RESUMEN
Parkinson's disease (PD) is diagnosed when striatal dopamine (DA) loss exceeds a certain threshold and the cardinal motor features become apparent. The presymptomatic compensatory mechanisms underlying the lack of motor manifestations despite progressive striatal depletion are not well understood. Most animal models of PD involve the induction of a severe dopaminergic deficit in an acute manner, which departs from the typical, chronic evolution of PD in humans. We have used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administered to monkeys via a slow intoxication protocol to produce a more gradual development of nigral lesion. Twelve control and 38 MPTP-intoxicated monkeys were divided into four groups. The latter included monkeys who were always asymptomatic, monkeys who recovered after showing mild parkinsonian signs, and monkeys with stable, moderate and severe parkinsonism. We found a close correlation between cell loss in the substantia nigra pars compacta (SNc) and striatal dopaminergic depletion and the four motor states. There was an overall negative correlation between the degree of parkinsonism (Kurlan scale) and in vivo PET ((18)F-DOPA K(i) and (11)C-DTBZ binding potential), as well as with TH-immunoreactive cell counts in SNc, striatal dopaminergic markers (TH, DAT and VMAT2) and striatal DA concentration. This intoxication protocol permits to establish a critical threshold of SNc cell loss and dopaminergic innervation distinguishing between the asymptomatic and symptomatic parkinsonian stages. Compensatory changes in nigrostriatal dopaminergic activity occurred in the recovered and parkinsonian monkeys when DA depletion was at least 88% of control, and accordingly may be considered too late to explain compensatory mechanisms in the early asymptomatic period. Our findings suggest the need for further exploration of the role of non-striatal mechanisms in PD prior to the development of motor features.
Asunto(s)
Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Neuronas/metabolismo , Trastornos Parkinsonianos/metabolismo , Sustancia Negra/metabolismo , Animales , Conducta Animal/fisiología , Recuento de Células , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/patología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Macaca fascicularis , Masculino , Actividad Motora/fisiología , Neuronas/patología , Trastornos Parkinsonianos/diagnóstico por imagen , Trastornos Parkinsonianos/patología , Síntomas Prodrómicos , Cintigrafía , Sustancia Negra/diagnóstico por imagen , Sustancia Negra/patología , Tirosina 3-Monooxigenasa/metabolismo , Proteínas de Transporte Vesicular de Monoaminas/metabolismoRESUMEN
Interaction of genetic and environmental factors is likely involved in Parkinson's disease (PD). Mutations and multiplications of alpha-synuclein (α-syn) cause familial PD, and chronic manganese (Mn) exposure can produce an encephalopathy with signs of parkinsonism. We exposed male transgenic C57BL/6J mice expressing human α-syn or the A53T/A30P doubly mutated human α-syn under the tyrosine hydroxylase promoter and non-transgenic littermates to MnCl2-enriched (1%) or control food, starting at the age of 4 months. Locomotor activity was increased by Mn without significant effect of the transgenes. Mice were sacrificed at the age of 7 or 20 months. Striatal Mn was significantly increased about three-fold in those exposed to MnCl2. The number of tyrosine hydroxylase positive substantia nigra compacta neurons was significantly reduced in 20 months old mice (-10%), but Mn or transgenes were ineffective (three-way ANOVA with the factors gene, Mn and age). In 7 months old mice, striatal homovanillic acid (HVA)/dopamine (DA) ratios and aspartate levels were significantly increased in control mice with human α-syn as compared to non-transgenic controls (+17 and +11%, respectively); after Mn exposure both parameters were significantly reduced (-16 and -13%, respectively) in human α-syn mice, but unchanged in non-transgenic animals and mice with mutated α-syn (two-way ANOVA with factors gene and Mn). None of the parameters were changed in the 20 months old mice. Single HVA/DA ratios and single aspartate levels significantly correlated across all treatment groups suggesting a causal relationship between the rate of striatal DA metabolism and aspartate release. In conclusion, under our experimental conditions, Mn and human α-syn, wild-type and doubly mutated, did not interact to induce PD-like neurodegenerative changes. However, Mn significantly and selectively interacted with human wild-type α-syn on indices of striatal DA neurotransmission, the neurotransmitter most relevant to PD.
