RESUMO
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.
Assuntos
Discinesias/tratamento farmacológico , Intoxicação por MPTP/fisiopatologia , Receptores Opioides mu/agonistas , Animais , Células CHO , Cricetinae , Cricetulus , Discinesias/etiologia , Ala(2)-MePhe(4)-Gly(5)-Encefalina/administração & dosagem , Ala(2)-MePhe(4)-Gly(5)-Encefalina/farmacologia , Ala(2)-MePhe(4)-Gly(5)-Encefalina/uso terapêutico , Feminino , Humanos , Levodopa/efeitos adversos , Levodopa/uso terapêutico , Intoxicação por MPTP/tratamento farmacológico , Macaca fascicularis , Neurotransmissores/administração & dosagem , Neurotransmissores/farmacologia , Neurotransmissores/uso terapêutico , Receptores Opioides mu/antagonistas & inibidoresRESUMO
Understanding the biological mechanisms of l-dopa-induced motor complications is dependent on our ability to investigate these phenomena in animal models of Parkinson's disease. The most common motor complications consist in wearing-off fluctuations and abnormal involuntary movements appearing when plasma levels of l-dopa are high, commonly referred to as peak-dose l-dopa-induced dyskinesia. Parkinsonian models exhibiting these features have been well-characterized in both rodent and nonhuman primate species. The first animal models of peak-dose l-dopa-induced dyskinesia were produced in monkeys lesioned with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and treated chronically with l-dopa to elicit choreic movements and dystonic postures. Seminal studies were performed in these models using both metabolic mapping and electrophysiological techniques, providing fundamental pathophysiological insights that have stood the test of time. A decade later, it was shown possible to reproduce peak-dose l-dopa-induced dyskinesia in rats and mice rendered parkinsonian with nigrostriatal 6-hydroxydopamine lesions. When treated with l-dopa, these animals exhibit abnormal involuntary movements having both hyperkinetic and dystonic components. These models have enabled molecular- and cellular-level investigations into the mechanisms of l-dopa-induced dyskinesia. A flourishing literature using genetically engineered mice is now unraveling the role of specific genes and neural circuits in the development of l-dopa-induced motor complications. Both non-human primate and rodent models of peak-dose l-dopa-induced dyskinesia have excellent construct validity and provide valuable tools for discovering therapeutic targets and evaluating potential treatments. © 2018 International Parkinson and Movement Disorder Society.
Assuntos
Antiparkinsonianos/efeitos adversos , Discinesia Induzida por Medicamentos/etiologia , Levodopa/efeitos adversos , Doença de Parkinson Secundária/tratamento farmacológico , Animais , Modelos Animais de Doenças , Discinesia Induzida por Medicamentos/patologia , Doença de Parkinson Secundária/induzido quimicamenteRESUMO
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 fármacosRESUMO
A role for enhanced peptidergic transmission, either opioidergic or not, has been proposed for the generation of l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID) on the basis of in situ hybridization studies showing that striatal peptidergic precursor expression consistently correlates with LID severity. Few studies, however, have focused on the actual peptides derived from these precursors. We used mass-spectrometry to study peptide profiles in the putamen and globus pallidus (internalis and externalis) collected from 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine treated macaque monkeys, acutely or chronically treated with l-DOPA. We identified that parkinsonian and dyskinetic states are associated with an abnormal production of proenkephalin-, prodynorphin- and protachykinin-1-derived peptides in both segments of the globus pallidus. Moreover, we report that peptidergic processing is dopamine-state dependent and highly structure-specific, possibly explaining the failure of previous clinical trials attempting to rectify abnormal peptidergic transmission.
