinetic profile of LY-404,039 in the marmoset, in order to select doses resulting in plasma concentrations known to be well tolerated in the clinic. Marmosets were then injected L-DOPA with either vehicle or LY-404,039 (0.1, 0.3, 1 and 10 mg/kg). The addition of LY-404,039 10 mg/kg to L-DOPA resulted in a significant reduction of global dyskinesia (by 55%, P < 0.01) and PLBs (by 50%, P < 0.05), as well as reduction of global parkinsonism (by 47%, P < 0.05). Our results provide additional support of the efficacy of mGluR2/3 orthosteric stimulation at alleviating dyskinesia, PLBs and parkinsonism. Because LY-404,039 has already been tested in clinical trials, it could be repurposed for indications related to PD., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)- Published
- 2023
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15. Dopamine Agonist Withdrawal Syndrome and Suicidality in Parkinson's Disease.
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Kwan C, Kolivakis T, and Huot P
- Subjects
- Humans, Dopamine Agonists adverse effects, Antiparkinson Agents adverse effects, Parkinson Disease complications, Parkinson Disease drug therapy, Suicide, Substance Withdrawal Syndrome, Disruptive, Impulse Control, and Conduct Disorders
- Published
- 2023
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16. Distribution of [ 11 C]-JNJ-42491293 in the marmoset brain: a positron emission tomography study.
- Author
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Kang MS, Hamadjida A, Bédard D, Nuara SG, Gourdon JC, Frey S, Aliaga A, Ross K, Hopewell R, Bdair H, Mathieu A, Tardif CL, Soucy JP, Massarweh G, Rosa-Neto P, and Huot P
- Subjects
- Rats, Animals, Brain diagnostic imaging, Brain metabolism, Binding Sites, Protein Binding, Callithrix, Positron-Emission Tomography methods
- Abstract
JNJ-42491293 is a metabotropic glutamate 2 (mGlu
2 ) positive allosteric modulator (PAM) that was radiolabelled with [11 C]- to serve as a positron emission tomography (PET) ligand. Indeed, in vitro, the molecule displays high selectivity at mGlu2 receptors. However, PET experiments performed in rats, macaques and humans, have suggested that [11 C]-JNJ-42491293 could interact with an unidentified, non-mGlu2 receptor binding site. The brain distribution of [11 C]-JNJ-42491293 has not been determined in the brain of the common marmoset, a small non-human primate increasingly used in neuroscience research. Here, we investigated the distribution of [11 C]-JNJ-42491293 in the marmoset brain. Three marmosets underwent brain magnetic resonance imaging (MRI) and 90-min dynamic PET scans with [11 C]-JNJ-42491293 in combination with vehicle or the mGlu2 PAM AZD8529 (0.1, 1 and 10 mg/kg). In the scans in which [11 C]-JNJ-42491293 was co-administered with vehicle, the brain areas with the highest standardised uptake values (SUVs) were the midbrain, cerebellum and thalamus, while the lowest SUVs were found in the pons. The addition of AZD8529 (0.1, 1 and 10 mg/kg) to [11 C]-JNJ-42491293 did not modify the SUVs obtained with [11 C]-JNJ-42491293 alone, and ex vivo blocking autoradiography with PAM AZD8529 (10, 100, 300 µM) on marmoset brain sections showed increased signals in the blocking conditions compared to vehicle, suggesting that no competition occurred between the 2 ligands. The results we obtained here do not suggest that [11 C]-JNJ-42491293 interacts selectively, or even at all, with mGlu2 receptors in the marmoset, in agreement with findings previously reported in macaque and human., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)- Published
- 2023
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17. Targeting metabotropic glutamate receptors for the treatment of Parkinson's disease.
- Author
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Huot P
- Subjects
- Humans, Levodopa, Parkinson Disease drug therapy, Receptors, Metabotropic Glutamate, Dyskinesia, Drug-Induced
- Published
- 2023
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18. Pemphigoid-like Skin Lesions Following Introduction of Safinamide.
- Author
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Lachance L and Huot P
- Subjects
- Humans, Antiparkinson Agents, Levodopa, Benzylamines, Alanine adverse effects, Pemphigoid, Bullous chemically induced, Pemphigoid, Bullous drug therapy
- Published
- 2023
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- View/download PDF
19. Pharmacokinetic profile of bitopertin, a selective GlyT 1 inhibitor, in the rat.
- Author
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Frouni I, Bédard D, Bourgeois-Cayer É, Hamadjida A, Gaudette F, Beaudry F, and Huot P
- Subjects
- Male, Rats, Female, Animals, Rats, Sprague-Dawley, Sulfones, Administration, Oral, Tandem Mass Spectrometry, Piperazines
- Abstract
Bitopertin, a selective glycine transporter 1 (GlyT
1 ) inhibitor, has been extensively studied for the treatment of schizophrenia, with known safety and tolerability profiles in the clinic. Whereas several rodent experiments have been reported, the pharmacokinetic (PK) profile of bitopertin in rodents has not been extensively reported, as only two studies disclosed limited PK parameters in male rats after oral administration. Here, we determined the PK profile of bitopertin in female Sprague-Dawley rats. Blood samples were taken serially, before and after sub-cutaneous (0.03, 0.1, 0.3, 1, and 3 mg/kg) or intra-venous (0.1 mg/kg) administration. Plasma levels were determined by high-performance liquid chromatography coupled with heat-assisted electrospray ionisation tandem mass spectrometry (HPLC-HESI MS/MS). Subsequently, PK parameters were calculated using non-compartmental analysis, including area under the curve (AUC), time (Tmax ) to maximal plasma concentration (Cmax ), clearance (CL), volume of distribution (Vz ), as well as half-life (T1/2 ). Following sub-cutaneous injection, bitopertin exhibited dose-dependent AUC0-∞ (439.6-34,018.9 ng/mL) and Tmax (3.7-24.0 h), a very long terminal T1/2 (35.06-110.32 h) and low CL (0.07-0.13 L/h/kg), suggesting that bitopertin is slowly absorbed and eliminated in the rat. The observed relationship between dose and the extent of drug exposure (AUC) was linear. Following administration of all sub-cutaneous doses, measured bitopertin plasma levels were comparable to levels achieved with doses already administered in the clinic. We hope that our results will be useful in the design of pre-clinical experiments in which this drug will eventually be administered sub-cutaneously., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)- Published
- 2023
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20. 5-HT 1A agonists for levodopa-induced dyskinesia in Parkinson's disease.
- Author
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Al-Kassmy J, Sun C, and Huot P
- Subjects
- Humans, Levodopa adverse effects, Serotonin, Serotonin 5-HT1 Receptor Agonists therapeutic use, Serotonin 5-HT1 Receptor Agonists pharmacology, Antiparkinson Agents adverse effects, Parkinson Disease complications, Parkinson Disease drug therapy, Dyskinesia, Drug-Induced drug therapy, Dyskinesia, Drug-Induced etiology
- Abstract
Levodopa is the most effective agent for treating the symptoms of Parkinson's disease (PD). However, levodopa-induced dyskinesia remains a significant complication that manifests after few years of treatment, for which therapeutic options remain limited. Several agonists of the serotonin type 1A (5-HT
1A ) receptor with varying levels of efficacy and interaction at other sites, have been tested in the clinic. Clinical trials testing 5-HT1A agonists have yielded inconsistent results in alleviating dyskinesia, especially that the antidyskinetic benefit observed was often accompanied by an adverse effect on motor function. In this article, we summarize and analyze the various clinical trials performed with 5-HT1A agonists in PD patients with dyskinesia and offer perspectives on the future of this class of agents in PD.- Published
- 2023
- Full Text
- View/download PDF
21. Anti-parkinsonian effect of the mGlu 2 positive allosteric modulator LY-487,379 as monotherapy and adjunct to a low L-DOPA dose in the MPTP-lesioned marmoset.
- Author
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Frouni I, Kwan C, Belliveau S, Hamadjida A, Bédard D, Nuara SG, Gourdon JC, and Huot P
- Subjects
- Animals, Antiparkinson Agents pharmacology, Antiparkinson Agents therapeutic use, Callithrix, Levodopa pharmacology, Levodopa therapeutic use, Parkinsonian Disorders drug therapy
- Abstract
In previous experiments, we have discovered that positive allosteric modulation of metabotropic glutamate 2 (mGlu
2 ) receptors enhances the anti-parkinsonian action of an optimal dose of L-3,4-dihydroxyphenylalanine (L-DOPA). Whether selective mGlu2 positive allosteric modulation would also alleviate parkinsonian disability as monotherapy or as adjunct to a sub-optimal dose of L-DOPA has not been determined. Here, we assessed the anti-parkinsonian effect of mGlu2 positive allosteric modulation as monotherapy and adjunct to a sub-optimal dose of L-DOPA in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets. The highly selective positive allosteric modulator (PAM) LY-487,379 was utilised to activate mGlu2 receptors. When administered as monotherapy, LY-487,379 10 mg/kg diminished global parkinsonism by 48% (P < 0.001) and increased duration of on-time by 7-fold, when compared to vehicle treatment (P < 0.05). When added to a sub-optimal dose of L-DOPA, LY-487,379 10 mg/kg decreased global parkinsonism by 44% (P < 0.001) and extended duration of on-time by 2.5-fold (P < 0.01). Our results indicate that selective mGlu2 positive allosteric modulation elicits anti-parkinsonian benefits as monotherapy and as adjunct to sub-optimal dose of L-DOPA paradigms, potentially suggesting that mGlu2 PAMs may have a therapeutic niche early in the treatment of PD as DOPA-sparing agents., Competing Interests: Declaration of competing interest There are no conflicts of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)- Published
- 2023
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22. Metabotropic glutamate receptors in Parkinson's disease.
