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1.
Nat Med ; 29(11): 2854-2865, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37932548

RESUMO

People with late-stage Parkinson's disease (PD) often suffer from debilitating locomotor deficits that are resistant to currently available therapies. To alleviate these deficits, we developed a neuroprosthesis operating in closed loop that targets the dorsal root entry zones innervating lumbosacral segments to reproduce the natural spatiotemporal activation of the lumbosacral spinal cord during walking. We first developed this neuroprosthesis in a non-human primate model that replicates locomotor deficits due to PD. This neuroprosthesis not only alleviated locomotor deficits but also restored skilled walking in this model. We then implanted the neuroprosthesis in a 62-year-old male with a 30-year history of PD who presented with severe gait impairments and frequent falls that were medically refractory to currently available therapies. We found that the neuroprosthesis interacted synergistically with deep brain stimulation of the subthalamic nucleus and dopaminergic replacement therapies to alleviate asymmetry and promote longer steps, improve balance and reduce freezing of gait. This neuroprosthesis opens new perspectives to reduce the severity of locomotor deficits in people with PD.


Assuntos
Estimulação Encefálica Profunda , Transtornos Neurológicos da Marcha , Doença de Parkinson , Masculino , Animais , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/terapia , Transtornos Neurológicos da Marcha/etiologia , Transtornos Neurológicos da Marcha/terapia , Marcha/fisiologia , Medula Espinal
2.
Mov Disord ; 33(10): 1632-1642, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29756234

RESUMO

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.


Assuntos
Antiparkinsonianos/efeitos adversos , Discinesia Induzida por Medicamentos/tratamento farmacológico , Levodopa/efeitos adversos , Transtornos Parkinsonianos/tratamento farmacológico , Xenônio/uso terapêutico , Administração por Inalação , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Discinesia Induzida por Medicamentos/etiologia , Transtornos Neurológicos da Marcha/tratamento farmacológico , Transtornos Neurológicos da Marcha/etiologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Intoxicação por MPTP/tratamento farmacológico , Camundongos , Camundongos Transgênicos , Oxidopamina/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/complicações , Ratos , Transtornos de Sensação/tratamento farmacológico , Transtornos de Sensação/etiologia , Simpatolíticos/toxicidade , Fatores de Tempo
3.
Exp Neurol ; 298(Pt B): 172-179, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28764902

RESUMO

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


Assuntos
Corpos de Lewy/metabolismo , Neurônios/metabolismo , Doença de Parkinson/metabolismo , alfa-Sinucleína/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Corpos de Lewy/patologia , Mutagênese Sítio-Dirigida/métodos , Doença de Parkinson/genética , Doença de Parkinson/patologia , alfa-Sinucleína/genética
4.
Eur J Pharmacol ; 813: 10-16, 2017 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-28739086

RESUMO

Eltoprazine, a serotonergic (5-HT)1A/B receptor agonist, is a potential treatment for L-DOPA-induced dyskinesia (LID) in Parkinson's disease (PD) but notably compromises the anti-parkinsonian effects of L-DOPA, as seen in rodent and monkey models of PD. Preladenant, a selective adenosine A2a receptor antagonist, mediates modest anti-parkinsonian effects in parkinsonian monkeys. In a recent investigation, combined eltoprazine and preladenant treatment with a sub-threshold dose of L-DOPA acutely attenuated dyskinesia without exacerbating PD disability in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaques. The aim of this study was to investigate the daily repeated treatment effects of eltoprazine (1mg/kg) alone, and in combination with preladenant (5mg/kg), on the motor symptoms of PD and LID in MPTP-treated macaques. The anti-dyskinetic and -parkinsonian effects of combinative drug administration with a sub-threshold dose of L-DOPA were measured over 14 days. Eltoprazine treatment alone produced a near-complete suppression of dyskinesia but consistently increased parkinsonism. The administration of preladenant with eltoprazine prevented the increased severity of parkinsonian motor symptoms but was unable to maintain a reduced expression of dyskinesia with repeated administration. These data demonstrate the clinical utility of the modulation of the serotonergic and adenosine neurotransmitter systems with selective pharmacological agents for only acute treatment of LID. This multi-targeted approach is unsuitable as a long-term treatment regimen due to unsustainable therapeutic effects on dyskinesia.