Assuntos
Antiparkinsonianos/toxicidade , Discinesia Induzida por Medicamentos/metabolismo , Globo Pálido/metabolismo , Levodopa/toxicidade , Neuropeptídeos/metabolismo , Transtornos Parkinsonianos/metabolismo , Putamen/química , Animais , Encefalinas/análise , Encefalinas/metabolismo , Feminino , Globo Pálido/química , Macaca mulatta , Neuropeptídeos/análise , Precursores de Proteínas/análise , Precursores de Proteínas/metabolismo , Putamen/metabolismo , Taquicininas/análise , Taquicininas/metabolismoRESUMO
L-Dopa-induced dyskinesia in patients with Parkinson's disease can be alleviated by amantadine, an antagonist at N-methyl-D-aspartate glutamate receptors. The antiepileptic drug topiramate, which blocks α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, has also been shown to reduce dyskinesia. The purpose of this study was to examine the behavioral pharmacology of topiramate alone and in combination with amantadine in animal models of PD and L-dopa-induced dyskinesia. The effects of topiramate (5-20 mg/kg) and amantadine (5-20 mg/kg) on abnormal involuntary movements (the rat homologue of dyskinesia) and Rotarod performance were assessed alone and in combination in the 6-hydroxydopamine-lesioned rat following chronic L-dopa treatment. Dyskinesia, parkinsonian disability, and "on-time" were assessed in the MPTP-lesioned nonhuman primate following administration of topiramate (5-20 mg/kg) and amantadine (0.1-1.0 mg/kg) alone and in combination. Topiramate and amantadine dose-dependently reduced dyskinesia in the 6-hydroxydopamine-lesioned rat, whereas topiramate reduced Rotarod performance; there was no effect on parkinsonian disability in the MPTP-lesioned nonhuman primate, in which both drugs reduced dyskinesia. Topiramate and amantadine exhibited differential antidyskinetic effects on dyskinesia elicited by the dopamine D1 receptor agonist SKF 38393 (2 mg/kg). Subthreshold doses of both drugs in combination had a synergistic effect on dyskinesia in the 6-hydroxydopamine-lesioned rat, with no worsening of motor performance; this effect was confirmed in the MPTP-lesioned nonhuman primate, with a selective reduction in "bad on-time." These data confirm the antidyskinetic potential of topiramate and suggest that combination with low-dose amantadine may allow better reduction of dyskinesia with no adverse motor effects.
Assuntos
Amantadina/farmacologia , Antiparkinsonianos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Discinesia Induzida por Medicamentos/tratamento farmacológico , Frutose/análogos & derivados , Intoxicação por MPTP/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Amantadina/administração & dosagem , Animais , Antiparkinsonianos/toxicidade , Callithrix , Modelos Animais de Doenças , Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/toxicidade , Sinergismo Farmacológico , Discinesia Induzida por Medicamentos/diagnóstico , Frutose/administração & dosagem , Frutose/farmacologia , Levodopa/toxicidade , Masculino , Ratos , Ratos Sprague-Dawley , TopiramatoRESUMO
l-DOPA treatment for Parkinson's disease frequently leads to dyskinesias, the pathophysiology of which is poorly understood. We used MALDI-MSI to map the distribution of l-DOPA and monoaminergic pathways in brains of dyskinetic and nondyskinetic primates. We report elevated levels of l-DOPA, and its metabolite 3-O-methyldopa, in all measured brain regions of dyskinetic animals and increases in dopamine and metabolites in all regions analyzed except the striatum. In dyskinesia, dopamine levels correlated well with l-DOPA levels in extrastriatal regions, such as hippocampus, amygdala, bed nucleus of the stria terminalis, and cortical areas, but not in the striatum. Our results demonstrate that l-DOPA-induced dyskinesia is linked to a dysregulation of l-DOPA metabolism throughout the brain. The inability of extrastriatal brain areas to regulate the formation of dopamine during l-DOPA treatment introduces the potential of dopamine or even l-DOPA itself to modulate neuronal signaling widely across the brain, resulting in unwanted side effects.