Asunto(s)
Cloruros/toxicidad , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , alfa-Sinucleína/genética , Animales , Western Blotting , Cromatografía Líquida de Alta Presión , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/patología , Humanos , Inmunohistoquímica , Compuestos de Manganeso , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Actividad Motora , Degeneración Nerviosa/genética , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/patología , Trastornos Parkinsonianos/genética , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/patología , Transmisión Sináptica/efectos de los fármacos , alfa-Sinucleína/metabolismoRESUMEN
BACKGROUND: Patients with Parkinson disease (PD) may be akinetic/rigid, be tremor dominant, or have comparable severity of these motor symptoms (classic). The pathophysiologic basis of different PD phenotypes is unknown. This study assessed pallidal and striatal dopamine level patterns in different motor subgroups of PD and normal control brains. METHODS: Globus pallidus and striatum dopamine (DA) levels were measured with high performance liquid chromatography in eight autopsy confirmed PD and five control frozen brains. RESULTS: DA levels in the external globus pallidus (GPe) of normal brains were nearly six times greater than in the internal pallidum (GPi). In PD, the mean loss of DA was marked (-82%) in GPe and moderate (-51%) in GPi. DA loss of variable degree was seen in different subdivisions of GPe and GPi in PD; however, DA levels were near normal in the ventral (rostral and caudal) GPi of PD cases with prominent tremor. There was marked loss of DA (-89%) in the caudate and severe loss (-98.4%) in the putamen in PD. The pattern of pallidal DA loss did not match the putaminal DA loss. CONCLUSION: There is sufficient loss of dopamine (DA) in external globus pallidus and the internal globus pallidum (GPi) as may contribute to the motor manifestations of Parkinson disease (PD). The possible functional disequilibrium between GABAergic and DAergic influences in favor of DA in the caudoventral parts of the GPi may contribute to resting tremor in tremor dominant and classic PD cases.
Asunto(s)
Dopamina/metabolismo , Globo Pálido/química , Globo Pálido/metabolismo , Trastornos de la Destreza Motora/metabolismo , Enfermedad de Parkinson/metabolismo , Anciano , Anciano de 80 o más Años , Química Encefálica/fisiología , Femenino , Globo Pálido/patología , Humanos , Masculino , Persona de Mediana Edad , Trastornos de la Destreza Motora/clasificación , Trastornos de la Destreza Motora/patología , Enfermedad de Parkinson/clasificación , Enfermedad de Parkinson/patologíaRESUMEN
This article gives a short historical account of the events and circumstances that led to the discovery of the occurrence of dopamine (DA) in the brain and its deficiency in Parkinson's disease (PD). Some important consequences, for both the basic science and the patient, of the work on DA in the PD brain are also highlighted.
Asunto(s)
Química Encefálica/fisiología , Dopamina/deficiencia , Enfermedad de Parkinson/historia , Enfermedad de Parkinson/metabolismo , Antiparkinsonianos/historia , Antiparkinsonianos/uso terapéutico , Historia del Siglo XX , Humanos , Levodopa/historia , Levodopa/uso terapéutico , Neostriado/metabolismoRESUMEN
The article traces the development of research on the naturally occurring amino acid L-3,4-dihydroxyphenylalanine (L-dopa), from the first synthesis of its D,L racemate in 1911, and the isolation of its L-isomer from seedling of Vicia faba beans to the amino acid's successful application, from 1961 onward, as the most efficacious drug treatment of Parkinson's disease (PD). Upon its isolation from legumes in 1913, L-dopa was declared to be biologically inactive. However, two early pharmacological studies, published in 1927 and 1930 respectively, proved (in the rabbit) that D,L-dopa exerted significant effects on glucose metabolism (causing marked hyperglycemia) and on arterial blood pressure. Interest in L-dopa's biological activity increased considerably following the discovery, in 1938, of the enzyme L-dopa decarboxylase and the demonstration that in the animal and human body L-dopa was enzymatically converted to dopamine (DA), the first biologically active amine in the biosynthetic chain of tissue catecholamines. This prompted, in the 1940s, many studies, both in animals and in humans, especially concerned with the vasopressor potential of L-dopa/DA. In the 1950s, the focus of L-dopa research shifted to its potential for replenishing the experimentally depleted (by insulin or reserpine) peripheral and brain catecholamine stores and the concomitant restoration of normal function. During that period, of special interest were the observations that L-dopa reversed the reserpine-induced state of "tranquilisation" and that its decarboxylation product DA occurred in high amounts in animal and human brain, with a preferential localization in the basal ganglia. These observations set the stage for the beginning of DA studies in PD brain. In 1960, the severe brain DA deficit, confined to patients with PD was discovered, and a year later L-dopa's strong therapeutic effect in patients with PD was demonstrated. In 1967, the chronic high-dose oral L-dopa regimen was successfully introduced into clinical practice. Despite some initial doubts about L-dopa's mechanism of action in PD, it is now generally recognized that L-dopa use in PD is a classic example of a brain neurotransmitter replacement therapy. However, the DA replacement potential of L-dopa may not be its sole action of interest, as suggested by recent evidence that L-dopa may also have its own biological activity in the CNS, independent of DA.