Assuntos
Antiparkinsonianos/efeitos adversos , Discinesia Induzida por Medicamentos/tratamento farmacológico , Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Piperazinas/farmacologia , Animais , Antiparkinsonianos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Interações Medicamentosas , Discinesia Induzida por Medicamentos/metabolismo , Discinesia Induzida por Medicamentos/fisiopatologia , Feminino , Levodopa/uso terapêutico , Macaca fascicularis , Atividade Motora/efeitos dos fármacos , Doença de Parkinson/complicações , Piperazinas/uso terapêutico , Fatores de Tempo
5.
Synapse ; 71(7)2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28295625

RESUMO

Mutations in the glucocerebrosidase 1 (GBA1) gene are related to both Parkinson disease (PD) and Gaucher disease (GD). In both cases, the condition is associated with deficiency of glucocerebrosidase (GCase), the enzyme encoded by GBA1. Ambroxol is a small molecule chaperone that has been shown in mice to cross the blood-brain barrier, increase GCase activity and reduce alpha-synuclein protein levels. In this study, we analyze the effect of ambroxol treatment on GCase activity in healthy nonhuman primates. We show that daily administration of ambroxol results in increased brain GCase activity. Our work further indicates that ambroxol should be investigated as a novel therapy for both PD and neuronopathic GD in humans.


Assuntos
Ambroxol/administração & dosagem , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Fármacos do Sistema Nervoso Central/administração & dosagem , Glucosilceramidase/metabolismo , Administração Oral , Animais , Macaca fascicularis , Masculino , Dados Preliminares , Cadeia beta da beta-Hexosaminidase/metabolismo
6.
Nature ; 539(7628): 284-288, 2016 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-27830790

RESUMO

Spinal cord injury disrupts the communication between the brain and the spinal circuits that orchestrate movement. To bypass the lesion, brain-computer interfaces have directly linked cortical activity to electrical stimulation of muscles, and have thus restored grasping abilities after hand paralysis. Theoretically, this strategy could also restore control over leg muscle activity for walking. However, replicating the complex sequence of individual muscle activation patterns underlying natural and adaptive locomotor movements poses formidable conceptual and technological challenges. Recently, it was shown in rats that epidural electrical stimulation of the lumbar spinal cord can reproduce the natural activation of synergistic muscle groups producing locomotion. Here we interface leg motor cortex activity with epidural electrical stimulation protocols to establish a brain-spine interface that alleviated gait deficits after a spinal cord injury in non-human primates. Rhesus monkeys (Macaca mulatta) were implanted with an intracortical microelectrode array in the leg area of the motor cortex and with a spinal cord stimulation system composed of a spatially selective epidural implant and a pulse generator with real-time triggering capabilities. We designed and implemented wireless control systems that linked online neural decoding of extension and flexion motor states with stimulation protocols promoting these movements. These systems allowed the monkeys to behave freely without any restrictions or constraining tethered electronics. After validation of the brain-spine interface in intact (uninjured) monkeys, we performed a unilateral corticospinal tract lesion at the thoracic level. As early as six days post-injury and without prior training of the monkeys, the brain-spine interface restored weight-bearing locomotion of the paralysed leg on a treadmill and overground. The implantable components integrated in the brain-spine interface have all been approved for investigational applications in similar human research, suggesting a practical translational pathway for proof-of-concept studies in people with spinal cord injury.


Assuntos
Interfaces Cérebro-Computador , Terapia por Estimulação Elétrica/instrumentação , Transtornos Neurológicos da Marcha/complicações , Transtornos Neurológicos da Marcha/terapia , Marcha/fisiologia , Próteses Neurais , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/terapia , Animais , Modelos Animais de Doenças , Estimulação Elétrica , Transtornos Neurológicos da Marcha/fisiopatologia , Perna (Membro)/fisiologia , Locomoção/fisiologia , Região Lombossacral , Macaca mulatta , Masculino , Microeletrodos , Córtex Motor/fisiopatologia , Paralisia/complicações , Paralisia/fisiopatologia , Paralisia/terapia , Reprodutibilidade dos Testes , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/fisiopatologia , Tecnologia sem Fio/instrumentação
7.
Neuropharmacology ; 110(Pt A): 48-58, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27424102

RESUMO

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.