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Kwan C, Kang W, Kim E, Belliveau S, Frouni I, and Huot P
- Subjects
- Humans, Amantadine, Glutamates, Parkinson Disease, Receptors, Metabotropic Glutamate
- Abstract
Parkinson's disease (PD) is a complex disorder that leads to alterations in multiple neurotransmitter systems, notably glutamate. As such, several drugs acting at glutamatergic receptors have been assessed to alleviate the manifestation of PD and treatment-related complications, culminating with the approval of the N-methyl-d-aspartate (NMDA) antagonist amantadine for l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia. Glutamate elicits its actions through several ionotropic and metabotropic (mGlu) receptors. There are 8 sub-types of mGlu receptors, with sub-types 4 (mGlu
4 ) and 5 (mGlu5 ) modulators having been tested in the clinic for endpoints pertaining to PD, while sub-types 2 (mGlu2 ) and 3 (mGlu3 ) have been investigated in pre-clinical settings. In this book chapter, we provide an overview of mGlu receptors in PD, with a focus on mGlu5 , mGlu4 , mGlu2 and mGlu3 receptors. For each sub-type, we review, when applicable, their anatomical localization and possible mechanisms underlying their efficacy for specific disease manifestation or treatment-induced complications. We then summarize the findings of pre-clinical studies and clinical trials with pharmacological agents and discuss the potential strengths and limitations of each target. We conclude by offering some perspectives on the potential use of mGlu modulators in the treatment of PD., (Copyright © 2023 Elsevier Inc. All rights reserved.)- Published
- 2023
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23. Quantitative determination of LY-404,039, a metabotropic glutamate 2/3 receptor agonist, in rat plasma using chemical derivatization and HPLC-MRM/MS.
- Author
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Kang W, Gaudette F, Bédard D, Beaudry F, and Huot P
- Subjects
- Animals, Chromatography, High Pressure Liquid methods, Kinetics, Rats, Reproducibility of Results, Glutamates, Tandem Mass Spectrometry methods
- Abstract
A rapid, selective and sensitive method was developed and validated for the determination of LY-404,039 concentration in rat plasma using a butylation derivatization step to improve chromatographic characteristics and enhance signal intensity. The method consisted of a protein precipitation extraction followed by derivatization with butanol/HCl and analysis by high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). The separation was achieved using a 100 × 2.1 mm (2.6 μm) Thermo Scientific Accucore RP-MS column combined with an isocratic mobile phase composed of 40:60 acetonitrile-0.1% formic acid in water. An analytical range of 2.0-1,000 ng/ml was validated and used to quantify LY-404,039 in rat plasma. The novel method met all of the requirements of specificity, sensitivity, linearity, precision, accuracy and stability. A pharmacokinetic study was performed in rats and the novel analytical method was used as a routine analysis method to provide enhanced measurements of plasma concentrations of LY-404,039. The plasma pharmacokinetic results indicate very short terminal half-life (0.27 h ± 0.8) and high clearance (0.97 L/h/kg ± 0.12), suggesting that LY-404,039 is rapidly eliminated in the rat. Dose-dependent pharmacokinetics were observed following subcutaneous administration of LY-404,039 at doses of 0.1, 0.3 and 1.0 mg/kg., (© 2022 John Wiley & Sons Ltd.)
- Published
- 2022
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24. Effect of glycine transporter 1 inhibition with bitopertin on parkinsonism and L-DOPA induced dyskinesia in the 6-OHDA-lesioned rat.
- Author
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Frouni I, Kang W, Bédard D, Belliveau S, Kwan C, Hadj-Youssef S, Bourgeois-Cayer É, Ohlund L, Sleno L, Hamadjida A, and Huot P
- Subjects
- Animals, Antiparkinson Agents adverse effects, Glycine Plasma Membrane Transport Proteins, Levodopa pharmacology, Oxidopamine, Piperazines, Rats, Sulfones, Dyskinesia, Drug-Induced drug therapy, Dyskinesia, Drug-Induced etiology, Parkinson Disease drug therapy, Parkinsonian Disorders chemically induced, Parkinsonian Disorders drug therapy
- Abstract
Dyskinesia remains an unmet need in Parkinson's disease (PD). We have previously demonstrated that glycine transporter 1 (GlyT1) inhibition with ALX-5407 reduces dyskinesia and slightly improves parkinsonism in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Here, we sought to determine the effect of bitopertin, a clinically-tested GlyT1 inhibitor, on parkinsonism and dyskinesia in the 6-hydroxydopamine (6-OHDA)-lesioned rat. To do so, we assessed the effect of bitopertin on parkinsonism as monotherapy and as adjunct to a low dose of L-3,4-dihydroxyphenylalanine (L-DOPA). We then assessed the efficacy of bitopertin on dyskinesia in the context of acute challenge and chronic administration studies. Lastly, we evaluated whether de novo treatment with bitopertin, started concurrently with L-DOPA, would diminish the development of dyskinesia. We discovered that bitopertin (0.3 mg/kg), when administered alone, reduced the severity of parkinsonism by 35% (P < 0.01). As adjunct to a low dose of L-DOPA, bitopertin (3 mg/kg) enhanced the anti-parkinsonian effect of L-DOPA by 36% (P < 0.05). Moreover, the acute addition of bitopertin (0.03 mg/kg) to L-DOPA reduced dyskinesia by 27% (P < 0.001), and there was no tolerance to the anti-dyskinetic benefit after 4 weeks of daily administration. Lastly, bitopertin (0.03 mg/kg) started concurrently with L-DOPA, also attenuated the development of dyskinesia, by 33% (P < 0.01), when compared to L-DOPA alone. Our results suggest that GlyT1 inhibition may simultaneously reduce parkinsonism and L-DOPA-induced dyskinesia and represents a novel approach to treat, possibly prevent, motor complications in PD., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2022
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- View/download PDF
25. Evaluation of the effects of the mGlu 2/3 antagonist LY341495 on dyskinesia and psychosis-like behaviours in the MPTP-lesioned marmoset.
- Author
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Nuara SG, Gourdon JC, and Huot P
- Subjects
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine pharmacology, Amino Acids, Animals, Antiparkinson Agents therapeutic use, Behavior, Animal, Callithrix, Levodopa adverse effects, Serotonin pharmacology, Xanthenes, Dyskinesia, Drug-Induced drug therapy, Parkinsonian Disorders chemically induced, Parkinsonian Disorders drug therapy, Psychotic Disorders drug therapy
- Abstract
Background: We have previously demonstrated that the metabotropic glutamate 2 and 3 (mGlu
2/3 ) antagonist LY341495 reverses the anti-dyskinetic and anti-psychotic benefits conferred by mGlu2 activation and serotonin 2A (5-HT2A ) antagonism. Here, we hypothesised that a higher dose of LY341495, associated with a higher antagonistic effect at mGlu3 receptors, would result in a reduction of the reversal of mGlu2 activation and 5-HT2A blockade on dyskinesia, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset., Methods: After induction of parkinsonism with MPTP, marmosets entered 3 streams of experiments, in which the following treatments were administered, in combination with l-3,4-dihydroxyphenylalanine (L-DOPA), after which dyskinesia, psychosis-like behaviours (PLBs) and parkinsonism were rated: 1. vehicle/vehicle, LY354740 (mGlu2/3 orthosteric agonist)/vehicle, LY354740/LY341495 1 mg/kg and LY354740/LY341495 3 mg/kg; 2. vehicle/vehicle, LY487379 (mGlu2 positive allosteric modulator)/vehicle, LY487379/LY341495 1 mg/kg and LY487379/LY341495 3 mg/kg; 3. vehicle/vehicle, EMD-281,014 (5-HT2A antagonist)/vehicle, EMD-281,014/LY341495 1 mg/kg and EMD-281,014/LY341495 3 mg/kg., Results: Each of LY354740, LY487379 and EMD-281,014 reduced the severity of L-DOPA-induced dyskinesia, by 55%, 39% and 40%, respectively (all p < 0.001), as well as the severity of PLBs, by 48%, 36% and 41%, respectively (all p < 0.001). Adding LY341495 1 and 3 mg/kg to each of LY354740, LY487379 and EMD-281,014 resulted in a dose-dependent reversal of their anti-dyskinetic and anti-psychotic actions. No effect on the anti-parkinsonian action of L-DOPA was noted with any treatment combination., Conclusion: These results suggest that an antagonistic effect at mGlu3 receptors may not be sufficient to overcome the deleterious effect of mGlu2 blockade on dyskinesia in PD. It remains to be seen whether similar effects would have been obtained with a selective mGlu3 antagonist., (© 2022. The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences.)- Published
- 2022
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26. An overview of the active clinical trials for Parkinson's disease psychosis.
