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1.
J Neurosci ; 40(35): 6812-6819, 2020 08 26.
Artículo en Inglés | MEDLINE | ID: mdl-32690616

RESUMEN

Parkinson's disease (PD) is characterized by severe locomotor deficits and is commonly treated with the dopamine precursor L-DOPA, but its prolonged usage causes dyskinesias referred to as L-DOPA-induced dyskinesia (LID). Several studies in animal models of PD have suggested that dyskinesias are associated with a heightened opioid cotransmitter tone, observations that have led to the notion of a LID-related hyperactive opioid transmission that should be corrected by µ opioid receptor antagonists. Reports that both antagonists and agonists of the µ opioid receptor may alleviate LID severity in primate models of PD and LID, together with the failure of nonspecific antagonist to improve LID in pilot clinical trials in patients, raises doubt about the reliability of the available data on the opioid system in PD and LID. After in vitro characterization of the functional activity at the µ opioid receptor, we selected prototypical agonists, antagonists, and partial agonists at the µ opioid receptor. We then showed that both oral and discrete intracerebral administration of a µ receptor agonist, but not of an antagonist as long thought, ameliorated LIDs in the gold-standard bilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned female macaque model of PD and LID. The results call for a reappraisal of opioid pharmacology in the basal ganglia as well as for the development of brain nucleus-targeted µ opioid receptor agonists.SIGNIFICANCE STATEMENT µ opioid receptors have long been considered as a viable target for alleviating the severity of L-DOPA-induced hyperkinetic side effects, induced by the chronic treatment of Parkinson's disease motor symptoms with L-DOPA. Conflicting results between experimental parkinsonism and Parkinson's disease patients, however, dampened the enthusiasm for the target. Here we reappraise the pharmacology and then demonstrate that both oral and discrete intracerebral administration of a µ receptor agonist, but not of an antagonist as long thought, ameliorates LIDs in the gold-standard bilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson's disease, calling for a reappraisal of the opioid pharmacology as well as for the development of brain nucleus-targeted µ receptor agonists.


Asunto(s)
Discinesias/tratamiento farmacológico , Intoxicación por MPTP/fisiopatología , Receptores Opioides mu/agonistas , Animales , Células CHO , Cricetinae , Cricetulus , Discinesias/etiología , Encefalina Ala(2)-MeFe(4)-Gli(5)/administración & dosificación , Encefalina Ala(2)-MeFe(4)-Gli(5)/farmacología , Encefalina Ala(2)-MeFe(4)-Gli(5)/uso terapéutico , Femenino , Humanos , Levodopa/efectos adversos , Levodopa/uso terapéutico , Intoxicación por MPTP/tratamiento farmacológico , Macaca fascicularis , Neurotransmisores/administración & dosificación , Neurotransmisores/farmacología , Neurotransmisores/uso terapéutico , Receptores Opioides mu/antagonistas & inhibidores
2.
Neurobiol Dis ; 139: 104846, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32205254

RESUMEN

BACKGROUND: Continuous compensation of dopamine represents an ideal symptomatic treatment for Parkinson's disease (PD). The feasibility in intracerebroventricular administration (i.c.v.) of dopamine previously failed because of unresolved dopamine oxidation. OBJECTIVES: We aim to test the feasibility, safety margins and efficacy of continuous i.c.v. of anaerobic-dopamine (A-dopamine) with a pilot translational study in a non-human primate model of PD. METHODS: Continuous and circadian i.c.v. of A-dopamine was administered through a micro-pump connected to a subcutaneous catheter implanted into the right frontal horn of 8 non-human primates treated with 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP). A-dopamine was assessed at acute doses previously reported for dopamine as well as evaluating the long term therapeutic index of A-dopamine in comparison to anaerobically prepared L-dopa or methyl ester L-dopa. RESULTS: Over 60 days of a continuous circadian i.c.v. of A-dopamine improved motor symptoms (therapeutic index from 30 to 70 mg/day) without tachyphylaxia. No dyskinesia was observed even with very high doses. Death after 1 to 10 days (without neuronal alteration) was only observed with doses in excess of 160 mg whereas L-dopa i.c.v. was not effective at any dose. The technical feasibility of the administration regimen was confirmed for an anaerobic preparation of dopamine and for administration of a minimal infusion volume by micro-pump at a constant flow that prevented obstruction. CONCLUSION: Continuous circadian i.c.v. of A-dopamine appears to be feasible and shows efficacy without dyskinesia with a safe therapeutic index.