Assuntos
Transtornos Cognitivos/tratamento farmacológico , Discinesia Induzida por Medicamentos/tratamento farmacológico , Levodopa/administração & dosagem , Intoxicação por MPTP/tratamento farmacológico , Purinas/administração & dosagem , Antagonistas do Receptor A2 de Adenosina/administração & dosagem , Animais , Transtornos Cognitivos/fisiopatologia , Transtornos Cognitivos/psicologia , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Quimioterapia Combinada , Discinesia Induzida por Medicamentos/fisiopatologia , Discinesia Induzida por Medicamentos/psicologia , Feminino , Hipocinesia/tratamento farmacológico , Hipocinesia/fisiopatologia , Hipocinesia/psicologia , Levodopa/toxicidade , Intoxicação por MPTP/fisiopatologia , Intoxicação por MPTP/psicologia , Macaca fascicularis , Transtornos das Habilidades Motoras/tratamento farmacológico , Transtornos das Habilidades Motoras/fisiopatologia , Transtornos das Habilidades Motoras/psicologia , Resultado do Tratamento
9.
Mov Disord ; 31(4): 501-11, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26871939

RESUMO

BACKGROUND: The serotonin 5-HT1A/1B receptor agonist eltoprazine suppressed dyskinetic-like behavior in animal models of Parkinson's disease (PD) but simultaneously reduced levodopa (l-dopa)-induced motility. Moreover, adenosine A2A receptor antagonists, such as preladenant, significantly increased l-dopa efficacy in PD without exacerbating dyskinetic-like behavior. OBJECTIVES: We evaluated whether a combination of eltoprazine and preladenant may prevent or suppress l-dopa-induced dyskinesia, without impairing l-dopa's efficacy in relieving motor signs, in 2 PD models: unilateral 6-hydroxydopamine-lesioned rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. METHODS: Rotational behavior and abnormal involuntary movements, or disability and l-dopa-induced dyskinesia were evaluated in 6-hydroxydopamine-lesioned rats and MPTP-treated monkeys, respectively. Moreover, in the rodent striatum, induction of immediate-early gene zif-268, an index of long-term changes, was correlated with dyskinesia. RESULTS: In 6-hydroxydopamine-lesioned rats, combined administration of l-dopa (4 mg/kg) plus eltoprazine (0.6 mg/kg) plus preladenant (0.3 mg/kg) significantly prevented or reduced dyskinetic-like behavior without impairing motor activity. Zif-268 was increased in the striatum of rats treated with l-dopa and l-dopa plus preladenant compared with vehicle. In contrast, rats treated with eltoprazine (with or without preladenant) had lower zif-268 activation after chronic treatment in both the dyskinetic and l-dopa-non-primed groups. Moreover, acute l-dopa plus eltoprazine plus preladenant prevented worsening of motor performance (adjusting step) and sensorimotor integration deficit. Similar results were obtained in MPTP-treated monkeys, where a combination of preladenant with eltoprazine was found to counteract dyskinesia and maintain the full therapeutic effects of a low dose of l-dopa. CONCLUSIONS: Our results suggest a promising nondopaminergic pharmacological strategy for the treatment of dyskinesia in PD. © 2016 International Parkinson and Movement Disorder Society.


Assuntos
Antiparkinsonianos/farmacologia , Comportamento Animal/efeitos dos fármacos , Discinesia Induzida por Medicamentos/tratamento farmacológico , Levodopa/farmacologia , Doença de Parkinson/tratamento farmacológico , Piperazinas/farmacologia , Pirimidinas/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Triazóis/farmacologia , Animais , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/efeitos adversos , Modelos Animais de Doenças , Quimioterapia Combinada , Discinesia Induzida por Medicamentos/prevenção & controle , Feminino , Levodopa/administração & dosagem , Levodopa/efeitos adversos , Macaca fascicularis , Masculino , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Agonistas do Receptor de Serotonina/administração & dosagem , Triazóis/administração & dosagem
10.
Neuron ; 88(4): 762-73, 2015 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-26590347

