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1.
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
2.
J Pharmacol Exp Ther ; 344(3): 624-36, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23257312

RESUMEN

Metabotropic glutamate receptor 7 (mGlu(7)) has been suggested to be a promising novel target for treatment of a range of disorders, including anxiety, post-traumatic stress disorder, depression, drug abuse, and schizophrenia. Here we characterized a potent and selective mGlu(7) negative allosteric modulator (NAM) (+)-6-(2,4-dimethylphenyl)-2-ethyl-6,7-dihydrobenzo[d]oxazol-4(5H)-one (ADX71743). In vitro, Schild plot analysis and reversibility tests at the target confirmed the NAM properties of the compound and attenuation of L-(+)-2-amino-4-phosphonobutyric acid-induced synaptic depression confirmed activity at the native receptor. The pharmacokinetic analysis of ADX71743 in mice and rats revealed that it is bioavailable after s.c. administration and is brain penetrant (cerebrospinal fluid concentration/total plasma concentration ratio at C(max) = 5.3%). In vivo, ADX71743 (50, 100, 150 mg/kg, s.c.) caused no impairment of locomotor activity in rats and mice or activity on rotarod in mice. ADX71743 had an anxiolytic-like profile in the marble burying and elevated plus maze tests, dose-dependently reducing the number of buried marbles and increasing open arm exploration, respectively. Whereas ADX71743 caused a small reduction in amphetamine-induced hyperactivity in mice, it was inactive in the mouse 2,5-dimethoxy-4-iodoamphetamine-induced head twitch and the rat conditioned avoidance response tests. In addition, the compound was inactive in the mouse forced swim test. These data suggest that ADX71743 is a suitable compound to help unravel the physiologic role of mGlu(7) and to better understand its implication in central nervous system diseases. Our in vivo tests using ADX71743, reported here, suggest that pharmacological inhibition of mGlu(7) is a valid approach for developing novel pharmacotherapies to treat anxiety disorders, but may not be suitable for treatment of depression or psychosis.


Asunto(s)
Conducta Animal/efectos de los fármacos , Oxazolona/farmacología , Receptores de Glutamato Metabotrópico/metabolismo , Regulación Alostérica , Anfetamina/farmacología , Animales , Trastornos de Ansiedad/tratamiento farmacológico , Trastornos de Ansiedad/metabolismo , Línea Celular , Emparejamiento Cromosómico/efectos de los fármacos , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/metabolismo , Femenino , Células HEK293 , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Oxazolona/farmacocinética , Unión Proteica/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/farmacología
3.
Bioorg Med Chem Lett ; 23(16): 4523-7, 2013 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-23850200

RESUMEN

A series of potent non-acetylinic negative allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5 NAMs) was developed starting from HTS screening hit 1. Potency was improved via iterative SAR, and physicochemical properties were optimized to deliver orally bioavailable compounds acceptable for in vivo testing. A lead molecule from the series demonstrated dose-dependent activity in the second phase of the rat formalin test from 30 mg/kg, and a preliminary PK/PD relationship was established.


Asunto(s)
Piridinas/síntesis química , Receptor del Glutamato Metabotropico 5/agonistas , Animales , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Unión Proteica/efectos de los fármacos , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/farmacología , Piridinas/química , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptor del Glutamato Metabotropico 5/química
4.
Brain Res ; 1809: 148349, 2023 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-36972837

