RESUMO
We performed a placebo-controlled cross-over trial of riluzole (100 mg b.i.d.) in 10 patients with probable multiple system atrophy (MSA) administering riluzole and placebo for 4 weeks each with a 4-week washout period. Outcome measures evaluated short-term anti-Parkinsonian effects using the Unified Parkinson's Disease Rating Scale (UPDRS) subscales (UPDRS-II, activities of daily living; UPDRS-III, motor examination; sum of UPDRS-II and -III) before and at the end of each treatment phase. Delta values were calculated by subtracting the UPDRS scores measured at the end of each treatment arm from those before onset of each medication phase. Riluzole was generally well tolerated. There were no significant anti-Parkinsonian effects of riluzole comparing the UPDRS delta values for both treatment arms using the Wilcoxon signed-rank test. It is unlikely that riluzole treatment could have clinically meaningful anti-Parkinsonian effects in MSA. A trial assessing the disease-modifying potential of riluzole in MSA is underway.
Assuntos
Atrofia de Múltiplos Sistemas/tratamento farmacológico , Riluzol/uso terapêutico , Idoso , Estudos Cross-Over , Feminino , Gastroenteropatias/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/complicações , Atrofia de Múltiplos Sistemas/epidemiologia , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Efeito Placebo , Riluzol/efeitos adversosRESUMO
We investigated neuroprotective effects of riluzole, an anti-glutamatergic agent that is FDA approved for disease-modifying therapy in amyotrophic lateral sclerosis (ALS), in an established double lesion rat model of striatonigral degeneration (SND), the neuropathological substrate of parkinsonism associated with MSA (MSA-P). Riluzole was administered prior to and consecutively for ten days following double lesion placement in the left-sided medial forebrain bundle and ipsilateral striatum. Assessment of motor behaviour using a flex field system showed a significant reduction of motor disturbance in animals with striatonigral lesions treated with riluzole compared to lesioned but untreated animals (P<0.001). DARPP-32 immunohistochemistry revealed a significant reduction of absolute striatal lesion volume in riluzole treated animals compared to lesioned but untreated animals (P<0.01). No significant difference in counts of nigral dopaminergic neurons was found in treated versus untreated double-lesioned animals. The results of our study indicate that riluzole mediates neuroprotective effects in the double lesion rat model of MSA-P. Whether riluzole also protects autonomic and cerebellar pathways that are frequently affected in MSA remains to be determined. Nonetheless, our study is the first to provide an experimental rationale for exploring possible neuroprotective effects of riluzole in MSA.
Assuntos
Corpo Estriado/efeitos dos fármacos , Atrofia de Múltiplos Sistemas/tratamento farmacológico , Degeneração Neural/tratamento farmacológico , Neurônios/efeitos dos fármacos , Transtornos Parkinsonianos/tratamento farmacológico , Riluzol/administração & dosagem , Animais , Biomarcadores/metabolismo , Corpo Estriado/lesões , Corpo Estriado/fisiopatologia , Denervação , Modelos Animais de Doenças , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Masculino , Feixe Prosencefálico Mediano/lesões , Feixe Prosencefálico Mediano/fisiopatologia , Feixe Prosencefálico Mediano/cirurgia , Movimento/efeitos dos fármacos , Movimento/fisiologia , Atrofia de Múltiplos Sistemas/metabolismo , Atrofia de Múltiplos Sistemas/fisiopatologia , Degeneração Neural/fisiopatologia , Degeneração Neural/prevenção & controle , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/efeitos adversos , Neurotoxinas , Oxidopamina , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/fisiopatologia , Ácido Quinolínico , Ratos , Ratos Wistar , Riluzol/efeitos adversos , Substância Negra/lesões , Substância Negra/fisiopatologia , Substância Negra/cirurgia , Resultado do TratamentoRESUMO
The present multidisciplinary study examined nigrostriatal dopamine and striatal amino acid transmission in the R6/1 line of transgenic Huntington's disease (HD) mice expressing exon 1 of the HD gene with 115 CAG repeats. Although the number of tyrosine hydroxylase-positive neurons was not reduced and nigrostriatal connectivity remained intact in 16-week-old R6/1 mice, the size of tyrosine hydroxylase-positive neurons in the substantia nigra was reduced by 15%, and approximately 30% of these cells exhibited aggregated huntingtin. In addition, using in vivo microdialysis, we found that basal extracellular striatal dopamine levels were reduced by 70% in R6/1 mice compared to their wild-type littermates. Intrastriatal perfusion with malonate in R6/1 mice resulted in a short-lasting, attenuated increase in local dopamine release compared to wild-type mice. Furthermore, the size of the malonate-induced striatal lesion was 80% smaller in these animals. Taken together, these findings suggest that a functional deficit in nigrostriatal dopamine transmission may contribute to the behavioral phenotype and the resistance to malonate-induced neurotoxicity characteristic of R6/1 HD mice.