RESUMO

A balanced interaction between dopaminergic and cholinergic signaling in the striatum is critical to goal-directed behavior. But how this interaction modulates corticostriatal synaptic plasticity underlying learned actions remains unclear--particularly in direct-pathway spiny projection neurons (dSPNs). Our studies show that in dSPNs, endogenous cholinergic signaling through M4 muscarinic receptors (M4Rs) promoted long-term depression of corticostriatal glutamatergic synapses, by suppressing regulator of G protein signaling type 4 (RGS4) activity, and blocked D1 dopamine receptor dependent long-term potentiation (LTP). Furthermore, in a mouse model of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) in Parkinson's disease (PD), boosting M4R signaling with positive allosteric modulator (PAM) blocked aberrant LTP in dSPNs, enabled LTP reversal, and attenuated dyskinetic behaviors. An M4R PAM also was effective in a primate LID model. Taken together, these studies identify an important signaling pathway controlling striatal synaptic plasticity and point to a novel pharmacological strategy for alleviating LID in PD patients.


Assuntos
Dopaminérgicos/toxicidade , Discinesia Induzida por Medicamentos/metabolismo , Levodopa/toxicidade , Neostriado/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Transtornos Parkinsonianos/tratamento farmacológico , Proteínas RGS/metabolismo , Receptor Muscarínico M4/metabolismo , Regulação Alostérica , Animais , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Discinesia Induzida por Medicamentos/etiologia , Ácido Glutâmico , Potenciação de Longa Duração/efeitos dos fármacos , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Macaca mulatta , Camundongos , Camundongos Transgênicos , Neostriado/metabolismo , Neurônios , Transdução de Sinais
11.
Neurobiol Learn Mem ; 124: 123-9, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26135120

RESUMO

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.


Assuntos
Doença de Alzheimer/fisiopatologia , Transtornos Cognitivos/fisiopatologia , Modelos Animais de Doenças , Doença de Parkinson/fisiopatologia , Pesquisa Translacional Biomédica/métodos , Animais , Encéfalo/fisiopatologia , Transtornos Cognitivos/genética , Humanos , Macaca , Primatas , Especificidade da Espécie
12.
Prog Neurobiol ; 132: 96-168, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26209473

RESUMO

Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa (L-dopa) therapy for Parkinson's disease (PD). L-dopa-induced dyskinesia (LID) are ultimately experienced by the vast majority of patients. In addition, psychiatric conditions often manifested as compulsive behaviours, are emerging as a serious problem in the management of L-dopa therapy. The present review attempts to provide an overview of our current understanding of dyskinesia and other L-dopa-induced dysfunctions, a field that dramatically evolved in the past twenty years. In view of the extensive literature on LID, there appeared a critical need to re-frame the concepts, to highlight the most suitable models, to review the central nervous system (CNS) circuitry that may be involved, and to propose a pathophysiological framework was timely and necessary. An updated review to clarify our understanding of LID and other L-dopa-related side effects was therefore timely and necessary. This review should help in the development of novel therapeutic strategies aimed at preventing the generation of dyskinetic symptoms.


Assuntos
Antiparkinsonianos/efeitos adversos , Sistema Nervoso Central/fisiopatologia , Discinesia Induzida por Medicamentos/fisiopatologia , Levodopa/efeitos adversos , Animais , Sistema Nervoso Central/efeitos dos fármacos , Humanos , Doença de Parkinson/tratamento farmacológico
13.
Neurobiol Dis ; 70: 138-48, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24969021