RESUMEN

Overactivity of the corticostriatal glutamatergic pathway is documented in Parkinson's disease (PD) and stimulation of presynaptic metabotropic glutamate (mGlu) receptors 4 on these striatal afferents inhibits glutamate release normalizing neuronal activity in the basal ganglia. Moreover, mGlu4 receptors are also expressed in glial cells and are able to modulate glial function making this receptor a potential target for neuroprotection. Hence, we investigated whether foliglurax, a positive allosteric modulator of mGlu4 receptors with high brain exposure after oral administration, has neuroprotective effects in MPTP mice to model early PD. Male mice were treated daily from day 1 to 10 with 1, 3 or 10 mg/kg of foliglurax and administered MPTP on the 5th day then euthanized on the 11th day. Dopamine neuron integrity was assessed with measures of striatal dopamine and its metabolites levels, striatal and nigral dopamine transporter (DAT) binding and inflammation with markers of striatal astrocytes (GFAP) and microglia (Iba1). MPTP lesion produced a decrease in dopamine, its metabolites and striatal DAT specific binding that was prevented by treatment with 3 mg/kg of foliglurax, whereas 1 and 10 mg/kg had no beneficial effect. MPTP mice had increased levels of GFAP; foliglurax treatment (3 mg/kg) prevented this increase. Iba1 levels were unchanged in MPTP mice compared to control mice. There was a negative correlation between dopamine content and GFAP levels. Our results show that positive allosteric modulation of mGlu4 receptors with foliglurax provided neuroprotective effects in the MPTP mouse model of PD.


Asunto(s)
1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Antiparkinsonianos , Neuronas Dopaminérgicas , Fármacos Neuroprotectores , Receptores de Glutamato Metabotrópico , Animales , Masculino , Ratones , Regulación Alostérica/efectos de los fármacos , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/farmacología , Ganglios Basales/metabolismo , Modelos Animales de Enfermedad , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Relación Dosis-Respuesta a Droga , Ratones Endogámicos C57BL , Fármacos Neuroprotectores/farmacología , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/metabolismo , Astrocitos/metabolismo , Microglía/metabolismo , Neostriado/efectos de los fármacos , Neostriado/metabolismo
5.
J Pharmacol Exp Ther ; 343(1): 167-77, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22787118

RESUMEN

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGluR4) have been proposed as a novel therapeutic approach for the treatment of Parkinson's disease. However, evaluation of this proposal has been limited by the availability of appropriate pharmacological tools to interrogate the target. In this study, we describe the properties of a novel mGluR4 PAM. 5-Methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine (ADX88178) enhances glutamate-mediated activation of human and rat mGluR4 with EC(50) values of 4 and 9 nM, respectively. The compound is highly selective for mGluR4 with minimal activities at other mGluRs. Oral administration of ADX88178 in rats is associated with high bioavailability and results in cerebrospinal fluid exposure of >50-fold the in vitro EC(50) value. ADX88178 reverses haloperidol-induced catalepsy in rats at 3 and 10 mg/kg. It is noteworthy that this compound alone has no impact on forelimb akinesia resulting from a bilateral 6-hydroxydopamine lesion in rats. However, coadministration of a low dose of L-DOPA (6 mg/kg) enabled a robust, dose-dependent reversal of the forelimb akinesia deficit. ADX88178 also increased the effects of quinpirole in lesioned rats and enhanced the effects of L-DOPA in MitoPark mice. It is noteworthy that the enhancement of the actions of L-DOPA was not associated with an exacerbation of L-DOPA-induced dyskinesias in rats. ADX88178 is a novel, potent, and selective mGluR4 PAM that is a valuable tool for exploring the therapeutic potential of mGluR4 modulation. The use of this novel tool molecule supports the proposal that activation of mGluR4 may be therapeutically useful in Parkinson's disease.


Asunto(s)
Modelos Animales de Enfermedad , Agonistas de Aminoácidos Excitadores/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Receptores de Glutamato Metabotrópico/fisiología , Regulación Alostérica/efectos de los fármacos , Regulación Alostérica/fisiología , Animales , Agonistas de Aminoácidos Excitadores/farmacología , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Enfermedad de Parkinson/fisiopatología , Ratas , Ratas Sprague-Dawley , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/biosíntesis
6.
Neuropharmacology ; 218: 109205, 2022 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-35940348