- Author
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Kwan C and Huot P
- Subjects
- Clinical Trials as Topic, Humans, Parkinson Disease drug therapy, Psychotic Disorders drug therapy
- Abstract
Tweetable abstract An overview of the active clinical trials for Parkinson's disease psychosis. In this article, we review the drugs currently undergoing clinical testing for Parkinson's disease psychosis and offer some perspectives on the treatment of the condition.
- Published
- 2022
- Full Text
- View/download PDF
27. Glutamate modulation for the treatment of levodopa induced dyskinesia: a brief review of the drugs tested in the clinic.
- Author
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Frouni I and Huot P
- Subjects
- Antiparkinson Agents adverse effects, Glutamic Acid therapeutic use, Humans, Levodopa adverse effects, N-Methylaspartate therapeutic use, Dyskinesia, Drug-Induced drug therapy, Parkinson Disease drug therapy
- Abstract
Levodopa is the standard treatment for Parkinson's disease, but its use is marred by the emergence of dyskinesia, for which treatment options remain limited. Here, we review the glutamatergic modulators that were assessed for their antidyskinetic potential in clinical trials, including N -methyl-D-aspartate (NMDA) antagonists, agonists at the glycine-binding site on NMDA receptors, metabotropic glutamate (mGlu) 4 agonists, mGlu
5 antagonists, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid antagonists and glutamate release inhibitors. Several agents that were investigated are not selective for their targets, raising uncertainty about the extent to which glutamatergic modulation contributed to their effects. Except for amantadine, the use of glutamatergic modulators for the treatment of dyskinesia in Parkinson's disease remains largely investigational, with promising results obtained with mGlu5 negative allosteric modulation.- Published
- 2022
- Full Text
- View/download PDF
28. Levodopa-induced dyskinesia: a brief review of the ongoing clinical trials.
- Author
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Huot P, Kang W, Kim E, Bédard D, Belliveau S, Frouni I, and Kwan C
- Subjects
- Humans, Longitudinal Studies, Clinical Trials as Topic, Dyskinesia, Drug-Induced etiology, Levodopa adverse effects
- Published
- 2022
- Full Text
- View/download PDF
29. Autoradiographic labelling of 5-HT 3 receptors in the hemi-parkinsonian rat brain.
- Author
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Kwan C, Lévesque C, Bédard D, Frouni I, Yesuf JM, Hamadjida A, Lévesque D, Clarke PB, and Huot P
- Subjects
- Animals, Antiparkinson Agents pharmacology, Disease Models, Animal, Levodopa pharmacology, Ondansetron, Oxidopamine, Rats, Rats, Sprague-Dawley, Serotonin, Dyskinesia, Drug-Induced, Subthalamic Nucleus
- Abstract
L-3,4-dihydroxyphenylalanine (l-DOPA) is the mainstay treatment for Parkinson's disease, but its effectiveness during early disease is marred by the eventual development of l-DOPA induced dyskinesia. In hemi-parkinsonian rats, the serotonin type 3 (5-HT
3 ) antagonists ondansetron and granisetron alleviated dyskinesia induced by l-DOPA without impeding its anti-parkinsonian action; in parkinsonian marmosets, ondansetron alleviated dyskinesia and enhanced l-DOPA anti-parkinsonian action. Here, we sought to gain insight into the mechanisms governing the anti-dyskinetic action of 5-HT3 antagonists and measured 5-HT3 receptor levels across different brain, using [3 H]GR65630 autoradiographic binding. Brain sections were chosen from 6-hydroxydopamine (6-OHDA)-lesioned rats exhibiting abnormal involuntary movements (AIMs), as well as l-DOPA-naïve 6-OHDA and sham-lesioned animals. [3 H]GR65630 binding increased in the ipsilateral subthalamic nucleus of 6-OHDA-lesioned rats with mild and severe AIMs, (3-fold changes, P < 0.001). [3 H]GR65630 binding also increased in the ipsilateral entopeduncular nucleus and thalamus of 6-OHDA-lesioned rats with severe AIMs (75 % and 88 %, P < 0.05). AIMs scores negatively correlated with [3 H]GR65630 binding in the ipsilateral dorsolateral striatum and contralateral subthalamic nucleus (P < 0.05). These results suggest that alterations in 5-HT3 mediated neurotransmission may contribute to the pathophysiology of l-DOPA induced dyskinesia., (Copyright © 2021 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.)- Published
- 2022
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- View/download PDF
30. Cognition and serotonin in Parkinson's disease.
- Author
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Frouni I, Kwan C, Belliveau S, and Huot P
- Subjects
- Butyrylcholinesterase therapeutic use, Cognition, Humans, Quality of Life, Parkinson Disease complications, Parkinson Disease drug therapy, Serotonin
- Abstract
Cognitive impairment affects up to 80% of patients with Parkinson's disease (PD) and is associated with poor quality of life. PD cognitive dysfunction includes poor working memory, impairments in executive function and difficulty in set-shifting. The pathophysiology underlying cognitive impairment in PD is still poorly understood, but there is evidence to support involvements of the cholinergic, dopaminergic, and noradrenergic systems. Only rivastigmine, an acetyl- and butyrylcholinesterase inhibitor, is efficacious for the treatment of PD dementia, which limits management of cognitive impairment in PD. Whereas the role of the serotonergic system in PD cognition is less understood, through its interactions with other neurotransmitters systems, namely, the cholinergic system, it may be implicated in cognitive processes. In this chapter, we provide an overview of the pharmacological, clinical and pathological evidence that implicates the serotonergic system in mediating cognition in PD., Competing Interests: Financial disclosure There are no conflicts of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
31. Co-registration of Imaging Modalities (MRI, CT and PET) to Perform Frameless Stereotaxic Robotic Injections in the Common Marmoset.
- Author
-
Kwan C, Kang MS, Nuara SG, Gourdon JC, Bédard D, Tardif CL, Hopewell R, Ross K, Bdair H, Hamadjida A, Massarweh G, Soucy JP, Luo W, Del Cid Pellitero E, Shlaifer I, Durcan TM, Fon EA, Rosa-Neto P, Frey S, and Huot P
- Subjects
- Animals, Callithrix, Magnetic Resonance Imaging, Positron-Emission Tomography, Stereotaxic Techniques, Tomography, X-Ray Computed, Neuronavigation, Robotic Surgical Procedures
- Abstract
The common marmoset has emerged as a popular model in neuroscience research, in part due to its reproductive efficiency, genetic and neuroanatomical similarities to humans and the successful generation of transgenic lines. Stereotaxic procedures in marmosets are guided by 2D stereotaxic atlases, which are constructed with a limited number of animals and fail to account for inter-individual variability in skull and brain size. Here, we developed a frameless imaging-guided stereotaxic system that improves upon traditional approaches by using subject-specific registration of computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) data to identify a surgical target, namely the putamen, in two marmosets. The skull surface was laser-scanned to create a point cloud that was registered to the 3D reconstruction of the skull from CT. Reconstruction of the skull, as well as of the brain from MR images, was crucial for surgical planning. Localisation and injection into the putamen was done using a 6-axis robotic arm controlled by a surgical navigation software (Brainsight™). Integration of subject-specific registration and frameless stereotaxic navigation allowed target localisation specific to each animal. Injection of alpha-synuclein fibrils into the putamen triggered progressive neurodegeneration of the nigro-striatal system, a key feature of Parkinson's disease. Four months post-surgery, a PET scan found evidence of nigro-striatal denervation, supporting accurate targeting of the putamen during co-registration and subsequent surgery. Our results suggest that this approach, coupled with frameless stereotaxic neuronavigation, is accurate in localising surgical targets and can be used to assess endpoints for longitudinal studies., (Copyright © 2021 IBRO. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
32. Additive effects of mGluR 2 positive allosteric modulation, mGluR 2 orthosteric stimulation and 5-HT 2A R antagonism on dyskinesia and psychosis-like behaviours in the MPTP-lesioned marmoset.