Assuntos
Corpo Estriado/patologia , Doença de Huntington/genética , Doença de Huntington/patologia , Estilbamidinas , Substância Negra/patologia , Animais , Contagem de Células , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Feminino , Corantes Fluorescentes , Malonatos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Transgênicos , Microdiálise , Vias Neurais/patologia , Neurônios/enzimologia , Neurônios/patologia , Substância Negra/metabolismo , Tirosina 3-Mono-Oxigenase/análiseRESUMO
A transgenic mouse model of Huntington's disease (R6/1 and R6/2 lines) expressing exon 1 of the HD gene with 115-150 CAG repeats resisted striatal damage following injection of quinolinic acid and other neurotoxins. We examined whether excitotoxin resistance characterizes mice with mutant huntingtin transgenes. In a new transgenic mouse with 3 kb of mutant human huntingtin cDNA with 18, 46, or 100 CAG repeats, we found no change in susceptibility to intrastriatal injections of the excitotoxin quinolinic acid, compared to wild-type littermates. The new transgenic mice were injected with the same dose of quinolinic acid (30 nmol) as had been the R6 mice. Our findings highlight the importance of studying pathogenetic mechanisms in different transgenic models of a disease.
Assuntos
Corpo Estriado/efeitos dos fármacos , Doença de Huntington/induzido quimicamente , Doenças Neurodegenerativas/induzido quimicamente , Neurônios/efeitos dos fármacos , Ácido Quinolínico , Animais , Contagem de Células , Morte Celular , Corpo Estriado/patologia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Heterozigoto , Humanos , Doença de Huntington/complicações , Doença de Huntington/genética , Doença de Huntington/patologia , Camundongos , Camundongos Transgênicos , Microinjeções , Doenças Neurodegenerativas/complicações , Doenças Neurodegenerativas/patologia , Neurônios/patologia , Ácido Quinolínico/administração & dosagem , Especificidade da Espécie , Expansão das Repetições de TrinucleotídeosRESUMO
Huntington's disease is an autosomal dominant hereditary neurodegenerative disorder characterized by severe striatal cell loss. Dopamine (DA) has been suggested to play a role in the pathogenesis of the disease. We have previously reported that transgenic mice expressing exon 1 of the human Huntington gene (R6 lines) are resistant to quinolinic acid-induced striatal toxicity. In this study we show that with increasing age, R6/1 and R6/2 mice develop partial resistance to DA- and 6-hydroxydopamine-mediated toxicity in the striatum. Using electron microscopy, we found that the resistance is localized to the cell bodies and not to the neuropil. The reduction of dopamine and cAMP regulated phosphoprotein of a molecular weight of 32 kDa (DARPP-32) in R6/2 mice does not provide the resistance, as DA-induced striatal lesions are not reduced in size in DARPP-32 knockout mice. Neither DA receptor antagonists nor a N-methyl-d-aspartate (NMDA) receptor blocker reduce the size of DA-induced striatal lesions, suggesting that DA toxicity is not dependent upon DA- or NMDA receptor-mediated pathways. Moreover, superoxide dismutase-1 overexpression, monoamine oxidase inhibition and the treatment with the free radical scavenging spin-trap agent phenyl-butyl-tert-nitrone (PBN) also did not block DA toxicity. Levels of the antioxidant molecules, glutathione and ascorbate were not increased in R6/1 mice. Because damage to striatal neurons following intrastriatal injection of 6-hydroxydopamine was also reduced in R6 mice, a yet-to-be identified antioxidant mechanism may provide neuroprotection in these animals. We conclude that striatal neurons of R6 mice develop resistance to DA-induced toxicity with age.