Assuntos
Discinesia Induzida por Medicamentos , Levodopa , Animais , Encéfalo/metabolismo , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Discinesia Induzida por Medicamentos/tratamento farmacológico , Discinesia Induzida por Medicamentos/etiologia , Discinesia Induzida por Medicamentos/metabolismo , Levodopa/efeitos adversos , Espectrometria de MassasRESUMO
Overactivity of striatal alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors is implicated in the pathophysiology of L-DOPA-induced dyskinesia (LID) in Parkinson's disease (PD). In this study, we evaluated the behavioural and molecular effects of acute and chronic blockade of Ca(2+)-permeable AMPA receptors in animal models of PD and LID. The acute effects of the Ca(2+)-permeable AMPA receptor antagonist 1-trimethylammonio-5-(1-adamantane-methylammoniopentane) dibromide hydrobromide (IEM 1460) on abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA)-lesioned rat and LID in the MPTP-lesioned non-human primate were assessed. Subsequently, the effects of chronic treatment of 6-OHDA-lesioned rats with vehicle, L-DOPA/benserazide (6/15 mg/kg, i.p.) + vehicle or L-DOPA + IEM 1460 (3 mg/kg, i.p.) on behavioural and molecular correlates of priming for LID were evaluated. In the 6-OHDA-lesioned rat and MPTP-lesioned non-human primate, acute treatment with IEM 1460 (1-3 mg/kg) dose-dependently reduced LID without adverse effects on motor performance. Chronic co-treatment for 21 days with IEM 1460 reduced the induction of AIMs by L-DOPA in the 6-OHDA-lesioned rat without affecting peak rotarod performance, and attenuated AIMs score by 75% following l-DOPA challenge (p < 0.05). Chronic IEM 1460 treatment reversed L-DOPA-induced up-regulation of pre-proenkephalin-A, and normalised pre-proenkephalin-B mRNA expression in the lateral striatum, indicating an inhibition of both behavioural and molecular correlates of priming. These data suggest that Ca(2+)-permeable AMPA receptors are critically involved in both the induction and subsequent expression of LID, and represent a potential target for anti-dyskinetic therapies.
Assuntos
Antiparkinsonianos/efeitos adversos , Comportamento Animal/efeitos dos fármacos , Cálcio/metabolismo , Discinesia Induzida por Medicamentos/psicologia , Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Receptores de AMPA/fisiologia , Adamantano/análogos & derivados , Adamantano/farmacologia , Animais , Benserazida/efeitos adversos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Callithrix , Discinesia Induzida por Medicamentos/etiologia , Discinesia Induzida por Medicamentos/metabolismo , Encefalinas/biossíntese , Masculino , Atividade Motora/efeitos dos fármacos , Oxidopamina , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Precursores de Proteínas/biossíntese , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/antagonistas & inibidoresRESUMO
The classic view of anatomofunctional organization of the basal ganglia is that striatopallidal neurons of the "indirect" pathway express D2 dopamine receptors and corelease enkephalin with GABA, whereas striatopallidal neurons of the "direct" pathway bear D1 dopamine receptors and corelease dynorphin and substance P with GABA. Although many studies have investigated the pathophysiology of the basal ganglia after dopamine denervation and subsequent chronic levodopa (L-dopa) treatment, none has ever considered the possibility of plastic changes leading to profound reorganization and/or biochemical phenotype modifications of medium spiny neurons. Therefore, we studied the phenotype of striatal neurons in four groups of nonhuman primates, including the following: normal, parkinsonian, parkinsonian chronically treated with L-dopa without exhibiting dyskinesia, and parkinsonian chronically treated with L-dopa exhibiting overt dyskinesia. To identify striatal cells projecting to external (indirect) or internal (direct) segments of the globus pallidus, the retrograde tracer cholera toxin subunit B (CTb) was injected stereotaxically into the terminal areas. Using immunohistochemistry techniques, brain sections were double labeled for CTb and dopamine receptors, opioid peptides, or the substance P receptor (NK1). We also used HPLC-RIA to assess opioid levels throughout structures of the basal ganglia. Our results suggest that medium spiny neurons retain their phenotype because no variations were observed in any experimental condition. Therefore, it appears unlikely that dyskinesia is related to a phenotype modification of the striatal neurons. However, this study supports the concept of axonal collateralization of striatofugal cells that project to both globus pallidus pars externa and globus pallidus pars interna. Striatofugal pathways are not as segregated in the primate as previously considered.