- Author
-
Nuara SG, Gourdon JC, Maddaford S, and Huot P
- Subjects
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Animals, Antiparkinson Agents administration & dosage, Antiparkinson Agents toxicity, Behavior, Animal drug effects, Bridged Bicyclo Compounds administration & dosage, Bridged Bicyclo Compounds pharmacology, Callithrix, Drug Therapy, Combination, Dyskinesia, Drug-Induced etiology, Dyskinesia, Drug-Induced prevention & control, Female, Indoles administration & dosage, Indoles pharmacology, Levodopa administration & dosage, Levodopa toxicity, Male, Parkinsonian Disorders psychology, Piperazines administration & dosage, Piperazines pharmacology, Psychotic Disorders etiology, Pyridines administration & dosage, Pyridines pharmacology, Receptors, Metabotropic Glutamate drug effects, Receptors, Metabotropic Glutamate metabolism, Serotonin 5-HT2 Receptor Antagonists administration & dosage, Serotonin 5-HT2 Receptor Antagonists pharmacology, Sulfonamides administration & dosage, Sulfonamides pharmacology, Antiparkinson Agents pharmacology, Levodopa pharmacology, Parkinsonian Disorders drug therapy, Psychotic Disorders drug therapy
- Abstract
Purpose: Antagonising serotonin (5-HT) type 2A receptors (5-HT
2A R) is an effective strategy to alleviate both dyskinesia and psychosis in Parkinson's disease (PD). We have recently shown that activation of metabotropic glutamate 2 receptors (mGluR2 ), via either orthosteric stimulation or positive allosteric modulation, enhances the anti-dyskinetic and anti-psychotic effects of 5-HT2A R antagonism. Here, we investigated if greater therapeutic efficacy would be achieved by combining 5-HT2A R antagonism with concurrent mGluR2 orthosteric stimulation and mGluR2 positive allosteric modulation., Methods: Five 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets exhibiting dyskinesia and psychosis-like behaviours (PLBs) were administered L-3,4-dihydroxyphenylalanine (L-DOPA) in combination with vehicle or the 5-HT2A R antagonist EMD-281,014. EMD-281,014 was itself administered alone or with the mGluR2 orthosteric agonist (OA) LY-354,740, the mGluR2 positive allosteric modulator (PAM) LY-487,379 and combination thereof, after which the severity of dyskinesia, PLBs and parkinsonism was rated., Results: EMD-281,014 reduced dyskinesia and PLBs by up to 47% and 40%, respectively (both P < 0.001). The addition of LY-354,740, LY-487,379 and LY-354,740/LY-487,379 decreased dyskinesia by 56%, 65% and 77%, while PLBs were diminished by 55%, 63% and 71% (all P < 0.001). All treatment combinations provided anti-dyskinetic and anti-psychotic benefits significantly greater than those conferred by EMD-281,014 alone (all P < 0.05). The combination of EMD-281,014/LY-354,740/LY-487,379 resulted in anti-dyskinetic and anti-psychotic effects significantly greater than those conferred by EMD-281,014 with either LY-354,740 or LY-487,379 (both P < 0.05). No deleterious effects on L-DOPA anti-parkinsonian action were observed., Conclusion: Our results suggest that combining 5-HT2A R antagonism with mGluR2 activation results in greater reduction of L-DOPA-induced dyskinesia and PD psychosis. They also indicate that further additive effect can be achieved when a mGluR2 OA and a mGluR2 PAM are combined with a 5-HT2A R antagonist than when a mGluR2 OA or a mGluR2 PAM are added to a 5-HT2A R antagonist., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)- Published
- 2021
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33. Effect of the glycine transporter 1 inhibitor ALX-5407 on dyskinesia, psychosis-like behaviours and parkinsonism in the MPTP-lesioned marmoset.
- Author
-
Frouni I, Belliveau S, Maddaford S, Nuara SG, Gourdon JC, and Huot P
- Subjects
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine pharmacology, Animals, Antiparkinson Agents therapeutic use, Behavior, Animal drug effects, Callithrix, Disease Models, Animal, Dyskinesia, Drug-Induced complications, Female, Levodopa adverse effects, Levodopa pharmacology, Levodopa therapeutic use, MPTP Poisoning, Male, Parkinsonian Disorders chemically induced, Parkinsonian Disorders complications, Psychoses, Substance-Induced complications, Sarcosine pharmacology, Sarcosine therapeutic use, Antiparkinson Agents pharmacology, Dyskinesia, Drug-Induced drug therapy, Glycine Plasma Membrane Transport Proteins antagonists & inhibitors, Parkinsonian Disorders drug therapy, Psychoses, Substance-Induced drug therapy, Sarcosine analogs & derivatives
- Abstract
Dyskinesia and psychosis are complications encountered in advanced Parkinson's disease (PD) following long-term therapy with L-3,4-dihydroxyphenylalanine (L-DOPA). Disturbances in the glutamatergic system have been associated with both dyskinesia and psychosis, making glutamatergic modulation a potential therapeutic approach for these. Treatments thus far have sought to dampen glutamatergic transmission, for example through blockade of N-methyl-D-aspartate (NMDA) receptors or modulation of metabotropic glutamate receptors 5. In contrast, activation of the glycine-binding site on NMDA receptors is required for their physiological response. Here, we investigated whether indirectly enhancing glutamatergic transmission through inhibition of glycine re-uptake would be efficacious in diminishing both dyskinesia and psychosis-like behaviours (PLBs) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned common marmoset. Six marmosets were rendered parkinsonian by MPTP injection. Following repeated administration of L-DOPA to induce dyskinesia and PLBs, they underwent acute challenges of the glycine transporter 1 (GlyT
1 ) inhibitor ALX-5407 (0.01, 0.1 and 1 mg/kg) or vehicle, in combination with L-DOPA, after which the severity of dyskinesia, PLBs and parkinsonian disability was evaluated. In combination with L-DOPA, ALX-5407 0.1 and 1 mg/kg significantly reduced the severity of dyskinesia, by 51% and 41% (both P < 0.001), when compared to vehicle. ALX-5407 0.01, 0.1 and 1 mg/kg also decreased the severity of global PLBs, by 25%, 51% and 38% (all P < 0.001), when compared to vehicle. The benefits on dyskinesia and PLBs were achieved without compromising the therapeutic effect of L-DOPA on parkinsonism. Our results suggest that GlyT1 inhibition may be a novel strategy to attenuate dyskinesia and PLBs in PD, without interfering with L-DOPA anti-parkinsonian action., (Copyright © 2021 Elsevier B.V. All rights reserved.)- Published
- 2021
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34. Further characterisation of psychosis-like behaviours induced by L-DOPA in the MPTP-lesioned marmoset.
- Author
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Kwan C, Nuara SG, Gourdon JC, and Huot P
- Subjects
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Animals, Behavior, Animal drug effects, Callithrix, Disease Models, Animal, Female, Male, Parkinsonian Disorders physiopathology, Psychotic Disorders etiology, Antiparkinson Agents toxicity, Levodopa toxicity, Parkinsonian Disorders psychology, Psychotic Disorders physiopathology
- Abstract
Parkinson's disease (PD) psychosis afflicts over half of patients and poses a significant burden on quality of life. The aetiology of PD psychosis is multifactorial and likely arises from the complex interaction between dopamine replacement therapy and disease state. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned common marmoset is a validated model to predict the efficacy of therapeutic compounds for treatment-related complications, including PD psychosis. In this model, psychosis-like behaviours (PLBs) encompass stereotypies that are idiosyncratic in nature and reproducible with each L-3,4-dihydroxyphenylanaline (L-DOPA) administration. In the present study, we sought to expand upon the existing repertoire of PLBs through the characterisation of novel stereotypical behaviours that appear dependent on the environment. We then discuss our findings in the context of clinical reports on stereotypical behaviours termed "punding" in subjects with PD, which consists of stereotypical repetitive and senseless behaviours. The poor understanding of the pathophysiology governing punding and consequent lack of effective therapies stand to benefit from enhanced characterisation of these stereotypical behaviours in a validated pre-clinical model. We hope that further characterisation of PLBs in the MPTP-lesioned marmoset will be helpful in the evaluation of interventions that seek to alleviate PD psychosis symptoms., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
- Published
- 2021
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35. Plasma pTau181 predicts cortical brain atrophy in aging and Alzheimer's disease.