Asunto(s)
Antiparkinsonianos/historia , Levodopa/historia , Enfermedad de Parkinson/historia , Animales , Antiparkinsonianos/química , Antiparkinsonianos/uso terapéutico , Encéfalo/metabolismo , Catecolaminas/metabolismo , Dopamina/metabolismo , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Levodopa/química , Levodopa/uso terapéutico , Estructura Molecular , Enfermedad de Parkinson/tratamiento farmacológicoRESUMEN
INTRODUCTION: In the present study, we determined whether certain proteins known to mediate dopamine signaling in striatum show abnormal levels in Parkinson's disease. METHODS: Protein levels were assayed by western blotting in samples of caudate nucleus and putamen obtained at autopsy from patients with Parkinson's disease and from control subjects. Levels of several markers of dopaminergic function were also assayed. RESULTS: Levels of the transcription factor DeltaFosB and of the G protein modulatory protein RGS9 were both increased in caudate and putamen from patients with Parkinson's disease. Levels of several other proteins were not affected. Interestingly, levels of both DeltaFosB and RGS9 correlated inversely with putamen levels of dopamine, dopamine metabolites, and the dopamine transporter. CONCLUSIONS: These findings are consistent with observations in laboratory animals, which have demonstrated elevated levels of DeltaFosB in striatum after denervation of the midbrain dopamine system, and confirm that similar adaptations in DeltaFosB and RGS9 occur in humans with Parkinson's disease. Knowledge of these adaptations can help us understand the changes in striatal function associated with Parkinson's disease and assist in the development of novel treatments.
Asunto(s)
Núcleo Caudado/patología , Glicoproteínas de Membrana , Proteínas del Tejido Nervioso , Enfermedad de Parkinson/patología , Proteínas Proto-Oncogénicas c-fos/análisis , Putamen/patología , Proteínas RGS/análisis , Western Blotting , Dopamina/análisis , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Humanos , Proteínas de Transporte de Membrana/análisis , Valores de ReferenciaAsunto(s)
Ganglios Basales/metabolismo , Química Encefálica/fisiología , Enfermedad de Parkinson/metabolismo , Ganglios Basales/patología , Ganglios Basales/fisiopatología , Dopamina/metabolismo , Ácido Glutámico/metabolismo , Humanos , Neuronas/metabolismo , Neuronas/patología , Neuropéptidos/metabolismo , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/fisiopatología , Ácido gamma-Aminobutírico/metabolismoAsunto(s)
Apoptosis , Dopamina/farmacología , Glicoproteínas de Membrana , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Norepinefrina/farmacología , Antineoplásicos/farmacología , Proteínas Portadoras/genética , Proteínas Portadoras/fisiología , Catecolaminas/antagonistas & inhibidores , Catecolaminas/farmacología , Ciclo Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Combinación de Medicamentos , Interacciones Farmacológicas , Compuestos Férricos/farmacología , Humanos , Neuroblastoma/patología , Norepinefrina/antagonistas & inhibidores , Estrés Oxidativo/fisiología , Células Tumorales CultivadasAsunto(s)
Antiparkinsonianos/historia , Encéfalo/fisiopatología , Dopamina/historia , Levodopa/historia , Enfermedad de Parkinson/historia , Antiparkinsonianos/uso terapéutico , Encéfalo/metabolismo , Dopamina/metabolismo , Historia del Siglo XX , Humanos , Levodopa/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismoRESUMEN
Although nigrostriatal dopaminergic dysfunction has been suggested in early onset primary torsion dystonia (PTD) with the DYT1 mutation, the actual status of brain dopamine (DA) is unknown. In a DYT1 mutation-positive autopsy patient with PTD, we found that nigral cellularity was normal and that subregional striatal DA levels were within the control range, except for those in the rostral portions of the putamen and caudate nucleus (50% to 54% of control means). Our data suggest that the DYT1 mutation is not associated with significant damage to the nigrostriatal DA system, in keeping with the absence of parkinsonism and levodopa response in this disorder.