Assuntos
Gânglios da Base/fisiopatologia , Corpo Estriado/fisiopatologia , Discinesias/fisiopatologia , Neurônios , Transtornos Parkinsonianos/fisiopatologia , Animais , Toxina da Cólera/administração & dosagem , Toxina da Cólera/farmacocinética , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Discinesias/patologia , Feminino , Globo Pálido/metabolismo , Imuno-Histoquímica , Injeções , Macaca fascicularis , Macaca mulatta , Neurônios/metabolismo , Peptídeos Opioides/metabolismo , Transtornos Parkinsonianos/patologia , Fenótipo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores da Neurocinina-1/metabolismo , Transmissão Sináptica , Distribuição TecidualRESUMO
BACKGROUND: A role for enhanced opioid peptide transmission has been suggested in the genesis of levodopa-induced dyskinesia. However, basal ganglia nuclei other than the striatum have not been regarded as potential sources, and the opioid precursors have never been quantified simultaneously with the levels of opioid receptors at the peak of dyskinesia severity. METHODS: The levels of messenger RNA (mRNA) encoding the opioid precursors preproenkephalin-A and preproenkephalin-B in the striatum and the subthalamic nucleus and the levels of mu, delta, and kappa opioid receptors were measured within the basal ganglia of four groups of nonhuman primates killed at the peak of effect: normal, parkinsonian, parkinsonian chronically-treated with levodopa without exhibiting dyskinesia, and parkinsonian chronically-treated with levodopa showing overt dyskinesia. RESULTS: Dyskinesia are associated with reduction in opioid receptor binding and specifically of kappa and mu receptor binding in the globus pallidus internalis (GPi), the main output structure of the basal ganglia. This decrease was correlated with enhancement of the expression of preproenkephalin-B mRNA but not that of preproenkephalin-A in the striatum and the subthalamic nucleus. CONCLUSIONS: Abnormal transmission of preproenkephalin-B-derived opioid coming from the striatum and the subthalamic nucleus converges upon GPi at the peak of dose to induce levodopa-induced dyskinesia.
Assuntos
Corpo Estriado/metabolismo , Discinesia Induzida por Medicamentos , Encefalinas/metabolismo , Regulação da Expressão Gênica/fisiologia , Precursores de Proteínas/metabolismo , Receptores Opioides/metabolismo , Núcleo Subtalâmico/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Análise de Variância , Animais , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/efeitos adversos , Interações Medicamentosas , Discinesia Induzida por Medicamentos/metabolismo , Discinesia Induzida por Medicamentos/patologia , Discinesia Induzida por Medicamentos/fisiopatologia , Encefalinas/genética , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hibridização In Situ/métodos , Levodopa/administração & dosagem , Levodopa/efeitos adversos , Macaca fascicularis , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/tratamento farmacológico , Precursores de Proteínas/genética , RNA Mensageiro/metabolismo , Ensaio Radioligante/métodos , Análise de RegressãoRESUMO
Dyskinesia represents a debilitating complication of L-3,4-dihydroxyphenylalanine (L-dopa) therapy for Parkinson's disease. Such motor manifestations are attributed to pathological activity in the motor parts of basal ganglia. However, because consistent funneling of information takes place between the sensorimotor, limbic, and associative basal ganglia domains, we hypothesized that nonmotor domains play a role in these manifestations. Here we report the changes in 2-deoxyglucose (2-DG) accumulation in the sensorimotor, limbic, and associative domains of basal ganglia and thalamic nuclei of four groups of nonhuman primates: normal, parkinsonian, parkinsonian chronically treated with L-dopa without exhibiting dyskinesia, and parkinsonian chronically treated with L-dopa and exhibiting overt dyskinesia. Although nondyskinetic animals display a rather normalized metabolic activity, dyskinetic animals are distinguished by significant changes in 2-DG accumulation in limbic- and associative-related structures and not simply in sensorimotor-related ones, suggesting that dyskinesia is linked to a pathological processing of limbic and cognitive information. We propose that these metabolic changes reflect the underlying neural mechanisms of not simply motor dyskinesias but also affective, motivational, and cognitive disorders associated with long-term exposure to L-dopa.