- Author
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Tissot C, L Benedet A, Therriault J, Pascoal TA, Lussier FZ, Saha-Chaudhuri P, Chamoun M, Savard M, Mathotaarachchi SS, Bezgin G, Wang YT, Fernandez Arias J, Rodriguez JL, Snellman A, Ashton NJ, Karikari TK, Blennow K, Zetterberg H, De Villers-Sidani E, Huot P, Gauthier S, and Rosa-Neto P
- Subjects
- Aging, Atrophy pathology, Brain diagnostic imaging, Brain pathology, Cross-Sectional Studies, Humans, Magnetic Resonance Imaging, Positron-Emission Tomography, Alzheimer Disease diagnostic imaging, Alzheimer Disease pathology
- Abstract
Background: To investigate the association of plasma pTau181, assessed with a new immunoassay, with neurodegeneration of white matter and gray matter cross-sectionally and longitudinally, in aging and Alzheimer's disease., Methods: Observational data was obtained from the Alzheimer's Disease Neuroimaging Initiative, in which participants underwent plasma assessment and magnetic resonance imaging. Based on their clinical diagnosis, participants were classified as cognitively unimpaired and cognitively impaired. Linear regressions and linear mixed-effect models were used to test the cross-sectional and longitudinal associations between baseline plasma pTau181 and neurodegeneration using voxel-based morphometry., Results: We observed a negative correlation at baseline between plasma pTau181 and gray matter volume in cognitively unimpaired individuals. In cognitively impaired individuals, we observed a negative association between plasma pTau181 and both gray and white matter volume. In longitudinal analyses conducted in the cognitively unimpaired group, plasma pTau181 was negatively correlated with gray matter volume, starting 36 months after baseline assessments. Finally, in cognitively impaired individuals, plasma pTau181 concentrations were negatively correlated with both gray and white matter volume as early as 12 months after baseline, and neurodegeneration increased in an incremental manner until 48 months., Conclusions: Higher levels of plasma pTau181 correlate with neurodegeneration and predict further brain atrophy in aging and Alzheimer's disease. Plasma pTau181 may be useful in predicting AD-related neurodegeneration, comparable to positron emission tomography or cerebrospinal fluid assessment with high specificity for AD neurodegeneration.
- Published
- 2021
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36. Combined 5-HT 2A and mGlu 2 modulation for the treatment of dyskinesia and psychosis in Parkinson's disease.
- Author
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Kwan C, Frouni I, Nuara SG, Belliveau S, Kang W, Hamadjida A, Bédard D, Beaudry F, Panisset M, Gourdon JC, and Huot P
- Subjects
- Animals, Callithrix, Drug Therapy, Combination, Dyskinesia, Drug-Induced metabolism, Female, Male, Parkinsonian Disorders metabolism, Psychoses, Substance-Induced metabolism, Receptor, Serotonin, 5-HT2A metabolism, Receptors, Metabotropic Glutamate metabolism, Serotonin 5-HT2 Receptor Antagonists administration & dosage, Treatment Outcome, Dyskinesia, Drug-Induced drug therapy, Indoles administration & dosage, Parkinsonian Disorders drug therapy, Piperazines administration & dosage, Psychoses, Substance-Induced drug therapy, Pyridines administration & dosage, Receptors, Metabotropic Glutamate agonists, Sulfonamides administration & dosage
- Abstract
Antagonising the serotonin 2A (5-HT
2A ) receptor is an efficacious way to alleviate dyskinesia and psychosis in Parkinson's disease (PD). However, previous research indicates that there might be a limit to the effects conferred by this approach. 5-HT2A receptors were shown to form hetero-dimers with metabotropic glutamate 2 (mGlu2 ) receptors, in which 5-HT2A blockade and mGlu2 activation elicit equivalent effects at the downstream signalling level. We have previously shown that mGlu2 activation reduces both dyskinesia and psychosis-like behaviours (PLBs) induced by L-3,4-dihydroxyphenylalanine (l-DOPA), in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. Here, we hypothesised that concurrent 5-HT2A antagonism and mGlu2 activation would provide greater anti-dyskinetic and anti-psychotic benefits than either approach alone. We conducted 3 series of experiments in the MPTP-lesioned marmoset. In the first series of experiments, the mGlu2 positive allosteric modulator LY-487,379 and the 5-HT2A antagonist EMD-281,014, either alone or in combination, were added to l-DOPA. In the second series of experiments, the mGlu2/3 orthosteric agonist LY-354,740 and EMD-281,014, either alone or in combination, were added to l-DOPA. In the last series of experiments, we investigated whether mGlu2 blockade would diminish the effects of antagonising 5-HT2A receptors. To this end, the mGlu2/3 orthosteric antagonist LY-341,495 and EMD-281,014, either alone or in combination, were added to l-DOPA. We found that the anti-dyskinetic effect of the combination LY-487,379/EMD-281,014 was greater than the ones conferred by LY-487,379 (by 35%, P < 0.05) and EMD-281,014 (by 38%, P < 0.01). The anti-dyskinetic and anti-psychotic effects of the combination LY-354,740/EMD-281,014 were also greater than the ones conferred by LY-354,740 (by 57% for dyskinesia and 54% for PLBs, both P < 0.001) and EMD-281,014 (by 61% for dyskinesia and 53% for PLBs, both P < 0.001). The anti-parkinsonian action of l-DOPA was maintained with all treatments. Lastly, the addition of LY-341,495 abolished the therapeutic effects of EMD-281,014 on dyskinesia and PLBs. Our results suggest that mGlu2 activation may enhance the anti-dyskinetic and anti-psychotic effects of 5-HT2A blockade and could provide relief to PD patients with dyskinesia and psychotic symptoms beyond what can be achieved with current therapies., (Copyright © 2021 Elsevier Ltd. All rights reserved.)- Published
- 2021
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37. Granisetron, a selective 5-HT3 antagonist, reduces L-3,4-dihydroxyphenylalanine-induced abnormal involuntary movements in the 6-hydroxydopamine-lesioned rat.
- Author
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Kwan C, Frouni I, Bédard D, Hamadjida A, and Huot P
- Subjects
- Animals, Antiparkinson Agents pharmacology, Antiparkinson Agents toxicity, Dose-Response Relationship, Drug, Dyskinesia, Drug-Induced etiology, Female, Granisetron administration & dosage, Levodopa pharmacology, Oxidopamine toxicity, Parkinsonian Disorders drug therapy, Rats, Rats, Sprague-Dawley, Serotonin 5-HT3 Receptor Antagonists administration & dosage, Dyskinesia, Drug-Induced drug therapy, Granisetron pharmacology, Levodopa toxicity, Serotonin 5-HT3 Receptor Antagonists pharmacology
- Abstract
Administration of L-3,4-dihydroxyphenylalanine (L-DOPA) provides Parkinson's disease patients with effective symptomatic relief. However, long-term L-DOPA therapy is often marred by complications such as dyskinesia. We have previously demonstrated that serotonin type 3 (5-HT3) receptor blockade with the clinically available and highly selective antagonist ondansetron alleviates dyskinesia in the 6-hydroxydopamine (6-OHDA)-lesioned rat. Here, we sought to explore the antidyskinetic efficacy of granisetron, another clinically available 5-HT3 receptor antagonist. Rats were rendered hemi-parkinsonian by 6-OHDA injection in the medial forebrain bundle. Following induction of stable abnormal involuntary movements (AIMs), granisetron (0.0001, 0.001, 0.01, 0.1 and 1 mg/kg) or vehicle was acutely administered in combination with L-DOPA and the severity of AIMs, both duration and amplitude, was determined. We also assessed the effect of granisetron on L-DOPA antiparkinsonian action by performing the cylinder test. Adding granisetron (0.0001, 0.001, 0.01, 0.1 and 1 mg/kg) to L-DOPA resulted in a significant reduction of AIMs duration and amplitude, with certain parameters being reduced by as much as 38 and 45% (P < 0.05 and P < 0.001, respectively). The antidyskinetic effect of granisetron was not accompanied by a reduction of L-DOPA antiparkinsonian action. These results suggest that 5-HT3 blockade may reduce L-DOPA-induced dyskinesia without impairing the therapeutic efficacy of L-DOPA. However, a U-shaped dose-response curve obtained with certain parameters may limit the therapeutic potential of this strategy and require further investigation., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2021
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38. Effect of the mGlu 2 positive allosteric modulator CBiPES on dyskinesia, psychosis-like behaviours and parkinsonism in the MPTP-lesioned marmoset.