Assuntos
Dopamina/genética , Resistência a Medicamentos/genética , Éxons/genética , Doença de Huntington/genética , Neostriado/efeitos dos fármacos , Proteínas do Tecido Nervoso , Neurotoxinas/genética , Oxidopamina/toxicidade , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Animais , Ácido Ascórbico/metabolismo , Dopamina/metabolismo , Dopamina/toxicidade , Fosfoproteína 32 Regulada por cAMP e Dopamina , Relação Dose-Resposta a Droga , Glutationa/metabolismo , Doença de Huntington/metabolismo , Doença de Huntington/fisiopatologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos/genética , Camundongos Transgênicos/metabolismo , Microscopia Eletrônica , Neostriado/metabolismo , Neostriado/patologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/ultraestrutura , Neurotoxinas/metabolismo , Neurotoxinas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Fosfoproteínas/deficiência , Fosfoproteínas/genética , Ácido Quinolínico/toxicidade , Degeneração Retrógrada/induzido quimicamente , Degeneração Retrógrada/patologia , Degeneração Retrógrada/fisiopatologia , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Substância Negra/patologia , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1 , Ácido Úrico/metabolismoRESUMO
Multiple system atrophy (MSA) is an adult-onset sporadic progressive neurodegenerative disorder of unknown etiology. It is clinically characterized by the variable combination of autonomic failure, parkinsonism, cerebellar ataxia, and pyramidal signs. The present review summarizes up-to-date knowledge on the clinical diagnosis and molecular pathology of MSA. We also review the role of additional investigations that may support a clinical diagnosis of MSA. Finally, we briefly discuss the management of MSA, focusing on possible future therapeutic strategies.
Assuntos
Atrofia de Múltiplos Sistemas/diagnóstico , Sistema Nervoso Central/patologia , Diagnóstico Diferencial , Humanos , Atrofia de Múltiplos Sistemas/terapiaRESUMO
Intrastriatal injection of 3-nitropropionic acid results in secondary excitotoxic local damage and retrograde neuronal cell loss in substantia nigra pars compacta, thus mimicking salient features of striatonigral degeneration, the core pathology underlying Parkinsonism associated with multiple system atrophy. We used 3-nitropropionic acid to create a rat model of advanced striatonigral degeneration in order to assess the effects of embryonic allografts upon rotational and complex-motor behavioural abnormalities. Following stereotaxic intrastriatal administration of 500nmol 3-nitropropionic acid in male Wistar rats we observed consistent amphetamine- and apomorphine-induced ipsiversive rotation. Furthermore, there were marked deficits of contralateral paw reaching. Subsequently, animals received intrastriatal implantations of either E14 mesencephalic or striatal or mixed embryonic cell suspensions. In addition, one group received sham injections. Grafted rats were followed for up to 21 weeks and repeated behavioural tests were obtained during this period. Drug-induced rotation asymmetries and complex motor deficits measured by paw reaching tests were not compensated by embryonic grafts. Persistence of drug-induced rotations and of paw reaching deficits following transplantation probably reflects severe atrophy of adult striatum, additional nigral degeneration as well as glial demarcation of embryonic grafts. We suggest that dopamine rich embryonic grafts fail to induce functional recovery in a novel 3-nitropropionic acid rat model of advanced striatonigral degeneration (multiple system atrophy).