Assuntos
Gânglios da Base/fisiopatologia , Discinesia Induzida por Medicamentos/fisiopatologia , Levodopa/toxicidade , Sistema Límbico/fisiopatologia , Animais , Gânglios da Base/química , Desoxiglucose/farmacocinética , Discinesia Induzida por Medicamentos/metabolismo , Feminino , Globo Pálido/química , Globo Pálido/fisiopatologia , Levodopa/uso terapêutico , Sistema Límbico/química , Macaca fascicularis , Córtex Motor/química , Córtex Motor/fisiopatologia , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/fisiopatologia , Núcleos Septais/química , Núcleos Septais/fisiopatologia , Córtex Somatossensorial/química , Córtex Somatossensorial/fisiopatologia , Substância Negra/química , Substância Negra/fisiopatologia , Núcleo Subtalâmico/química , Núcleo Subtalâmico/fisiopatologiaRESUMO
BACKGROUND: Two-Dimensional Difference In Gel Electrophoresis (2D-DIGE) is a powerful tool for measuring differences in protein expression between samples or conditions. However, to remove systematic variability within and between gels the data has to be normalized. In this study we examined the ability of four existing and four novel normalization methods to remove systematic bias in data produced with 2D-DIGE. We also propose a modification of an existing method where the statistical framework determines whether a set of proteins shows an association with the predefined phenotypes of interest. This method was applied to our data generated from a monkey model (Macaca fascicularis) of Parkinson's disease. RESULTS: Using 2D-DIGE we analysed the protein content of the striatum from 6 control and 21 MPTP-treated monkeys, with or without de novo or long-term L-DOPA administration. There was an intensity and spatial bias in the data of all the gels examined in this study. Only two of the eight normalization methods evaluated ('2D loess+scale' and 'SC-2D+quantile') successfully removed both the intensity and spatial bias. In 'SC-2D+quantile' we extended the commonly used loess normalization method against dye bias in two-channel microarray systems to suit systems with three or more channels.Further, by using the proposed method, Differential Expression in Predefined Proteins Sets (DEPPS), several sets of proteins associated with the priming effects of L-DOPA in the striatum in parkinsonian animals were identified. Three of these sets are proteins involved in energy metabolism and one set involved proteins which are part of the microtubule cytoskeleton. CONCLUSION: Comparison of the different methods leads to a series of methodological recommendations for the normalization and the analysis of data, depending on the experimental design. Due to the nature of 2D-DIGE data we recommend that the p-values obtained in significance tests should be used as rankings only. Individual proteins may be interesting as such, but by studying sets of proteins the interpretation of the results are probably more accurate and biologically informative.