RESUMEN

By decreasing glutamate transmission, mGlu4 receptor positive allosteric modulators (mGlu4-PAM), in combination with levodopa (l-DOPA) may restore the synergy between glutamatergic and dopaminergic transmissions, thus maximizing the improvement of motor function in Parkinson's disease (PD). This study aimed to clarify the effects of foliglurax, a selective mGlu4-PAM, on the loss of bidirectional synaptic plasticity associated with l-DOPA-induced dyskinesia (LID). Behavioral assessments compared dyskinesia intensity in 6-hydroxydopamine (6-OHDA)-lesioned rats treated with l-DOPA or l-DOPA plus foliglurax. In slices from the same rats, patch-clamp techniques were used to examine electrophysiological differences in glutamatergic synapses, evaluating the EPSCs mediated by NMDA and AMPA receptors in striatal spiny projection neurons. High-frequency stimulation of corticostriatal fibers was used as long-term potentiation (LTP)-inducing protocol. Conversely, 15 min of low-frequency stimulation was applied to depotentiate LTP. The density of dendritic spines was measured in striatal slices in the same experimental conditions. Our results show that, in corticostriatal slices, foliglurax decreased spontaneous glutamatergic transmission in both sham-operated and 6-OHDA lesioned rats. When co-administered with l-DOPA in 6-OHDA-lesioned rats, foliglurax fully restored dendritic spine density in a dose-dependent manner. Moreover, this co-treatment rescued striatal bidirectional plasticity and attenuated the intensity of l-DOPA-induced dyskinesia. This is the first demonstration in an animal model of PD and dyskinesia that a mGlu4 PAM can restore striatal synaptic plasticity.


Asunto(s)
Discinesia Inducida por Medicamentos , Enfermedad de Parkinson , Trastornos Parkinsonianos , Animales , Antiparkinsonianos/efectos adversos , Cuerpo Estriado , Modelos Animales de Enfermedad , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Levodopa/efectos adversos , Oxidopamina/toxicidad , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/tratamiento farmacológico , Ratas
7.
Ann Neurol ; 66(1): 117-22, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19670442

RESUMEN

X-linked adrenoleukodystrophy (X-ALD) is the most common inherited peroxisomal disorder characterized by a progressive demyelination of the central nervous system. The marked loss of myelin and oligodendrocytes observed in the disease prompted us to evaluate the therapeutic potential of insulin-like growth factor-1 and neurotrophin-3, two potent inducers of myelin formation and oligodendrocyte survival. Viral vectors engineered to produce insulin-like growth factor-1 or neurotrophin-3 were administrated into the cerebrospinal fluid of an X-linked adrenoleukodystrophy mouse model. We show that viral-based, long-lasting delivery of insulin-like growth factor-1 and neurotrophin-3 significantly halts the progression of the disease and leads to potent protective effect against the demyelination process. Ann Neurol 2009;66:117-122.


Asunto(s)
Adrenoleucodistrofia/complicaciones , Terapia Genética/métodos , Factor I del Crecimiento Similar a la Insulina/genética , Trastornos del Movimiento/etiología , Trastornos del Movimiento/terapia , Neurotrofina 3/genética , Subfamilia D de Transportadores de Casetes de Unión al ATP , Transportadoras de Casetes de Unión a ATP/genética , Adrenoleucodistrofia/genética , Análisis de Varianza , Animales , Conducta Animal/fisiología , Quimiocina CCL22/deficiencia , Dependovirus/genética , Modelos Animales de Enfermedad , Técnicas de Transferencia de Gen , Proteínas Fluorescentes Verdes/genética , Humanos , Factor I del Crecimiento Similar a la Insulina/líquido cefalorraquídeo , Ratones , Ratones Noqueados , Neurotrofina 3/líquido cefalorraquídeo
8.
Mol Imaging Biol ; 21(3): 500-508, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30066121