Asunto(s)
Dopamina/administración & dosificación , Infusiones Intraventriculares , Actividad Motora/efectos de los fármacos , Enfermedad de Parkinson/tratamiento farmacológico , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Animales , Antiparkinsonianos/farmacología , Modelos Animales de Enfermedad , Agonistas de Dopamina/farmacología , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Levodopa/análogos & derivados , Levodopa/farmacología , Macaca , Masculino , Trastornos Parkinsonianos/tratamiento farmacológico , Proyectos Piloto
3.
Brain ; 142(8): 2402-2416, 2019 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-31243443

RESUMEN

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


Asunto(s)
Antiparkinsonianos/administración & dosificación , GTP Ciclohidrolasa/administración & dosificación , Vectores Genéticos/uso terapéutico , Levodopa/biosíntesis , Trastornos Parkinsonianos/terapia , Putamen/metabolismo , Tirosina 3-Monooxigenasa/administración & dosificación , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversos , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/análogos & derivados , Animales , Antiparkinsonianos/uso terapéutico , Dependovirus/genética , Evaluación Preclínica de Medicamentos , Femenino , GTP Ciclohidrolasa/análisis , GTP Ciclohidrolasa/genética , GTP Ciclohidrolasa/metabolismo , Genes Reporteros , Genes Sintéticos , Vectores Genéticos/administración & dosificación , Humanos , Macaca mulatta , Masculino , Actividad Motora/efectos de los fármacos , Trastornos Parkinsonianos/inducido químicamente , Porción Compacta de la Sustancia Negra/química , Porción Compacta de la Sustancia Negra/patología , Prueba de Estudio Conceptual , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/análisis , Proteínas Recombinantes/uso terapéutico , Tirosina 3-Monooxigenasa/análisis , Tirosina 3-Monooxigenasa/genética , Tirosina 3-Monooxigenasa/metabolismo
4.
Mov Disord ; 33(10): 1619-1631, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30216534

RESUMEN

BACKGROUND: Levodopa remains the gold-standard treatment for PD. However, it becomes less effective as the disease progresses and produces debilitating side effects, such as motor fluctuations and l-dopa-induced dyskinesia. Modulation of metabotropic glutamate receptor 4 represents a promising antiparkinsonian approach in combination with l-dopa, but it has not been demonstrated in primates. OBJECTIVE: We studied whether a novel positive allosteric modulator of the metabotropic glutamate receptor 4, PXT002331 (foliglurax), could reduce parkinsonism in primate models. METHODS: We assessed the therapeutic potential of PXT002331 in three models of MPTP-induced parkinsonism in macaques. These models represent three different stages of disease evolution: early stage and advanced stage with and without l-dopa-induced dyskinesia. RESULTS: As an adjunct to l-dopa, PXT002331 induced a robust and dose-dependent reversal of parkinsonian motor symptoms in macaques, including bradykinesia, tremor, posture, and mobility. Moreover, PXT002331 strongly decreased dyskinesia severity, thus having therapeutic efficacy on both parkinsonian motor impairment and l-dopa-induced dyskinesia. PXT002331 brain penetration was also assessed using PET imaging in macaques, and pharmacodynamic analyses support target engagement in the therapeutic effects of PXT002331. CONCLUSIONS: This work provides a demonstration that a positive allosteric modulator of metabotropic glutamate receptor 4 can alleviate the motor symptoms of PD and the motor complications induced by l-dopa in primates. PXT002331 is the first compound of its class to enter phase IIa clinical trials. © 2018 International Parkinson and Movement Disorder Society.