Assuntos
Corpo Estriado/metabolismo , Eletroforese em Gel Bidimensional/métodos , Perfilação da Expressão Gênica/métodos , Proteínas do Tecido Nervoso/metabolismo , Doença de Parkinson Secundária/metabolismo , Proteoma/metabolismo , Animais , Corpo Estriado/efeitos dos fármacos , Modelos Animais de Doenças , Levodopa , Macaca fascicularis , Transtornos dos Movimentos/etiologia , Transtornos dos Movimentos/metabolismo , Doença de Parkinson Secundária/induzido quimicamenteRESUMO
Endocannabinoids and cannabinoid CB1 receptors play a role in the control of movement by modulating GABA, glutamate, and other neurotransmitters throughout the basal ganglia. Roles for abnormalities in endocannabinoid signaling in Parkinson's disease (PD) and the major side effect of current treatments, levodopa-induced dyskinesia (LID), have been suggested by rodent studies. Here we show that signaling by endocannabinoids contributes to the pathophysiology of parkinsonism and LID in MPTP-lesioned, non-human primate models of Parkinson's disease. In MPTP-lesioned marmosets previously treated with levodopa to establish LID, attenuation of CB1 signaling by systemic administration of rimonabant (1 and 3 mg/kg) had anti-parkinsonian actions, equivalent to a 71% increase in motor activity at 3 mg/kg. Rimonabant did not elicit dyskinesia. Co-administration of levodopa (8 mg/kg) and rimonabant (1 and 3 mg/kg) resulted in significantly less dyskinesia than levodopa alone, without significantly affecting the anti-parkinsonian action of levodopa. These data suggest that enhanced endocannabinoid signaling may be involved in the pathophysiology of both parkinsonism and LID. To define potential mechanisms by which such a role might be mediated, we determined the levels of the endocannabinoids anandamide and 2-arachidonyl glycerol (2-AG) throughout the basal ganglia in normal and three groups of MPTP-lesioned cynomolgus monkeys (untreated; acutely treated with L-DOPA, non-dyskinetic; long-term treated, with levodopa-induced dyskinesia). In the untreated, MPTP-lesioned primate, parkinsonism was associated with increases in both 2-AG (+88%) and anandamide (+49%) in the striatum, and of 2-AG (+97%) in the substantia nigra, changes that are consistent with the previously suggested role for endocannabinoids in mechanisms attempting to compensate for loss of dopamine in untreated parkinsonism. Increased levels of anandamide (+34%) in the external globus pallidus of MPTP-lesioned animals were normalized by levodopa treatment and may contribute to the generation of parkinsonian symptoms. However, no clear alteration in endocannabinoid levels could be correlated with the expression of LID. These data highlight the potential roles played by endocannabinoids and CB1 in PD and LID and suggest the need for further research to pursue the multiple therapeutic opportunities for manipulating this system in movement disorders.
Assuntos
Moduladores de Receptores de Canabinoides/fisiologia , Discinesia Induzida por Medicamentos/etiologia , Endocanabinoides , Levodopa/toxicidade , Intoxicação por MPTP/etiologia , Animais , Ácidos Araquidônicos/análise , Callithrix , Moduladores de Receptores de Canabinoides/análise , Feminino , Glicerídeos/análise , Intoxicação por MPTP/tratamento farmacológico , Masculino , Piperidinas/uso terapêutico , Alcamidas Poli-Insaturadas , Pirazóis/uso terapêutico , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/fisiologia , Rimonabanto , Ácido gama-Aminobutírico/metabolismoRESUMO
It is well established that members of the hedgehog family are involved in tissue patterning during development. We herein show that sonic hedgehog signaling molecules are differentially regulated by dopamine depletion in the basal ganglia of adult animals and specifically that sonic hedgehog levels are reduced in an animal model of Parkinson's disease. In addition, we show that sonic hedgehog protein inhibits electrical activity in the subthalamic nucleus, a key element of basal ganglia, within minutes of application. As the subthalamic nucleus is overactive in parkinsonism, we suggest that enhancement of sonic hedgehog signaling in the subthalamic nucleus may be of therapeutic value in Parkinson's disease.