- Author
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Frouni I, Kwan C, Nuara SG, Belliveau S, Kang W, Hamadjida A, Bédard D, Gourdon JC, and Huot P
- Subjects
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Animals, Antiparkinson Agents pharmacology, Antiparkinson Agents therapeutic use, Behavior, Animal, Callithrix, Humans, Levodopa, Dyskinesia, Drug-Induced drug therapy, Parkinsonian Disorders drug therapy, Psychotic Disorders drug therapy
- Abstract
Advanced Parkinson's disease (PD) is often complicated by the occurrence of dyskinesia, motor fluctuations and psychosis. To this day, few treatment options are available for each of these phenomena, and they are at times not effective or elicit adverse events, leaving some patients short of therapeutic options. We have recently shown that positive allosteric modulation of metabotropic 2 (mGlu
2 ) receptors with the prototypical positive allosteric modulator (PAM) LY-487,379 is efficacious at alleviating both dyskinesia and psychosis-like behaviours (PLBs), while simultaneously enhancing the anti-parkinsonian action of L-3,4-dihydroxyphenylalanine (L-DOPA), in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Here, we assessed the effects of CBiPES, a mGlu2 PAM derived from LY-487,379, but with improved pharmacokinetic properties. Six MPTP-lesioned marmosets with reproducible dyskinesia and PLBs were administered L-DOPA in combination with vehicle or CBiPES (0.1, 1 and 10 mg/kg), after which their behaviour was rated. CBiPES 10 mg/kg reduced global dyskinesia by 60% (P < 0.0001), while peak dose dyskinesia was reduced by 66% (P < 0.001), compared to L-DOPA/vehicle. CBiPES 10 mg/kg also diminished global PLBs by 56% (P < 0.0001), while peak dose PLBs were reduced by 64% (P < 0.001), compared to L-DOPA/vehicle. Lastly, CBiPES enhanced the anti-parkinsonian action of L-DOPA, by reducing global parkinsonian disability by 43% (P < 0.01), compared to L-DOPA/vehicle. Our results provide further evidence that mGlu2 positive allosteric modulation may be an approach that could be efficacious for the treatment of dyskinesia, psychosis and motor fluctuations in PD.- Published
- 2021
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39. Selective blockade of the 5-HT 3 receptor acutely alleviates dyskinesia and psychosis in the parkinsonian marmoset.
- Author
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Kwan C, Nuara SG, Bédard D, Gaudette F, Gourdon JC, Beaudry F, and Huot P
- Subjects
- Animals, Callithrix, Dose-Response Relationship, Drug, Female, MPTP Poisoning physiopathology, MPTP Poisoning psychology, Male, Psychotic Disorders physiopathology, Psychotic Disorders psychology, Anti-Anxiety Agents therapeutic use, MPTP Poisoning drug therapy, Ondansetron therapeutic use, Psychotic Disorders drug therapy, Serotonin 5-HT3 Receptor Antagonists therapeutic use
- Abstract
In Parkinson's disease (PD), management of L-3,4-dihydroxyphenylalanine (l-DOPA)-related complications, such as l-DOPA induced dyskinesia and psychosis, remains inadequate, which poses a significant burden on the quality of life of patients. We have shown, in the hemi-parkinsonian rat model of PD, that the selective serotonin type 3 (5-HT
3 ) receptor antagonists ondansetron and granisetron decreased the severity of established dyskinesia, and ondansetron even attenuated the development of dyskinesia. Here, we seek to confirm these favourable data on dyskinesia and to explore the effect of ondansetron on the severity of psychosis-like behaviours (PLBs) in the gold standard model of PD, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned non-human primate. We first determined the pharmacokinetic profile of ondansetron in the marmoset. Subsequently, six MPTP-lesioned marmosets were administered l-DOPA chronically until they exhibited stable and reproducible dyskinesia and PLBs upon each administration of l-DOPA. On behavioural assessment days, ondansetron (0.01, 0.1 and 1 mg/kg) or vehicle was administered in conjunction with l-DOPA, and the severity of dyskinesia, PLBs and parkinsonism was evaluated. Ondansetron 0.1 mg/kg alleviated global dyskinesia severity by 73% (P < 0.0001) and decreased duration of on-time with disabling dyskinesia by 88% (P = 0.0491). Ondansetron 0.1 mg/kg reduced the severity of global PLBs by 80% (P < 0.0001) and suppressed on-time with disabling PLBs (P = 0.0213). Ondansetron enhanced the anti-parkinsonian action of l-DOPA, reducing global parkinsonism by 53% compared to l-DOPA (P = 0.0004). These results suggest that selective blockade of the 5-HT3 receptor with ondansetron may be an effective approach to alleviate l-DOPA-related complications., (Copyright © 2020. Published by Elsevier Ltd.)- Published
- 2021
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40. Stereological investigation of 5-HT 3 receptors in the substantia nigra and dorsal raphe nucleus in the rat.
- Author
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Belliveau S, Kang W, Bovaird S, Hamadjida A, Bédard D, Dancause N, Stroh T, and Huot P
- Subjects
- Animals, Female, Male, Rats, Serotonin Plasma Membrane Transport Proteins metabolism, Tyrosine 3-Monooxygenase metabolism, Dorsal Raphe Nucleus metabolism, Neurons metabolism, Receptors, Serotonin, 5-HT3 metabolism, Substantia Nigra metabolism
- Abstract
Serotonin (5-HT) is a common neurotransmitter in mammals, playing a central role in the regulation of various processes such as sleep, perception, cognitive and autonomic functions in the nervous system. Previous studies have demonstrated that 5-HT type 3 (5-HT
3 ) receptors are expressed in either or both the substantia nigra (SN) and the dorsal raphe nucleus (DRN) in humans, marmosets, rats and Syrian hamsters. Here, we quantify the distribution of 5-HT3 receptors across these regions in the adult rat. Fluorescent immunohistochemistry was performed on sections of rat brain covering the entire rostro-caudal extent of the SN and DRN with antibodies specific to the 5-HT3A receptor subunit, as well as others targeting the monoaminergic markers tyrosine hydroxylase (TH) and the 5-HT transporter (SERT). The number of 5-HT3A receptor-positive, TH-positive (n = 28,428 ± 888, Gundersen's m = 1 coefficient of error [CE] = 0.05) and SERT-positive (n = 12,852 ± 462, CE = 0.06) cells were estimated in both the SN and the DRN using stereology. We found that 5-HT3A receptor-positive cells are present in the SNr (n = 1250 ± 64, CE = 0.24), but they did not co-localise with TH-positive cells, nor were they present in the SNc. In contrast, no 5-HT3A receptor-positive cells were found in the DRN. These results support the presence of 5-HT3 receptors in the SN, but not in the DRN, and do not support their expression on monoaminergic cells within these two brain areas., (Copyright © 2020 Elsevier B.V. All rights reserved.)- Published
- 2021
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41. Monoamine oxidase A inhibition and Parkinson's disease.
- Author
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Huot P
- Subjects
- Antidepressive Agents therapeutic use, Depression drug therapy, Humans, Monoamine Oxidase Inhibitors therapeutic use, Parkinson Disease drug therapy
- Published
- 2020
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42. Monoamine oxidase A inhibition with moclobemide enhances the anti-parkinsonian effect of L-DOPA in the MPTP-lesioned marmoset.
- Author
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Hamadjida A, Nuara SG, Kwan C, Frouni I, Bédard D, Gourdon JC, and Huot P
- Subjects
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Animals, Antiparkinson Agents toxicity, Basal Ganglia enzymology, Basal Ganglia physiopathology, Behavior, Animal drug effects, Callithrix, Disease Models, Animal, Drug Synergism, Drug Therapy, Combination, Dyskinesia, Drug-Induced etiology, Dyskinesia, Drug-Induced physiopathology, Female, Levodopa toxicity, Male, Motor Activity drug effects, Parkinsonian Disorders chemically induced, Parkinsonian Disorders enzymology, Parkinsonian Disorders physiopathology, Psychoses, Substance-Induced etiology, Psychoses, Substance-Induced psychology, Antiparkinson Agents pharmacology, Basal Ganglia drug effects, Levodopa pharmacology, Moclobemide pharmacology, Monoamine Oxidase metabolism, Monoamine Oxidase Inhibitors pharmacology, Parkinsonian Disorders drug therapy
- Abstract
Whereas monoamine oxidase (MAO) type B inhibitors are used as adjunct to L-3,4-dihydroxyphenylalanine (L-DOPA) in the treatment of Parkinson's disease (PD), the enzyme MAO type A (MAO-A) also participates in the metabolism of dopamine in the human and primate striatum. Here, we sought to assess the effect of the selective reversible MAO-A inhibitor moclobemide on L-DOPA anti-parkinsonian in the gold standard animal model of PD, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. We also assessed the effect of moclobemide on L-DOPA-induced dyskinesia and psychosis-like behaviours (PLBs). Experiments were performed in six MPTP-lesioned marmosets chronically treated with L-DOPA and exhibiting stable dyskinesia and PLBs upon each administration. In a randomised within-subject design, animals were administered a therapeutic dose of L-DOPA in combination with moclobemide (0.1, 1 and 10 mg/kg) or its vehicle, after which the severity of parkinsonism, dyskinesia, and PLBs was rated by an experienced blinded rater. Moclobemide significantly reduced the global parkinsonian disability (- 36% with 0.1 mg/kg, P < 0.05; - 38% with 1 mg/kg, P < 0.01; - 47% with 10 mg/kg, P < 0.01), when compared with its vehicle. This reduction of parkinsonism was not accompanied by an exacerbation of dyskinesia or PLBs. Reversible MAO-A inhibition with moclobemide appears as an effective way to increase the anti-parkinsonian action of L-DOPA, without negatively affecting dyskinesia or dopaminergic psychosis.
- Published
- 2020
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43. Monoamine oxidase A inhibition as monotherapy reverses parkinsonism in the MPTP-lesioned marmoset.