Asunto(s)
Cuerpo Estriado/metabolismo , Dopamina/análisis , Distonía Muscular Deformante/genética , Distonía Muscular Deformante/metabolismo , Ácido Homovanílico/análisis , Edad de Inicio , Secuencia de Bases , Niño , Humanos , Masculino , Mutación/genéticaRESUMEN
OBJECTIVE: To determine the mechanism leading to striatal dopamine (DA) loss in dopa-responsive dystonia (DRD). BACKGROUND: Although mutations in the gene GCH1, coding for the tetrahydrobiopterin (BH4) biosynthetic enzyme guanosine triphosphate-cyclohydrolase I, have been identified in some patients with DRD, the actual status of brain BH4 (the cofactor for tyrosine hydroxylase [TH]) is unknown. METHODS: The authors sequenced GCH1 and measured levels of total biopterin (BP) and total neopterin (NP), TH, and dopa decarboxylase (DDC) proteins, and the DA and vesicular monoamine transporters (DAT, VMAT2) in autopsied brain of two patients with typical DRD. RESULTS: Patient 1 had two GCH1 mutations but Patient 2 had no mutation in the coding region of this gene. Striatal BP levels were markedly reduced (<20% of control subjects) in both patients and were also low in two conditions characterized by degeneration of nigrostriatal DA neurons (PD and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treated primate), whereas brain NP concentrations were selectively decreased (<45%) in the DRD patients. In the putamen, both DRD patients had severely reduced (<3%) TH protein levels but had normal concentrations of DDC protein, DAT, and VMAT2. CONCLUSIONS: The data suggest that 1) brain BH4 is decreased substantially in dopa-responsive dystonia, 2) dopa-responsive dystonia can be distinguished from degenerative nigrostriatal dopamine deficiency disorders by the presence of reduced brain neopterin, and 3) the striatal dopamine reduction in dopa-responsive dystonia is caused by decreased TH activity due to low cofactor concentration and to actual loss of TH protein. This reduction of TH protein, which might be explained by reduced enzyme stability/expression consequent to congenital BH4 deficiency, can be expected to limit the efficacy of acute BH4 administration on dopamine biosynthesis in dopa-responsive dystonia.
Asunto(s)
Biopterinas/metabolismo , Cuerpo Estriado/metabolismo , Dihidroxifenilalanina/uso terapéutico , Distonía/genética , Distonía/metabolismo , Tirosina 3-Monooxigenasa/metabolismo , Adulto , Anciano , Distonía/tratamiento farmacológico , Femenino , HumanosRESUMEN
The importance of the striatal dopamine (DA) deficiency and the DA substituting property of levodopa for the pathophysiology and therapy of Parkinson's disease (PD) is reiterated. In addition, it is shown that in PD, significantly reduced DA levels are also found in the nucleus accumbens, external and internal segments of the globus pallidus, the substantia nigra reticulata, and the subthalamic nucleus. It is proposed that, in addition to the critical role played by the striatal DA loss, the DA changes in the extrastriatal nuclei of the basal ganglia are importantly involved in the pathophysiologic mechanisms resulting in the parkinsonian movement disorder, and that the therapeutic and/or side effects of DA substitution therapy may, in part, be mediated through these brain regions which, like the striatum, suffer DAergic deafferentation in PD. From observations in brain of patients with secondary parkinsonism, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine parkinsonism in the rhesus monkey, as well as the regional DA transporter distribution in the primate substantia nigra, it is concluded that PD may be caused by any exogenous and/or endogenous toxin using the transporter system for DA and to some degree the other brain monoamines (noradrenaline, serotonin), to enter, and damage, the respective monoamine neurons. Based on converging evidence, the view is advanced that endogenous, genetically based (excessive) formation, or accumulation, of toxic DA transporter substrates, such as isoquinoline or beta-carboline derivatives, may in fact represent the primary cause of substantia nigra cell degeneration in patients with PD.
Asunto(s)
Cuerpo Estriado/química , Dopamina/metabolismo , Enfermedad de Parkinson/metabolismo , Química Encefálica , Cuerpo Estriado/metabolismo , HumanosRESUMEN
In four generations of a family, 13 members were afflicted with an autosomal dominant disorder characterized by young age at onset, early weight loss, and rapidly progressive dopa-responsive parkinsonism, followed later by dementia and, in some, by hypotension. Intellectual dysfunction began with subjective memory loss and objective visuospatial dysfunction and was followed later by decline of frontal lobe cognitive and memory functions. Neuropathological examination in 4 autopsied cases showed neuronal loss in the substantia nigra and locus ceruleus and widespread Lewy bodies, many of them in the cerebral cortex; those in the hypothalamus and locus ceruleus were often of bizarre shapes. Other findings were vacuolation of the temporal cortex, unusual neuronal loss and gliosis in the hippocampus (CA 2/3), and neuronal loss in the nucleus basalis. There were no neuritic plaques, neurofibrillary tangles, or amyloid deposits. Positron emission tomography in 3 patients showed decreased striatal uptake of fluorodopa. Neurochemical analysis of an autopsied brain showed a pronounced decrease in choline acetyltransferase activity in the frontal and temporal cortices and hippocampus and a severe depletion of striatal dopamine with a pattern not typical of classic Parkinson's disease.