Assuntos
Neurotransmissores/farmacologia , Núcleo Subtalâmico/fisiologia , Transativadores/farmacologia , Animais , Células Cultivadas , Condutividade Elétrica , Globo Pálido/metabolismo , Proteínas Hedgehog , Modelos Neurológicos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Neurotransmissores/genética , Neurotransmissores/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Técnicas de Patch-Clamp , RNA Mensageiro/metabolismo , Ratos , Núcleo Subtalâmico/citologia , Núcleo Subtalâmico/efeitos dos fármacos , Transativadores/genética , Transativadores/metabolismoRESUMO
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 farmacológicoRESUMO
L-3,4 dihydroxyphenylalanine (levodopa)-induced dyskinesia in Parkinson's disease patients is characterized by a mixture of chorea and dystonia. Electrophysiological studies suggest that chorea is associated with abnormal synchronization of firing of basal ganglia neurons while dystonia is not. Levetiracetam is a novel anti-epileptic drug known to exhibit unique desynchronizing properties in contrast to other anti-epileptic drugs. We assessed the anti-dyskinetic efficacy of levetiracetam (13, 30 and 60 mg/kg, p.o.) administered in combination with an individually tailored dose of levodopa (Levodopa/carbidopa, 4:1 ratio, 19+/-1.8 mg/kg, p.o.), in six dyskinetic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned macaques. Levetiracetam (60 mg/kg) significantly reduced levodopa-induced chorea during the first hour post-treatment but had no effect on dystonia. Levetiracetam, at all doses tested, had no effect on the anti-parkinsonian action of levodopa. These results suggest that levetiracetam may provide a novel therapeutic approach specifically aimed at the choreic form of levodopa-induced dyskinesia.
Assuntos
Coreia/tratamento farmacológico , Discinesia Induzida por Medicamentos/tratamento farmacológico , Levodopa/efeitos adversos , Intoxicação por MPTP/tratamento farmacológico , Piracetam/uso terapêutico , Animais , Coreia/fisiopatologia , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Discinesia Induzida por Medicamentos/fisiopatologia , Feminino , Levetiracetam , Levodopa/uso terapêutico , Intoxicação por MPTP/fisiopatologia , Macaca fascicularis , Piracetam/análogos & derivadosRESUMO
OBJECTIVE: Levetiracetam (LEV; Keppra, UCB Pharma) has been shown to reduce established l-3,4 dihydroxyphenylalanine (l-dopa)-induced dyskinesia. This study investigated whether LEV can modify induction of dyskinesia by l-dopa or the process of priming. METHODS: Drug-naive MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) -lesioned marmosets were treated for 21 days with l-dopa/LEV or l-dopa alone. Subsequently, the animals were left untreated for 1 week and then both groups were challenged with a single dose of l-dopa alone on day 29. Behavior was assessed by automated activity counts and by post hoc analysis of videotapes using validated rating scales. RESULTS: LEV had no significant effect on the appearance of dyskinesia when administered de novo in combination with l-dopa. However, after a week of drug holiday, the 2 groups exhibited a different response to an acute l-dopa challenge. Thus, animals previously treated with l-dopa alone exhibited a similar level of dyskinesia to that seen on day 21 of the repeated treatment phase of the study. However, animals previously treated with l-dopa/LEV demonstrated significantly reduced dyskinesia compared with day 21 of the repeated treatment phase of the study. CONCLUSIONS: LEV does not modify the onset of dyskinesia following de novo treatment with l-dopa. However, concomitant treatment with l-dopa/LEV reduces the level of dyskinesia induced by l-dopa following a drug holiday. Thus, prior treatment with LEV appears to modify the mechanisms responsible for the maintenance of l-dopa-induced dyskinesia.
Assuntos
Anticonvulsivantes/uso terapêutico , Discinesias/tratamento farmacológico , Levodopa/antagonistas & inibidores , Intoxicação por MPTP/tratamento farmacológico , Piracetam/uso terapêutico , Análise de Variância , Animais , Antiparkinsonianos/antagonistas & inibidores , Callithrix , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Esquema de Medicação , Interações Medicamentosas , Quimioterapia Combinada , Levetiracetam , Piracetam/análogos & derivados , Distribuição Aleatória , Fatores de TempoRESUMO
BACKGROUND: The antiepileptic drug topiramate reduces levodopa-induced dyskinesia without exacerbating parkinsonism in animal models. We report a randomized, double-blind, placebo-controlled crossover trial in patients with Parkinson's disease and levodopa-induced dyskinesia. METHODS: Fifteen patients with Parkinson's disease and stable levodopa-induced dyskinesia were enrolled into the study, of whom 13 were randomized to topiramate or placebo. The study medication was titrated to 100 mg/day over four weeks, and assessments were carried out after a further two weeks. Dyskinesia severity assessed by a blinded rater from video recordings was the primary outcome measure. RESULTS: Seven patients (mean age 58.9 ± 12.8 years) completed the study. Patients taking topiramate vs. placebo showed a significant increase in dyskinesia severity compared to baseline (Wilcoxon signed rank test, P = 0.043). Five patients withdrew from the study whilst taking topiramate due to adverse effects. CONCLUSIONS: Topiramate tended to worsen dyskinesia in patients with Parkinson's disease, and was poorly tolerated.