- Author
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Hamadjida A, Nuara SG, Frouni I, Kwan C, Bédard D, Gourdon JC, and Huot P
- Subjects
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Animals, Basal Ganglia enzymology, Basal Ganglia physiopathology, Behavior, Animal drug effects, Callithrix, Disease Models, Animal, Female, Levodopa pharmacology, Male, Motor Activity drug effects, Parkinsonian Disorders chemically induced, Parkinsonian Disorders enzymology, Parkinsonian Disorders physiopathology, Antiparkinson Agents pharmacology, Basal Ganglia drug effects, Moclobemide pharmacology, Monoamine Oxidase metabolism, Monoamine Oxidase Inhibitors pharmacology, Parkinsonian Disorders drug therapy
- Abstract
Monoamine oxidase (MAO) type B (MAO-B) inhibition was shown to confer anti-parkinsonian benefit as monotherapy and adjunct to L-3,4-dihydroxyphenylalanine (L-DOPA) in clinical trials. Here, we explore the anti-parkinsonian effect of MAO type A (MAO-A) inhibition as monotherapy, as the enzyme MAO-A is also encountered within the primate and human basal ganglia, where it metabolises dopamine, albeit to a lesser extent than MAO-B. In six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets, we assessed the anti-parkinsonian effect of the reversible MAO-A inhibitor moclobemide (0.1 and 1 mg/kg) as monotherapy and compared it to that of L-DOPA and vehicle treatments. Moclobemide significantly reversed parkinsonism (by 39%, P < 0.01), while eliciting only mild dyskinesia and psychosis-like behaviours (PLBs). In contrast, L-DOPA anti-parkinsonian effect was accompanied by marked dyskinesia and PLBs. MAO-A inhibition with moclobemide may provide anti-parkinsonian benefit when administered without L-DOPA and might perhaps be considered as monotherapy for the treatment of Parkinson's disease in the early stages of the condition.
- Published
- 2020
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44. Neurological complications of coronavirus infection; a comparative review and lessons learned during the COVID-19 pandemic.
- Author
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Sharifian-Dorche M, Huot P, Osherov M, Wen D, Saveriano A, Giacomini PS, Antel JP, and Mowla A
- Subjects
- COVID-19, Consciousness Disorders etiology, Cranial Nerve Diseases etiology, Encephalitis, Viral etiology, Humans, Magnetic Resonance Imaging, Muscular Diseases etiology, Neuroimaging, Peripheral Nervous System Diseases etiology, SARS-CoV-2, Seizures etiology, Severe Acute Respiratory Syndrome complications, Stroke etiology, Betacoronavirus, Coronavirus Infections complications, Nervous System Diseases etiology, Pandemics, Pneumonia, Viral complications
- Abstract
Introduction: Coronavirus disease-19 (COVID-19) pandemic continues to grow all over the world. Several studies have been performed, focusing on understanding the acute respiratory syndrome and treatment strategies. However, there is growing evidence indicating neurological manifestations occur in patients with COVID-19. Similarly, the other coronaviruses (CoV) epidemics; severe acute respiratory syndrome (SARS-CoV-1) and Middle East respiratory syndrome (MERS-CoV) have been associated with neurological complications., Methods: This systematic review serves to summarize available information regarding the potential effects of different types of CoV on the nervous system and describes the range of clinical neurological complications that have been reported thus far in COVID-19., Results: Two hundred and twenty-five studies on CoV infections associated neurological manifestations in human were reviewed. Of those, 208 articles were pertinent to COVID-19. The most common neurological complaints in COVID-19 were anosmia, ageusia, and headache, but more serious complications, such as stroke, impairment of consciousness, seizures, and encephalopathy, have also been reported., Conclusion: There are several similarities between neurological complications after SARS-CoV-1, MERS-CoV and COVID-19, however, the scope of the epidemics and number of patients are very different. Reports on the neurological complications after and during COVID-19 are growing on a daily basis. Accordingly, comprehensive knowledge of these complications will help health care providers to be attentive to these complications and diagnose and treat them timely., Competing Interests: Declaration of Competing Interest Authors have no relevant financial disclosure to report., (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Published
- 2020
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45. The MPTP-lesioned marmoset model of Parkinson's disease: proposed efficacy thresholds that may potentially predict successful clinical trial results.
- Author
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Beaudry F and Huot P
- Subjects
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Animals, Antiparkinson Agents therapeutic use, Behavior, Animal, Callithrix, Humans, Levodopa, Dyskinesia, Drug-Induced, Parkinson Disease
- Abstract
The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned common marmoset has been used extensively to model Parkinson's disease, L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia and, more recently, dopaminergic psychosis. Whereas several experimental drugs have been tested in this primate, many of which subsequently underwent clinical trials, efficacy thresholds in the marmoset that would predict efficacy in the clinic are lacking. Here, we aimed to determine such efficacy end points that would be indicative of likely efficacy in clinical studies. To do so, we used the evidence-based medicine reviews published by the International Parkinson and Movement Disorder Society (IPMDS) to select drugs that were rated as clinically efficacious, likely efficacious or not efficacious for the treatment of parkinsonism, dyskinesia and psychosis. We then reviewed the literature in the MPTP-lesioned marmoset and identified articles reporting the effects of drugs that were included in the IPMDS recommendations, following which we estimated efficacy thresholds in the marmoset that would predict efficacy at the clinical level. We propose that, when drugs are administered as monotherapy, ≥ 50% reduction of global parkinsonism may be necessary to predict the possibility of clinical efficacy. As adjunct to a low dose of L-DOPA, we propose that an additional reduction of global parkinsonism ≥ 25% might predict clinical efficacy. As adjunct to an optimal dose of L-DOPA, we propose that additional anti-parkinsonian benefit ≥ 20%, with global parkinsonism as the end point, might predict clinical efficacy. For the treatment of dyskinesia, we suggest that the predictability threshold be set at ≥ 25% reduction of peak dose dyskinesia, while we believe that this threshold should be > 50% reduction of peak dose psychosis-like behaviours for psychosis-related end points. This article represents the first step in determining what efficacy might be necessary to achieve in pre-clinical studies in the MPTP-lesioned marmoset prior to confidently advancing drugs to clinical trials. We hope that it will help in the drug discovery and development process, notably by avoiding exposing patients to drugs that have little probability of clinical efficacy based upon pre-clinical experiments.
- Published
- 2020
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46. Combined mGlu 2 orthosteric stimulation and positive allosteric modulation alleviates L-DOPA-induced psychosis-like behaviours and dyskinesia in the parkinsonian marmoset.
- Author
-
Nuara SG, Hamadjida A, Kwan C, Bédard D, Frouni I, Gourdon JC, and Huot P
- Subjects
- Animals, Antiparkinson Agents pharmacology, Antiparkinson Agents therapeutic use, Behavior, Animal, Callithrix, Levodopa, Dyskinesia, Drug-Induced drug therapy, Psychotic Disorders drug therapy
- Abstract
In recent studies performed in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset model of Parkinson's disease (PD), we have demonstrated that activation of the metabotropic glutamate 2 (mGlu
2 ) receptor with the orthosteric agonist (OA) LY-354,740 and the positive allosteric modulator (PAM) LY-487,379 is effective at alleviating both dyskinesia and psychosis-like behaviours (PLBs) triggered by the administration of L-3,4-dihydroxyphenylalanine (L-DOPA). Because mGlu2 OAs and PAMs bind to different sites on the receptor, we hypothesised that greater reductions of dyskinesia and PLBs would be obtained upon concurrent administration of LY-354,740 and LY-487,379. In experiments performed in six MPTP-lesioned marmosets, we administered LY-354,740 (0.1 mg/kg), LY-487,379 (1 mg/kg), LY-354,740 (0.1 mg/kg) + LY-487,379 (1 mg/kg), or vehicle, in combination with L-DOPA and determined the effect of each treatment on dyskinesia, PLBs, and parkinsonism. When compared to vehicle, LY-354,740 and LY-487,379, administered alone or concurrently, significantly reduced dyskinesia. The combination LY-354,740 + LY-487,379 provided mild additional benefit when compared to LY-487,379 alone, but not compared to LY-354,740. For PLBs, when compared to vehicle treatment, LY-354,740, LY-487,379, and combination thereof all alleviated the abnormal behaviours, but the combination LY-354,740 + LY-487,379 did not provide greater relief than either drug alone. The anti-parkinsonian effect of L-DOPA was not altered by any of the treatments. Our results provide further evidence that mGlu2 activation might be a novel approach to treat L-DOPA-induced dyskinesia and dopaminergic psychosis in PD. However, they do not suggest that greater therapeutic effect would be achieved upon combining an mGlu2 OA and an mGlu2 PAM.- Published
- 2020
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47. Pharmacokinetic profile of the selective 5-HT 3 receptor antagonist ondansetron in the rat: an original study and a minireview of the behavioural pharmacological literature in the rat.