Assuntos
Transplante de Tecido Encefálico/fisiologia , Transplante de Tecido Fetal/fisiologia , Atividade Motora/fisiologia , Atrofia de Múltiplos Sistemas/fisiopatologia , Atrofia de Múltiplos Sistemas/cirurgia , Neurônios/fisiologia , Animais , Apomorfina/farmacologia , Corpo Estriado/patologia , Dextroanfetamina/farmacologia , Modelos Animais de Doenças , Humanos , Masculino , Mesencéfalo , Atividade Motora/efeitos dos fármacos , Atrofia de Múltiplos Sistemas/patologia , Neurônios/patologia , Neurônios/transplante , Neurotoxinas , Nitrocompostos , Propionatos , Desempenho Psicomotor/efeitos dos fármacos , Desempenho Psicomotor/fisiologia , Ratos , Ratos Wistar , Substância Negra/patologia , Fatores de TempoAssuntos
Encéfalo/patologia , Prazosina/análogos & derivados , Receptores Adrenérgicos alfa 1/fisiologia , Síndrome de Shy-Drager/patologia , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Antiparkinsonianos/farmacologia , Encéfalo/metabolismo , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Modelos Animais de Doenças , Dopaminérgicos/farmacologia , Epilepsia Tônico-Clônica/metabolismo , Epilepsia Tônico-Clônica/patologia , Epilepsia Tônico-Clônica/fisiopatologia , Humanos , Corpos de Inclusão/metabolismo , Corpos de Inclusão/patologia , Levodopa/farmacologia , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/fisiopatologia , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/fisiopatologia , Prazosina/farmacologia , Receptores Adrenérgicos alfa 1/genética , Receptores Adrenérgicos alfa 1/metabolismo , Síndrome de Shy-Drager/metabolismo , Síndrome de Shy-Drager/fisiopatologia , Síndrome , Sinucleínas , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Animal models reproducing early stages of striatonigral degeneration (SND), the core pathology underlying parkinsonism in multiple system atrophy, are lacking. We have developed a new model of early-stage SND by using a simultaneous unilateral administration of quinolinic acid (QA) and 6-hydroxydopamine (6-OHDA) into the putaminal equivalent of the rat striatum. Spontaneous and drug-induced behavior, thigmotactic scanning, paw reaching deficits, and histopathology were studied in rat groups: group 1 (control), group 2 (QA), group 3 (6-OHDA), and group 4 (QA + 6-OHDA). The double toxin administration resulted in reduction of the spontaneous and the amphetamine-induced ipsiversive bias in the 6-OHDA group and in a reduction of the apomorphine-induced ipsiversive rotations in the QA group. Simultaneous QA and 6-OHDA also reduced the thigmotactic bias observed in the 6-OHDA rats. Combined toxin elicited a nonsignificant contralateral deficit in paw reaching but a significant deficit on the ipsilateral side. Histopathology revealed a significant reduction of the lesioned striatal surface (-27%) with neuronal loss and increased astrogliosis in group 4 compared to group 2, consistent with an exacerbation of QA toxicity by additional 6-OHDA. By contrast, the mean loss of the TH-positive neurons in the ipsilateral substantia nigra pars compacta (SNc) of group 4 was less marked (-15%) than in the 6-OHDA group (-36%), indicating a possible protective action of intrastriatal QA upon 6-OHDA retrograde SNc degeneration. This study shows that a combined unilateral intrastriatal administration of QA and 6-OHDA may serve as a model of early stage SND which is more suitable for early therapeutic interventions.
Assuntos
Corpo Estriado/patologia , Modelos Animais de Doenças , Doenças Neurodegenerativas/patologia , Oxidopamina , Ácido Quinolínico , Substância Negra/patologia , Animais , Comportamento Animal/efeitos dos fármacos , Contagem de Células , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/fisiopatologia , Membro Anterior , Masculino , Microinjeções , Atividade Motora/efeitos dos fármacos , Destreza Motora/efeitos dos fármacos , Atrofia de Múltiplos Sistemas/patologia , Atrofia de Múltiplos Sistemas/fisiopatologia , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/fisiopatologia , Neurônios/enzimologia , Neurônios/patologia , Oxidopamina/administração & dosagem , Ácido Quinolínico/administração & dosagem , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Substância Negra/efeitos dos fármacos , Substância Negra/fisiopatologia , Tato/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
A recombinant AAV-2 vector encoding the green fluorescent protein (gfp) under the control of the cytomegalovirus (CMV) promoter was injected into the striatum at varying antero-posterior coordinates. When the virus was delivered to the anterior part of the striatum, transduction efficiency was low and limited to the vicinity of the needle tract. In contrast, after injection into the posterior part of the striatum, in addition to a localized transduced area in the striatum, efficient and widespread transduction was observed at distance from the injection site, in the globus pallidus. In the latter case, labelled cells were also detected in the internal capsule and in the stria terminalis. The number of transduced cells in the striatum increased up to I month and then decreased whereas in the globus pallidus, transduction was maximal as early as 2 weeks post-injection. In the striatum and in the globus pallidus, the labelled cells had a neuron-like morphology. In contrast, in the internal capsule, labelled cells had a glial-like morphology.