Asunto(s)
Antiparkinsonianos/uso terapéutico , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Trastornos Parkinsonianos/tratamiento farmacológico , Receptores de Glutamato Metabotrópico/metabolismo , Regulación Alostérica/efectos de los fármacos , Regulación Alostérica/fisiología , Animales , Antiparkinsonianos/química , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/etiología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Discinesia Inducida por Medicamentos/etiología , Antagonistas de Aminoácidos Excitadores/química , Levodopa/efectos adversos , Macaca fascicularis , Trastornos Parkinsonianos/complicaciones , Tomografía de Emisión de Positrones , Receptores de Glutamato Metabotrópico/química , Factores de Tiempo
5.
Mov Disord ; 33(10): 1632-1642, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-29756234

RESUMEN

Parkinson's disease motor symptoms are treated with levodopa, but long-term treatment leads to disabling dyskinesia. Altered synaptic transmission and maladaptive plasticity of corticostriatal glutamatergic projections play a critical role in the pathophysiology of dyskinesia. Because the noble gas xenon inhibits excitatory glutamatergic signaling, primarily through allosteric antagonism of the N-methyl-d-aspartate receptors, we aimed to test its putative antidyskinetic capabilities. We first studied the direct effect of xenon gas exposure on corticostriatal plasticity in a murine model of levodopa-induced dyskinesia We then studied the impact of xenon inhalation on behavioral dyskinetic manifestations in the gold-standard rat and primate models of PD and levodopa-induced dyskinesia. Last, we studied the effect of xenon inhalation on axial gait and posture deficits in a primate model of PD with levodopa-induced dyskinesia. This study shows that xenon gas exposure (1) normalized synaptic transmission and reversed maladaptive plasticity of corticostriatal glutamatergic projections associated with levodopa-induced dyskinesia, (2) ameliorated dyskinesia in rat and nonhuman primate models of PD and dyskinesia, and (3) improved gait performance in a nonhuman primate model of PD. These results pave the way for clinical testing of this unconventional but safe approach. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.


Asunto(s)
Antiparkinsonianos/efectos adversos , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Levodopa/efectos adversos , Trastornos Parkinsonianos/tratamiento farmacológico , Xenón/uso terapéutico , Administración por Inhalación , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Discinesia Inducida por Medicamentos/etiología , Trastornos Neurológicos de la Marcha/tratamiento farmacológico , Trastornos Neurológicos de la Marcha/etiología , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Intoxicación por MPTP/tratamiento farmacológico , Ratones , Ratones Transgénicos , Oxidopamina/toxicidad , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/complicaciones , Ratas , Trastornos de la Sensación/tratamiento farmacológico , Trastornos de la Sensación/etiología , Simpaticolíticos/toxicidad , Factores de Tiempo
6.
Neurobiol Learn Mem ; 124: 123-9, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26135120

RESUMEN

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


Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Trastornos del Conocimiento/fisiopatología , Modelos Animales de Enfermedad , Enfermedad de Parkinson/fisiopatología , Investigación Biomédica Traslacional/métodos , Animales , Encéfalo/fisiopatología , Trastornos del Conocimiento/genética , Humanos , Macaca , Primates , Especificidad de la Especie
7.
Mov Disord ; 29(6): 772-9, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24610195

RESUMEN

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


Asunto(s)
Amantadina/uso terapéutico , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Imidazoles/uso terapéutico , Análisis de Varianza , Animales , Antiparkinsonianos/efectos adversos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Discinesia Inducida por Medicamentos/etiología , Femenino , Levodopa/efectos adversos , Intoxicación por MPTP/tratamiento farmacológico , Macaca fascicularis
8.
Mov Disord ; 29(8): 1074-9, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24865335

RESUMEN

BACKGROUND: Blocking metabotropic glutamate receptor type 5 (mGluR5) has been proposed as a target for levodopa-induced dyskinesias (LID) in Parkinson's disease (PD). We assessed the effect on LID of dipraglurant, a potent selective mGluR5 receptor negative allosteric modulator in the gold-standard LID macaque model. METHODS: Dipraglurant (3, 10, and 30 mg/kg, by mouth) was tested in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) macaque model of LID in a four-way crossover, single-dose, controlled study (n = 8). RESULTS: Dipraglurant inhibited dyskinesias in the LID macaque model, with best effect reached at 30 mg/kg dose with no alteration of levodopa efficacy. CONCLUSION: Acute challenges of dipraglurant were efficacious on choreic and dystonic LID in the MPTP-macaque model. Dipraglurant pharmacokinetic variables were similar to those of levodopa, suggesting that both drugs can be co-administered simultaneously in further studies.