Asunto(s)
Demencia/genética , Salud de la Familia , Enfermedad de Parkinson/genética , Adulto , Antiparkinsonianos/administración & dosificación , Colina O-Acetiltransferasa/análisis , Demencia/diagnóstico por imagen , Demencia/tratamiento farmacológico , Dopamina/análisis , Femenino , Genes Dominantes , Hipocampo/química , Hipocampo/enzimología , Hipocampo/patología , Ácido Homovanílico/análisis , Humanos , Levodopa/administración & dosificación , Cuerpos de Lewy/patología , Locus Coeruleus/química , Locus Coeruleus/patología , Masculino , Persona de Mediana Edad , Neostriado/química , Neostriado/patología , Degeneración Nerviosa/patología , Pruebas Neuropsicológicas , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/tratamiento farmacológico , Linaje , Sustancia Innominada/química , Sustancia Innominada/patología , Sustancia Negra/química , Sustancia Negra/patología , Lóbulo Temporal/química , Lóbulo Temporal/enzimología , Lóbulo Temporal/patología , Tomografía Computarizada de EmisiónRESUMEN
We evaluated the influence of gender on penetrance of GTP-cyclohydrolase I (GCH) gene mutations in hereditary progressive dystonia/dopa-responsive dystonia (HPD/DRD) and determined whether some apparently sporadic HPD/DRD patients owe their disorder to a de novo mutation of the GCH gene. Previous clinical investigations of HPD/DRD have shown a predominance of affected women, with approximately half of HPD/DRD patients being sporadic. We conducted genomic DNA sequencing of the GCH gene in five HPD/DRD families having at least two generations of affected members and in four apparently sporadic cases and all of their parents. In the nine HPD/DRD pedigrees, we found independent mutations of the GCH gene (five deletions, one insertion, one nonsense mutation, and two point mutations at splice acceptor sites). The female-to-male ratio of the HPD/DRD patients was 4.3 with the penetrance of GCH gene mutations in women being 2.3 times higher than that in men (87% versus 38%, p = 0.026). There was no significant difference in the penetrance between maternally and paternally transmitted offspring. All of the four sporadic cases had de novo mutations because none of their parents were carriers. The results demonstrate gender-related incomplete penetrance of GCH gene mutations in HPD/DRD and suggest that this may not be due to genomic imprinting. Our data also suggest a relatively high spontaneous mutation rate of the GCH gene in this autosomal dominant disorder.
Asunto(s)
Distonía/genética , GTP Ciclohidrolasa/genética , Penetrancia , Mutación Puntual , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Análisis Mutacional de ADN , Dopaminérgicos/uso terapéutico , Distonía/tratamiento farmacológico , Distonía/enzimología , Exones/genética , Salud de la Familia , Femenino , Genes Dominantes , Humanos , Intrones/genética , Levodopa/uso terapéutico , Masculino , Persona de Mediana Edad , Factores SexualesRESUMEN
To determine the extent that different dopamine (DA) neuronal markers provide similar estimates of striatal (caudate and putamen) DA nerve terminal loss in idiopathic Parkinson's disease (PD), we compared, in postmortem striatum of 12 patients with PD and 10 matched controls, levels of five different DA neuronal markers. These markers included DA itself, three different estimates of the density of the DA transporter (DAT) ([3H])GBR 12,935 and [3H]WIN 35,428 binding; DAT protein immunoreactivity), and one estimate of the vesicular monoamine transporter (VMAT2; [3H]DTBZ binding). Striatal levels of all examined DA markers in PD were significantly intercorrelated. However, the magnitude of loss relative to controls was unequal (DAT protein = DA > [3H]WIN 35,428 > [3H]DTBZ > [3H]GBR 12, 935), with the differences more marked in the severely affected putamen. The less severe reduction of binding of the DAT/VMAT2 radioligands relative to DA and DAT protein could be explained by differential regulation/degeneration of different DA nerve terminal components or lack of specificity of the radioligands for the DA neuron. These postmortem data may help in interpretation of in vivo neuroimaging studies in PD in which only one radioligand is routinely employed.