RESUMEN

PURPOSE: Modulation of presynaptic metabotropic glutamate receptor 4 (mGlu4) by an allosteric ligand has been proposed as a promising therapeutic target in Parkinson's disease and levodopa-induced dyskinesia. A positron emission tomography (PET) ligand for an allosteric site of mGlu4 may provide evidence that a clinical drug candidate reaches and binds the target. A carbon-11-labeled PET radioligand binding an allosteric site of mGlu4, [11C]PXT012253, has been recently developed. Here, we describe the detailed characterization of this novel radiolabeled mGlu4 ligand in nonhuman primates. PROCEDURES: [11C]PXT012253 binding in the brain of cynomolgus monkeys, under the baseline and blocking conditions with the structurally different mGlu4 allosteric ligand PXT002331, currently in clinical trials for Parkinson's disease, was quantified with compartment and graphical modeling approaches using a radiometabolite-corrected plasma input function. Whole-body biodistribution of [11C]PXT012253 was then assessed using PET/x-ray computed tomography to estimate the human effective doses of [11C]PXT012253 for further clinical studies. RESULTS: [11C]PXT012253 displayed binding in mGlu4-expressing regions in the brain of cynomolgus monkeys. Brain regional time-activity curves of [11C]PXT012253 were well described in the two-tissue compartment model (2TC). Total distribution volume was stably estimated using Logan plot and multilinear analysis (MA1) although 2TC showed unstable values in some cases. Competition with PXT002331 showed high specific binding in the total distribution volume. Whole-body PET showed high accumulation of [11C]PXT012253 in the liver, kidney, heart, and brain in the initial phase. The radioligand was excreted through both the gastrointestinal and the urinary tracts. Effective dose of [11C]PXT012253 was estimated to be 0.0042 mSv/MBq. CONCLUSIONS: [11C]PXT012253 was shown to be a promising PET radioligand for mGlu4 allosteric modulators in the monkey brain. MA1 would be the choice of quantitative method. Further development of [11C]PXT012253 in human subjects is warranted.


Asunto(s)
Radioisótopos de Carbono/química , Tomografía de Emisión de Positrones , Radiofármacos/química , Receptores de Glutamato Metabotrópico/metabolismo , Regulación Alostérica , Animales , Encéfalo/diagnóstico por imagen , Relación Dosis-Respuesta en la Radiación , Femenino , Humanos , Macaca fascicularis , Masculino , Factores de Tiempo , Tomografía Computarizada por Rayos X , Imagen de Cuerpo Entero
9.
Neuropharmacology ; 135: 308-315, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29578036

RESUMEN

2017 is the 200th anniversary of the first published description of Parkinson's disease (PD). Fifty years ago, the clinical benefit of levodopa was first documented, representing the most important advance in the treatment of PD so far. Among the novel targets identified in the last decade, positive allosteric modulators (PAM) of mGlu4 receptors show great promise, with the potential to change the paradigm of the PD treatment approach. mGlu4 PAMs have shown consistent efficacy in various preclinical models of PD, and entered clinical trials for the first time in 2017. This review synthesizes the rationale for mGlu4 PAM development for PD and progress to date, reporting the key achievements from preclinical studies to the first-in-class compound assessment in man.


Asunto(s)
Regulación Alostérica/efectos de los fármacos , Antiparkinsonianos/uso terapéutico , Terapia Molecular Dirigida/métodos , Enfermedad de Parkinson/tratamiento farmacológico , Receptores de Glutamato Metabotrópico/agonistas , Animales , Antiparkinsonianos/farmacología , Quimioterapia Combinada , Humanos , Levodopa/uso terapéutico , Modelos Neurológicos , Receptores de Glutamato Metabotrópico/efectos de los fármacos
10.
Nat Rev Drug Discov ; 17(11): 804-822, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30262889

RESUMEN

Existing therapeutic strategies for managing Parkinson disease (PD), which focus on addressing the loss of dopamine and dopaminergic function linked with degeneration of dopaminergic neurons, are limited by side effects and lack of long-term efficacy. In recent decades, research into PD pathophysiology and pharmacology has focused on understanding and tackling the neurodegenerative processes and symptomology of PD. In this Review, we discuss the challenges associated with the development of novel therapies for PD, highlighting emerging agents that aim to target cell death, as well as new targets offering a symptomatic approach to managing features and progression of the disease.

11.
Nat Rev Drug Discov ; 17(11): 844, 2018 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-30310231

RESUMEN

This corrects the article DOI: 10.1038/nrd.2018.136.