Asunto(s)
Discinesia Inducida por Medicamentos/tratamiento farmacológico , Antagonistas de Aminoácidos Excitadores/química , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Intoxicación por MPTP/tratamiento farmacológico , Análisis de Varianza , Animales , Antiparkinsonianos/efectos adversos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Discinesia Inducida por Medicamentos/sangre , Antagonistas de Aminoácidos Excitadores/sangre , Imidazoles/farmacología , Imidazoles/uso terapéutico , Levodopa/efectos adversos , Macaca mulatta , Masculino , Actividad Motora/efectos de los fármacos , Piridinas/farmacología , Piridinas/uso terapéutico , Receptor del Glutamato Metabotropico 5/metabolismo , Índice de Severidad de la Enfermedad , Factores de Tiempo
10.
Mov Disord ; 28(5): 663-7, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23238827

RESUMEN

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


Asunto(s)
Antiparkinsonianos/uso terapéutico , Trastornos del Conocimiento/inducido químicamente , Levodopa/uso terapéutico , Intoxicación por MPTP/complicaciones , Movimiento/efectos de los fármacos , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/administración & dosificación , Análisis de Varianza , Animales , Trastornos del Conocimiento/fisiopatología , Condicionamiento Operante/efectos de los fármacos , Modelos Animales de Enfermedad , Intoxicación por MPTP/tratamiento farmacológico , Macaca fascicularis , Masculino , Estimulación Luminosa , Factores de Tiempo
12.
Mov Disord ; 28(8): 1088-96, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23389842

RESUMEN

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


Asunto(s)
Discinesia Inducida por Medicamentos/tratamiento farmacológico , Piperazinas/uso terapéutico , Agonistas de Receptores de Serotonina/uso terapéutico , Amantadina/uso terapéutico , Anfetamina , Animales , Apomorfina/farmacología , Modelos Animales de Enfermedad , Dopaminérgicos/efectos adversos , Discinesia Inducida por Medicamentos/etiología , Femenino , Levodopa/efectos adversos , Macaca fascicularis , Haz Prosencefálico Medial/fisiología , Actividad Motora/efectos de los fármacos , Oxidopamina/toxicidad , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/etiología , Trastornos Parkinsonianos/tratamiento farmacológico , Desempeño Psicomotor/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Tirosina 3-Monooxigenasa/metabolismo
13.
J Med Chem ; 64(12): 8246-8262, 2021 06 24.
Artículo en Inglés | MEDLINE | ID: mdl-34107215

RESUMEN

Adenosine A1/A2A receptors (A1R/A2AR) represent targets in nondopaminergic treatment of motor disorders such as Parkinson's disease (PD). As an innovative strategy, multitargeting ligands (MTLs) were developed to achieve comprehensive PD therapies simultaneously addressing comorbid symptoms such as sleep disruption. Recognizing the wake-promoting capacity of histamine H3 receptor (H3R) antagonists in combination with the "caffeine-like effects" of A1R/A2AR antagonists, we designed A1R/A2AR/H3R MTLs, where a piperidino-/pyrrolidino(propyloxy)phenyl H3R pharmacophore was introduced with overlap into an adenosine antagonist arylindenopyrimidine core. These MTLs showed distinct receptor binding profiles with overall nanomolar H3R affinities (Ki < 55 nM). Compound 4 (ST-2001, Ki (A1R) = 11.5 nM, Ki (A2AR) = 7.25 nM) and 12 (ST-1992, Ki (A1R) = 11.2 nM, Ki (A2AR) = 4.01 nM) were evaluated in vivo. l-DOPA-induced dyskinesia was improved after administration of compound 4 (1 mg kg-1, i.p. rats). Compound 12 (2 mg kg-1, p.o. mice) increased wakefulness representing novel pharmacological tools for PD therapy.