Assuntos
Anticonvulsivantes/uso terapêutico , Discinesia Induzida por Medicamentos/tratamento farmacológico , Frutose/análogos & derivados , Doença de Parkinson/tratamento farmacológico , Adulto , Idoso , Antiparkinsonianos/efeitos adversos , Estudos Cross-Over , Método Duplo-Cego , Feminino , Frutose/uso terapêutico , Humanos , Levodopa/efeitos adversos , Masculino , Pessoa de Meia-Idade , TopiramatoRESUMO
Current neuroimaging techniques have very limited abilities to directly identify and quantify neurotransmitters from brain sections. We have developed a molecular-specific approach for the simultaneous imaging and quantitation of multiple neurotransmitters, precursors, and metabolites, such as tyrosine, tryptamine, tyramine, phenethylamine, dopamine, 3-methoxytyramine, serotonin, GABA, glutamate, acetylcholine, and L-alpha-glycerylphosphorylcholine, in histological tissue sections at high spatial resolutions. The method is employed to directly measure changes in the absolute and relative levels of neurotransmitters in specific brain structures in animal disease models and in response to drug treatments, demonstrating the power of mass spectrometry imaging in neuroscience.
Assuntos
Encéfalo/metabolismo , Imagem Molecular/métodos , Neurotransmissores/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Animais , Camundongos , RatosRESUMO
Abnormal corticostriatal plasticity is a key mechanism of L-DOPA-induced dyskinesia (LID) in Parkinson's disease (PD). Antagonists at glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, such as IEM 1460, reduce induction and expression of dyskinesia in rat and non-human primate models of PD. AMPA receptor function is regulated by post-transcriptional splicing of subunit mRNA to produce flip and flop isoforms, which may therefore influence corticostriatal plasticity. The aim of this work was to evaluate alterations in alternative splicing of striatal AMPA receptor subunits in the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of LID and PD. Male Sprague-Dawley rats received 12.5 µg 6-OHDA injections into the right medial forebrain bundle. In experiment 1, to assess acute dyskinesia, rats received L-DOPA/benserazide (6/15 mg/kg, i.p.) or vehicle for 21 days. In experiment 2, to assess dyskinesia priming, rats received vehicle, L-DOPA+vehicle or L-DOPA+IEM 1460 (3 mg/kg, i.p.) for 21 days. Animals were humanely killed 1h following final treatment in experiment 1, and 48 h following final treatment in experiment 2. Coronal sections of rostral striatum were processed for in situ hybridisation histochemistry, using oligonucleotide probes specific for the GluR1 and GluR2 subunits and their flip and flop isoforms. L-DOPA treatment increased GluR2-flip mRNA expression in the lesioned striatum of both groups; this was blocked by the Ca(2+)-permeable AMPA receptor antagonist IEM 1460. GluR1-flip expression was increased after 48 h drug washout but not in acute LID. There were no changes in expression of flop isoforms. Alternative splicing of AMPAR subunits contributes to abnormal striatal plasticity in the induction and expression of LID. Increases in GluR2-flip expression depend on activation of Ca(2+)-permeable AMPA receptors, which are a potential target of anti-dyskinetic therapies.