12.
J Med Chem ; 60(20): 8515-8537, 2017 10 26.
Artículo en Inglés | MEDLINE | ID: mdl-28902994

RESUMEN

The metabotropic glutamate receptor 4 (mGluR4) is an emerging target for the treatment of Parkinson's disease (PD). However, since the discovery of its therapeutic potential, no ligand has been successfully developed enough to be tested in the clinic. In the present paper, we report for the first time the medicinal chemistry efforts conducted around the pharmacological tool (-)-PHCCC. This work led to the identification of compound 40, a potent and selective mGluR4 positive allosteric modulator (PAM) with good water solubility and demonstrating consistent activity across validated preclinical rodent models of PD motor symptoms after intraperitoneal administration: haloperidol-induced catalepsy in mouse and the rat 6-hydroxydopamine (6-OHDA) lesion model. Moreover, we also describe the identification of compound 60 a close analogue of compound 40 with improved pharmacokinetic profile after oral administration. On the basis of its favorable and unique preclinical profile, compound 60 (PXT002331, now foliglurax) was nominated as a candidate for clinical development.


Asunto(s)
Antiparkinsonianos/farmacología , Encéfalo/efectos de los fármacos , Descubrimiento de Drogas , Receptores de Glutamato Metabotrópico/efectos de los fármacos , Regulación Alostérica , Animales , Antiparkinsonianos/farmacocinética , Cromatografía Liquida , Células HEK293 , Humanos , Espectrometría de Masas , Ratones , Espectroscopía de Protones por Resonancia Magnética , Ratas , Relación Estructura-Actividad
14.
PLoS One ; 4(12): e8287, 2009 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-20016831

RESUMEN

BACKGROUND: Huntington's disease (HD) is a polyglutamine-expanded related neurodegenerative disease. Despite the ubiquitous expression of expanded, polyQ-Huntingtin (ExpHtt) in the brain, striatal neurons present a higher susceptibility to the mutation. A commonly admitted hypothesis is that Dopaminergic inputs participate to this vulnerability. We previously showed that D2 receptor stimulation increased aggregate formation and neuronal death induced by ExpHtt in primary striatal neurons in culture, and chronic D2 antagonist treatment protects striatal dysfunctions induced by ExpHtt in a lentiviral-induced model system in vivo. The present work was designed to elucidate the signalling pathways involved, downstream D2 receptor (D2R) stimulation, in striatal vulnerability to ExpHtt. METHODOLOGY/PRINCIPAL FINDINGS: Using primary striatal neurons in culture, transfected with a tagged-GFP version of human exon 1 ExpHtt, and siRNAs against D2R or D1R, we confirm that DA potentiates neuronal dysfunctions via D2R but not D1R stimulation. We demonstrate that D2 agonist treatment induces neuritic retraction and growth cone collapse in Htt- and ExpHtt expressing neurons. We then tested a possible involvement of the Rho/ROCK signalling pathway, which plays a key role in the dynamic of the cytoskeleton, in these processes. The pharmacological inhibitors of ROCK (Y27632 and Hydroxyfasudil), as well as siRNAs against ROCK-II, reversed D2-related effects on neuritic retraction and growth cone collapse. We show a coupling between D2 receptor stimulation and Rho activation, as well as hyperphosphorylation of Cofilin, a downstream effector of ROCK-II pathway. Importantly, D2 agonist-mediated potentiation of aggregate formation and neuronal death induced by ExpHtt, was totally reversed by Y27632 and Hydroxyfasudil and ROCK-II siRNAs. CONCLUSIONS/SIGNIFICANCE: Our data provide the first demonstration that D2R-induced vulnerability in HD is critically linked to the activation of the Rho/ROCK signalling pathway. The inclusion of Rho/ROCK inhibitors could be an interesting therapeutic option aimed at forestalling the onset of the disease.