Asunto(s)
Antagonistas del Receptor de Adenosina A1/uso terapéutico , Antagonistas del Receptor de Adenosina A2/uso terapéutico , Antagonistas de los Receptores Histamínicos H3/uso terapéutico , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Antagonistas del Receptor de Adenosina A1/síntesis química , Antagonistas del Receptor de Adenosina A1/metabolismo , Antagonistas del Receptor de Adenosina A2/síntesis química , Antagonistas del Receptor de Adenosina A2/metabolismo , Animales , Discinesias/tratamiento farmacológico , Antagonistas de los Receptores Histamínicos H3/síntesis química , Antagonistas de los Receptores Histamínicos H3/metabolismo , Humanos , Levodopa/farmacología , Masculino , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Oxidopamina , Enfermedad de Parkinson Secundaria/inducido químicamente , Piperidinas/síntesis química , Piperidinas/metabolismo , Piperidinas/uso terapéutico , Pirimidinas/síntesis química , Pirimidinas/metabolismo , Pirimidinas/uso terapéutico , Pirrolidinas/síntesis química , Pirrolidinas/metabolismo , Pirrolidinas/uso terapéutico , Ratas Sprague-Dawley , Receptor de Adenosina A2A/metabolismo , Receptores Histamínicos H3/metabolismo , Vigilia/efectos de los fármacos
14.
Heliyon ; 6(12): e05771, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33385085

RESUMEN

BACKGROUND: Gastrointestinal (GI) and metabolic function are frequently altered in Parkinson's disease (PD). Although enteric nervous system anatomopathological alterations have previously been reported in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model of PD, the resulting gastric emptying and intestinal permeability functional parameters are unknown. The current exploratory study was, thus, designed to investigate these GI functional factors and insulin resistance in the MPTP-treated monkey. METHODS: Eight rhesus macaque monkeys (4 controls and 4 MPTP-treated) received the oral acetaminophen absorption test to measure gastric emptying, the oral FITC-dextran absorption test to investigate intestinal permeability, and the intravenous glucose tolerance test to assess insulin resistance. Constipation was evaluated using the Bristol stool scale. RESULTS: None of the tests, acetaminophen absorption, FITC-dextran absorption or glucose tolerance, showed a difference between control and MPTP-treated monkeys. MPTP-treated monkeys did present signs of transit acceleration. CONCLUSION: While the MPTP monkey model reliably displays motor and certain non-motor symptoms of PD, the current study did not demonstrate the GI symptoms associated with PD.

15.
J Neurosci ; 27(52): 14338-48, 2007 Dec 26.
Artículo en Inglés | MEDLINE | ID: mdl-18160641

RESUMEN

Chronic L-dopa treatment of Parkinson's disease (PD) often leads to debilitating involuntary movements, termed L-dopa-induced dyskinesia (LID), mediated by dopamine (DA) receptors. RGS9-2 is a GTPase accelerating protein that inhibits DA D2 receptor-activated G proteins. Herein, we assess the functional role of RGS9-2 on LID. In monkeys, Western blot analysis of striatal extracts shows that RGS9-2 levels are not altered by MPTP-induced DA denervation and/or chronic L-dopa administration. In MPTP monkeys with LID, striatal RGS9-2 overexpression--achieved by viral vector injection into the striatum--diminishes the involuntary movement intensity without lessening the anti-parkinsonian effects of the D1/D2 receptor agonist L-dopa. In contrasts, in these animals, striatal RGS9-2 overexpression diminishes both the involuntary movement intensity and the anti-parkinsonian effects of the D2/D3 receptor agonist ropinirole. In unilaterally 6-OHDA-lesioned rats with LID, we show that the time course of viral vector-mediated striatal RGS9-2 overexpression parallels the time course of improvement of L-dopa-induced involuntary movements. We also find that unilateral 6-OHDA-lesioned RGS9-/- mice are more susceptible to L-dopa-induced involuntary movements than unilateral 6-OHDA-lesioned RGS9+/+ mice, albeit the rotational behavior--taken as an index of the anti-parkinsonian response--is similar between the two groups of mice. Together, these findings suggest that RGS9-2 plays a pivotal role in LID pathophysiology. However, the findings also suggest that increasing RGS9-2 expression and/or function in PD patients may only be a suitable therapeutic strategy to control involuntary movements induced by nonselective DA agonist such as L-dopa.