- Author
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Kwan C, Bédard D, Frouni I, Gaudette F, Beaudry F, Hamadjida A, and Huot P
- Subjects
- Absorption, Physiological, Animals, Dose-Response Relationship, Drug, Female, Half-Life, Injections, Intravenous, Injections, Subcutaneous, Male, Models, Animal, Ondansetron administration & dosage, Rats, Serotonin 5-HT3 Receptor Antagonists administration & dosage, Tissue Distribution, Ondansetron pharmacokinetics, Serotonin 5-HT3 Receptor Antagonists pharmacokinetics
- Abstract
The availability of agonists and antagonists to modulate the activity of the 5-hydroxytryptamine (5-HT) type 3 (5-HT
3 ) receptor has renewed interest in its role as a therapeutic target. Ondansetron is a highly selective 5-HT3 receptor antagonist that is well tolerated as an anti-emetic for patients undergoing chemotherapy. Preclinical studies in rat have shown the effects of small doses of ondansetron on cognition, behavioural sensitisation, and epilepsy. However, the pharmacokinetic (PK) profile of ondansetron in rat has not been described, which limits the translational relevance of these findings. Here, we aim to determine, in the rat, the PK profile of ondansetron in the plasma and to determine associated brain levels. The plasma PK profile was determined following acute subcutaneous administration of ondansetron (0.1, 1, and 10 μg/kg). Brain levels were measured following subcutaneous administration of ondansetron at 1 μg/kg. Plasma and brain levels of ondansetron were determined using high-performance liquid chromatography - tandem mass spectrometry. Following administration of all three doses, measured ondansetron plasma levels (≈30-3000 pg/mL) were below levels achieved with doses usually administered in the clinic, with a rapid absorption phase and a short half-life (≈30-40 min). We also found that brain levels of ondansetron at 1 μg/kg were significantly lower than plasma levels, with brain to plasma ratios of 0.45 and 0.46 in the motor and pre-frontal cortices. We discuss our findings in the context of a minireview of the literature. We hope that our study will be helpful to the design of preclinical studies with therapeutic end-points.- Published
- 2020
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48. The mGlu 2/3 antagonist LY-341,495 reverses the anti-dyskinetic and anti-psychotic effects of the mGlu 2 activators LY-487,379 and LY-354,740 in the MPTP-lesioned marmoset.
- Author
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Nuara SG, Hamadjida A, Gourdon JC, and Huot P
- Subjects
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Animals, Antiparkinson Agents pharmacology, Behavior, Animal, Levodopa, Callithrix, Dyskinesia, Drug-Induced
- Abstract
We have recently shown that activation of metabotropic glutamate 2 (mGlu
2 ) receptors through positive allosteric modulation and orthosteric stimulation is a novel approach to reduce L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia and dopaminergic psychosis in Parkinson's disease (PD). We have obtained these benefits with the mGlu2 -positive allosteric modulator (PAM) LY-487,379 and the mGlu2/3 orthosteric agonist (OA) LY-354,740 in experiments conducted in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Here, we sought to pharmacologically characterise the anti-dyskinetic and anti-psychotic effects of LY-487,379 and LY-354,740, by assessing whether their benefits would be reversed by the mGlu2/3 orthosteric antagonist LY-341,495. Six MPTP-lesioned marmosets exhibiting stable dyskinesia and psychosis-like behaviours (PLBs) entered the experiments. In the first series of experiments, animals were injected L-DOPA in combination with either vehicle, LY-487,379 (10 mg/kg), LY-341,495 (1 mg/kg) or LY-487,379/LY-341,495. In the second series of experiments, marmosets were injected L-DOPA in combination with either vehicle, LY-354,740 (1 mg/kg), LY-341,495 (1 mg/kg) or LY-354,740/LY-341495. As we previously demonstrated, both LY-487,379 and LY-354,740 alleviated dyskinesia (by 44% and 47%, both P < 0.001) and PLBs (by 44% and 39%, P < 0.01 and P < 0.001) when compared to vehicle treatment. When LY-487,379 and LY-354,740 were administered concurrently with LY-341,495, the anti-dyskinetic and anti-psychotic benefits were abolished. When administered with L-DOPA in the absence of LY-487,379 and LY-354,740, LY-341,495 did not worsen dyskinesia or PLBs and did not hamper L-DOPA anti-parkinsonian action. Our results indicate that the anti-dyskinetic and anti-psychotic effects of mGlu2 -positive allosteric modulation and mGlu2/3 orthosteric stimulation are reversed by mGlu2/3 orthosteric blockade.- Published
- 2020
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49. The highly selective mGlu 2 receptor positive allosteric modulator LY-487,379 alleviates l-DOPA-induced dyskinesia in the 6-OHDA-lesioned rat model of Parkinson's disease.
- Author
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Hamadjida A, Sid-Otmane L, Kwan C, Frouni I, Nafade V, Bédard D, Gagnon D, Wallman MJ, Rouillard C, Parent A, Parent M, and Huot P
- Subjects
- Animals, Antiparkinson Agents, Callithrix, Disease Models, Animal, Levodopa, Oxidopamine toxicity, Rats, Dyskinesia, Drug-Induced drug therapy, Parkinson Disease
- Abstract
l-3,4-Dihydroxyphenylalanine (l-DOPA) is the most effective treatment for Parkinson's disease (PD), but its use over a long period is marred by motors complications such as dyskinesia. We previously demonstrated that selective metabotropic glutamate 2/3 (mGlu
2/3 ) receptor activation with LY-354,740 alleviates dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset and the 6-hydroxydopamine (6-OHDA)-lesioned rat. Here, we sought to determine the role played by selective mGlu2 activation in the anti-dyskinetic effect of mGlu2/3 stimulation and have investigated the effect of the highly selective mGlu2 positive allosteric modulator LY-487,379 at alleviating established, and preventing the development of, l-DOPA-induced dyskinesia in the 6-OHDA-lesioned rat. First, dyskinetic 6-OHDA-lesioned rats were administered l-DOPA in combination with LY-487,379 (0.1, 1 and 10 mg/kg) or vehicle, and the severity of dyskinesia was determined. Second, 6-OHDA-lesioned rats were administered LY-487,379 (0.1 or 1 mg/kg), started concurrently with l-DOPA, once daily for 22 days, and dyskinesia severity was evaluated weekly for four consecutive weeks. We also assessed the effect of LY-487,379 on l-DOPA anti-parkinsonian effect. We found that acute challenges of LY-487,379 0.1 mg/kg in combination with l-DOPA, significantly diminished dyskinesia severity, by ≈54% (p < .01), when compared to vehicle. Moreover, animals treated with l-DOPA/LY-487,379 0.1 and 1 mg/kg during the dyskinesia induction phase exhibited milder dyskinesia, by ≈74% and ≈61%, respectively (both p < .01), when compared to l-DOPA/vehicle. LY-487,379 did not impair l-DOPA anti-parkinsonian activity. These results suggest that mGlu2 activation may be an effective and promising therapeutic strategy to alleviate the severity and prevent the development of dyskinesia., (© 2020 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)- Published
- 2020
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50. Effect of Antidepressants on Psychotic Symptoms in Parkinson Disease: A Review of Case Reports and Case Series.
- Author
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Sid-Otmane L, Huot P, and Panisset M
- Subjects
- Adult, Aged, Aged, 80 and over, Amoxapine therapeutic use, Citalopram therapeutic use, Clomipramine therapeutic use, Female, Humans, Male, Mianserin therapeutic use, Middle Aged, Mirtazapine therapeutic use, Parkinson Disease psychology, Venlafaxine Hydrochloride therapeutic use, Antidepressive Agents therapeutic use, Parkinson Disease complications, Psychotic Disorders drug therapy
- Abstract
Objectives: The treatment of Parkinson disease (PD) psychosis remains a challenge. Only a few treatments eliciting significant relief of psychotic symptoms have passed the test of randomized controlled trials., Methods: Here, we conducted a review of the literature on the effect of antidepressants on PD psychosis. Because there is no randomized controlled trial that assessed the antipsychotic effects of antidepressants in PD, only case reports, case series, and open-label trials were available to review. Because of the scarce literature, statistical analysis could not be performed., Results: The following antidepressants alleviated hallucinations in PD: amoxapine, citalopram, clomipramine, escitalopram, mianserin, mirtazapine, and venlafaxine. The antidepressants were generally well tolerated, with the exception of amoxapine, which exacerbated parkinsonism., Conclusions: Whereas the conclusions that can be drawn on the efficacy of antidepressants at reducing PD psychosis are limited because of the poor quality of the reported studies, it is encouraging to notice that there are positive anecdotal reports. Further studies are needed to confirm the potential of these drugs and also to determine if a subtype of patients or of psychotic features may be more likely to be improved by antidepressants.
- Published
- 2020
- Full Text
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