Asunto(s)
Neostriado/fisiopatología , Neuronas/enzimología , Péptidos/toxicidad , Receptores de Dopamina D2/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/toxicidad , Proteínas de Unión al GTP rho/metabolismo , Quinasas Asociadas a rho/metabolismo , Animales , Muerte Celular/efectos de los fármacos , Dopamina/farmacología , Activación Enzimática/efectos de los fármacos , Conos de Crecimiento/efectos de los fármacos , Conos de Crecimiento/patología , Humanos , Ratones , Neostriado/efectos de los fármacos , Neostriado/enzimología , Neuritas/efectos de los fármacos , Neuritas/metabolismo , Neuronas/efectos de los fármacos , Estructura Cuaternaria de Proteína , Quinpirol/farmacología , ARN Interferente Pequeño , Receptores de Dopamina D1/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/química , Expansión de Repetición de Trinucleótido/genética
15.
Neurobiol Dis ; 29(1): 22-9, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17905594

RESUMEN

Huntington's disease (HD) results from an abnormal polyglutamine extension in the N-terminal region of the huntingtin protein. This mutation causes preferential degeneration of striatal projection neurons. We previously demonstrated, in vitro, that dopaminergic D2 receptor stimulation acted synergistically with mutated huntingtin (expHtt) to increase aggregate formation and striatal death. In the present work, we extend these observations to an in vivo system based on lentiviral-mediated expression of expHtt in the rat striatum. The early and chronic treatment with the D2 antagonist haloperidol decanoate protects striatal neurons from expHtt-induced dysfunction, as analyzed by DARPP-32 and NeuN stainings. Haloperidol treatment also reduces aggregates formation, an effect that is maintained over time. These findings indicate that D2 receptors activation contributes to the deleterious effects of expHtt on striatal function and may represent an interesting early target to alter the subsequent course of neuropathology in HD.


Asunto(s)
Antipsicóticos/uso terapéutico , Cuerpo Estriado/patología , Haloperidol/análogos & derivados , Enfermedad de Huntington/prevención & control , Mutación/fisiología , Proteínas del Tejido Nervioso/genética , Neuronas/efectos de los fármacos , Proteínas Nucleares/genética , Factores de Edad , Animales , Recuento de Células/métodos , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Fosfoproteína 32 Regulada por Dopamina y AMPc/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Haloperidol/uso terapéutico , Proteína Huntingtina , Enfermedad de Huntington/genética , Enfermedad de Huntington/patología , Lentivirus/fisiología , Fosfopiruvato Hidratasa/metabolismo , Ratas , Ratas Wistar
16.
Hum Mol Genet ; 15(24): 3544-58, 2006 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-17101632

RESUMEN

Mutations of the spastin gene (Sp) are responsible for the most frequent autosomal dominant form of spastic paraplegia, a disease characterized by the degeneration of corticospinal tracts. We show that a deletion in the mouse Sp gene, generating a premature stop codon, is responsible for progressive axonal degeneration, restricted to the central nervous system, leading to a late and mild motor defect. The degenerative process is characterized by focal axonal swellings, associated with abnormal accumulation of organelles and cytoskeletal components. In culture, mutant cortical neurons showed normal viability and neurite density. However, they develop neurite swellings associated with focal impairment of retrograde transport. These defects occur near the growth cone, in a region characterized by the transition between stable microtubules rich in detyrosinated alpha-tubulin and dynamic microtubules composed almost exclusively of tyrosinated alpha-tubulin. Here, we show that the Sp mutation has a major impact on neurite maintenance and transport both in vivo and in vitro. These results highlight the link between spastin and microtubule dynamics in axons, but not in other neuronal compartments. In addition, it is the first description of a human neurodegenerative disease which involves this specialized region of the axon.


Asunto(s)
Adenosina Trifosfatasas/genética , Axones/metabolismo , Microtúbulos/metabolismo , Mutación , Adenosina Trifosfatasas/fisiología , Animales , Axones/patología , Axones/ultraestructura , Secuencia de Bases , Conducta Animal , Transporte Biológico , Western Blotting , Células Cultivadas , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Sistema Nervioso Central/ultraestructura , Corteza Cerebral/citología , Corteza Cerebral/metabolismo , Exones/genética , Eliminación de Gen , Heterocigoto , Homocigoto , Ratones , Ratones Noqueados , Microscopía Electrónica de Transmisión , Proteínas Asociadas a Microtúbulos/metabolismo , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Neuronas Motoras/ultraestructura , Neuritas/metabolismo , Neuritas/fisiología , Estructura Terciaria de Proteína , Espastina
17.
Proc Natl Acad Sci U S A ; 102(34): 12218-23, 2005 Aug 23.
Artículo en Inglés | MEDLINE | ID: mdl-16103364