RESUMO

Regulators of G-protein signalling (RGS) proteins are implicated in striatal G-protein coupled receptor (GPCR) sensitisation in the pathophysiology of l-DOPA-induced abnormal involuntary movements (AIMs), also known as dyskinesia (LID), in Parkinson's disease (PD). In this study, we investigated RGS protein subtype 4 in the expression of AIMs in the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of LID. The effects of RGS4 antisense brain infusion on the behavioural and molecular correlates of l-DOPA priming in 6-OHDA-lesioned rats were assessed. In situ hybridisation revealed that repeated l-DOPA/benserazide treatment caused an elevation of RGS4 mRNA levels in the striatum, predominantly in the lateral regions. The increased expression of RGS4 mRNA in the rostral striatum was found to positively correlate with the behavioural (AIM scores) and molecular (pre-proenkephalin B, PPE-B expression) markers of LID. We found that suppressing the elevation of RGS4 mRNA in the striatum by continuous infusion of RGS4 antisense oligonucleotides, via implanted osmotic mini-pumps, during l-DOPA priming, reduced the induction of AIMs. Moreover, ex vivo analyses of the rostral dorsolateral striatum showed that RGS4 antisense infusion attenuated l-DOPA-induced elevations of PPE-B mRNA and dopamine-stimulated [(35)S]GTPγS binding, a marker used for measuring dopamine receptor super-sensitivity. Taken together, these data suggest that (i) RGS4 proteins play an important pathophysiological role in the development and expression of LID and (ii) suppressing the elevation of RGS4 mRNA levels in l-DOPA priming attenuates the associated pathological changes in LID, dampening its physiological expression. Thus, modulating RGS4 proteins could prove beneficial in the treatment of dyskinesia in PD.


Assuntos
Antiparkinsonianos/efeitos adversos , Corpo Estriado/fisiopatologia , Discinesia Induzida por Medicamentos/fisiopatologia , Levodopa/efeitos adversos , Transtornos Parkinsonianos/fisiopatologia , Proteínas RGS/metabolismo , Animais , Antiparkinsonianos/farmacologia , Células Cultivadas , Corpo Estriado/efeitos dos fármacos , Discinesia Induzida por Medicamentos/terapia , Encefalinas/metabolismo , Lateralidade Funcional , Expressão Gênica/efeitos dos fármacos , Terapia Genética , Levodopa/farmacologia , Masculino , Oligonucleotídeos Antissenso/administração & dosagem , Oxidopamina , Transtornos Parkinsonianos/tratamento farmacológico , Precursores de Proteínas/metabolismo , Proteínas RGS/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Regulação para Cima/efeitos dos fármacos
14.
Mov Disord ; 29(6): 772-9, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24610195

RESUMO

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.


Assuntos
Amantadina/uso terapêutico , Discinesia Induzida por Medicamentos/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Imidazóis/uso terapêutico , Análise de Variância , Animais , Antiparkinsonianos/efeitos adversos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Discinesia Induzida por Medicamentos/etiologia , Feminino , Levodopa/efeitos adversos , Intoxicação por MPTP/tratamento farmacológico , Macaca fascicularis
15.
Neurosci Lett ; 566: 72-6, 2014 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-24572591

RESUMO

In animal models of Parkinson's disease (PD), the serotonergic (5-hydroxytryptamine, 5-HT) system is thought to play an important pathophysiological role in the development and expression of l-3,4-dihydroxyphenylalanine (l-3,4-dihydroxyphenylalanine-DOPA)-induced dyskinesia (LID). These abnormal involuntary movements are associated with the unregulated release of dopamine from 5-HT fibres. Thus, modulating the false neurotransmitter release from 5-HT neurons, via attuning the serotonin tone, may be a potential therapeutic strategy in the treatment of LID. In this study, we investigated the effects of the primary precursor of 5-HT, l-tryptophan, on LID in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaques. l-tryptophan treatment (0.5-5.0g) dramatically abolished the expression of LID. However, this effect was associated with worsening of the therapeutic effects of L-DOPA. These behavioural data further support the role of the serotonergic system in expression of LID, highlighting the difficult challenge of targeting 5-HT neurons for alleviating dyskinesia and maintaining the therapeutic response of L-DOPA.


Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Antiparkinsonianos/efeitos adversos , Discinesia Induzida por Medicamentos/fisiopatologia , Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Triptofano/farmacologia , Animais , Antiparkinsonianos/uso terapêutico , Corpo Estriado/metabolismo , Dopamina/metabolismo , Discinesia Induzida por Medicamentos/etiologia , Discinesia Induzida por Medicamentos/metabolismo , Feminino , Levodopa/uso terapêutico , Macaca fascicularis , Atividade Motora/efeitos dos fármacos , Doença de Parkinson/etiologia , Doença de Parkinson/fisiopatologia
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