Asunto(s)
Dihidroxifenilalanina/efectos adversos , Dopaminérgicos/efectos adversos , Discinesias/etiología , Discinesias/fisiopatología , Proteínas RGS/metabolismo , Conducta Estereotipada/fisiología , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Cuerpo Estriado/metabolismo , Cuerpo Estriado/fisiopatología , Modelos Animales de Enfermedad , Discinesias/terapia , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/fisiología , Intoxicación por MPTP/tratamiento farmacológico , Macaca fascicularis , Ratones , Ratones Noqueados , Oxidopamina/farmacología , Proteínas RGS/administración & dosificación , Conducta Estereotipada/efectos de los fármacos , Simpaticolíticos/farmacología
16.
Neuropharmacology ; 110(Pt A): 48-58, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27424102

RESUMEN

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


Asunto(s)
Trastornos del Conocimiento/tratamiento farmacológico , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Levodopa/administración & dosificación , Intoxicación por MPTP/tratamiento farmacológico , Purinas/administración & dosificación , Antagonistas del Receptor de Adenosina A2/administración & dosificación , Animales , Trastornos del Conocimiento/fisiopatología , Trastornos del Conocimiento/psicología , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Quimioterapia Combinada , Discinesia Inducida por Medicamentos/fisiopatología , Discinesia Inducida por Medicamentos/psicología , Femenino , Hipocinesia/tratamiento farmacológico , Hipocinesia/fisiopatología , Hipocinesia/psicología , Levodopa/toxicidad , Intoxicación por MPTP/fisiopatología , Intoxicación por MPTP/psicología , Macaca fascicularis , Trastornos de la Destreza Motora/tratamiento farmacológico , Trastornos de la Destreza Motora/fisiopatología , Trastornos de la Destreza Motora/psicología , Resultado del Tratamiento
17.
Neurochem Int ; 45(7): 995-1004, 2004 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-15337298

RESUMEN

The substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) are the two major mesencephalic dopaminergic systems. Mesencephalic dopamine denervation is followed by long-term modifications in striatum and cortex that preserve dopamine functions. Here, we have studied the impact of isolated bilateral 6-hydroxydopamine lesioning of the SNc or the VTA on D(1) and D(2) dopamine receptor binding in striatal and cortical areas of rat. Neither SNc nor VTA bilateral partial lesioning changed D(2) binding at the striatal or cortical level. Intriguingly, only VTA lesioning increased D(1) binding in the cortex, whereas both bilateral partial lesioning of the SNc or the VTA increased striatal D(1) binding. This suggests that increased cortical D(1) binding could be an indicator of VTA lesioning. Further behavioural experiments may explain the pathophysiological meaning of increased cortical D(1) binding, and determine whether this observation is involved in compensatory mechanisms.


Asunto(s)
Corteza Cerebral/metabolismo , Cuerpo Estriado/metabolismo , Mesencéfalo/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Animales , Unión Proteica/fisiología , Ratas , Ratas Wistar
18.
Brain Res ; 1022(1-2): 251-3, 2004 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-15353237

RESUMEN

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


Asunto(s)
Mesencéfalo/patología , Neuronas/metabolismo , Tirosina 3-Monooxigenasa/metabolismo , Animales , Recuento de Células/métodos , Modelos Animales de Enfermedad , Inmunohistoquímica/métodos , Masculino , Mesencéfalo/lesiones , Ratones , Ratones Endogámicos C57BL , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Probabilidad , Ratas , Ratas Wistar
19.
Neurol Res ; 25(2): 127-9, 2003 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-12635510

RESUMEN

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


Asunto(s)
Modelos Animales de Enfermedad , Macaca fascicularis , Dolor Intratable/fisiopatología , Animales , Conducta Animal , Enfermedad Crónica , Desnervación , Femenino , Reproducibilidad de los Resultados , Rizotomía , Automutilación/fisiopatología
20.
Behav Brain Res ; 261: 249-57, 2014 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-24333574

RESUMEN

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


Asunto(s)
Procesamiento Automatizado de Datos , Hipocampo/fisiopatología , Aprendizaje por Laberinto/fisiología , Trastornos de la Memoria/patología , Análisis de Varianza , Animales , Modelos Animales de Enfermedad , Agonistas de Aminoácidos Excitadores/toxicidad , Masculino , Trastornos de la Memoria/inducido químicamente , Ratones , Ratones Endogámicos C57BL , N-Metilaspartato/toxicidad , Tiempo de Reacción , Recompensa
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