RESUMEN

Huntington's disease (HD), an inherited neurodegenerative disorder, results from an abnormal polyglutamine extension in the N-terminal region of the huntingtin protein. This mutation leads to protein aggregation and neurotoxicity. Despite its widespread expression in the brain and body, mutated huntingtin causes selective degeneration of striatal projection neurons. In the present study, we investigate the role of dopamine (DA) in this preferential vulnerability. Using primary cultures of striatal neurons transiently expressing GFP-tagged-exon 1 of mutated huntingtin, we show that low doses of DA (100 microM) act synergistically with mutated huntingtin to activate the proapoptotic transcription factor c-Jun. Surprisingly, DA also increases aggregate formation of mutated huntingtin in all cellular compartments, including neurites, soma, and nuclei. DA-dependent potentiation of c-Jun activation was reversed by ascorbate, a reactive oxygen species (ROS) scavenger, and SP-600125, a selective inhibitor of the c-Jun N-terminal kinase (JNK) pathway. By contrast, DA effects on aggregate formation were reversed by a selective D2 receptor antagonist and reproduced by a D2 agonist. Similarly, striatal neurons from D2 knockout mice showed no effect of DA on aggregate formation. Blocking ROS production, JNK activation, or D2 receptor stimulation significantly reversed DA aggravation of mutated huntingtin-induced striatal death. The combined treatment with the ROS scavenger and D2 antagonist totally reversed DA's effects on mutated huntingtin-induced striatal death. Thus, the present results provide insights into the cellular mechanisms that govern striatal vulnerability in HD and strongly support a dual role of JNK activation and D2 receptor signaling in this process.


Asunto(s)
Dopamina/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Enfermedad de Huntington/genética , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/genética , Especies Reactivas de Oxígeno/metabolismo , Receptores de Dopamina D2/metabolismo , Transducción de Señal/efectos de los fármacos , Análisis de Varianza , Animales , Antracenos/farmacología , Apoptosis/efectos de los fármacos , Dopamina/metabolismo , Antagonistas de los Receptores de Dopamina D2 , Técnica del Anticuerpo Fluorescente , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Proteína Huntingtina , Enfermedad de Huntington/metabolismo , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogénicas c-jun/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-jun/metabolismo , Receptores de Dopamina D2/agonistas , Transducción de Señal/fisiología
18.
Hum Mol Genet ; 12(1): 71-8, 2003 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-12490534

RESUMEN

Mutations of spastin are responsible for the most common autosomal dominant form of hereditary spastic paraplegia (AD-HSP), a disease characterized by axonal degeneration of corticospinal tracts and posterior columns. Generation of polyclonal antibodies specific to spastin has revealed two isoforms of 75 and 80 kDa in both human and mouse tissues with a tissue-specific variability of the isoform ratio. Spastin is an abundant protein in neural tissues and immunolabeling experiments have shown that spastin is expressed in neurons but not in glial cells. These data indicate that axonal degeneration linked to spastin mutations is caused by a primary defect of neurons. Protein and transcript analyses of patients carrying either nonsense or frameshift spastin mutations revealed neither truncated protein nor mutated transcripts, providing evidence that these mutations are responsible for a loss of spastin function. Identifying agents able to induce the expression of the non-mutated spastin allele should represent an attractive therapeutic strategy in this disease.


Asunto(s)
Adenosina Trifosfatasas/metabolismo , Proteínas de Unión al Calcio/fisiología , Núcleo Celular/metabolismo , Mutación/genética , Paraplejía Espástica Hereditaria/genética , Paraplejía Espástica Hereditaria/patología , Adenosina Trifosfatasas/genética , Alelos , Animales , Línea Celular , Expresión Génica , Células HeLa , Humanos , Espastina
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