Assuntos
Corpo Estriado/fisiologia , Dependovirus , Vetores Genéticos , Globo Pálido/fisiologia , Neurônios/fisiologia , Animais , Linhagem Celular , Citomegalovirus/genética , Técnicas de Transferência de Genes , Genes Reporter , Proteínas de Fluorescência Verde , Humanos , Proteínas Luminescentes/análise , Proteínas Luminescentes/genética , Masculino , Neuroglia/fisiologia , Regiões Promotoras Genéticas , Ratos , Ratos Sprague-Dawley , Transfecção/métodos , TropismoRESUMO
This study characterizes paw reaching, stepping and balance abnormalities in a double lesion rat model of striatonigral degeneration, the core pathology underlying levodopa unresponsive parkinsonism associated with multiple system atrophy. Extensive unilateral nigral or striatal lesions induced by 6-hydroxydopamine or quinolinic acid, respectively, produced a similarly marked contralateral paw reaching deficit without further deterioration following a secondary (complementary) lesion of ipsilateral striatum or substantia nigra. Contralateral stepping rates were reduced by unilateral 6-hydroxydopamine lesions without further deterioration following the secondary striatal lesion. In contrast, initial unilateral striatal quinolinic acid injections induced bilateral stepping deficits that significantly worsened contralaterally following the secondary nigral lesion. Contralateral sidefalling rates were significantly increased following primary nigral and striatal lesions. Secondary nigral but not secondary striatal lesions worsened contralateral sidefalling rates. Histological studies revealed subtotal (>90%) depletion of dopaminergic neurons in substantia nigra pars compacta and variable degrees of striatal degeneration depending on the lesion sequence. Animals pre-lesioned with 6-hydroxydopamine showed significantly larger residual striatal surface areas following the secondary striatal quinolinic acid lesion compared to animals with primary striatal quinolinic acid lesions (P<0.001). These findings are in line with previous experimental studies demonstrating that striatal dopamine depletion confers neuroprotection against subsequent excitotoxic injury. Whether loss of dopaminergic neurons protects against the striatal disease process occurring in multiple system atrophy (Parkinson-type) remains to be elucidated. In summary, this is the first experimental study to investigate spontaneous motor behaviour in a unilateral double lesion rat model. Our observations are consistent with a complex interaction of nigral and striatal lesions producing distinct behavioural and histological changes depending on the lesion sequence. Tests of forelimb akinesia and complex motor behaviour appear to provide a reliable tool that will be helpful for monitoring the effects of interventional strategies such as embryonic neuronal transplantation in the rat model of striatonigral degeneration.
Assuntos
Modelos Animais de Doenças , Atividade Motora/fisiologia , Degeneração Estriatonigral/metabolismo , Animais , Corpo Estriado/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Atrofia de Múltiplos Sistemas/induzido quimicamente , Atrofia de Múltiplos Sistemas/metabolismo , Oxidopamina , Ácido Quinolínico , Ratos , Ratos Wistar , Degeneração Estriatonigral/induzido quimicamente , Substância Negra/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
The effects of embryonic neural transplantation in experimental models of neurodegenerative disorders are commonly assessed by behavioral tests and postmortem neurochemical or anatomical analysis. The purpose of the present study was to evaluate embryonic neuronal grafts in a novel rat model of multiple system atrophy (MSA) with the help of in vivo magnetic resonance imaging (MRI) and to correlate imaging with histological parameters. Striatonigral double lesions were created in male Wistar rats by unilateral intrastriatal injection of 3-nitropropionic acid (3-NP). Seven weeks following lesion surgery animals were divided into four transplantation groups receiving either pure mesencephalic, pure striatal, mesencephalic-striatal cografts, or sham grafts. In vivo structural imaging was performed 21 weeks after transplantation using a whole body 1.5 Tesla MR scanner. The imaging protocol comprised T2-weighted TSE and T1-weighted TIR sequences. Immunohistochemistry using DARPP-32 as striatal marker and tyrosinhydroxylase as marker for nigral neurons was performed for correlation analysis of imaging and histological parameters. The sensitivity of graft detection by in vivo MRI was 100%. The graft tissue was clearly demarcated from the remaining striatal tissue in both T2- and T1-weighted sequences. Morphometrically, cross-sectional areas of the grafts and spared intact striatum as defined by immunohistochemistry correlated significantly with measurements obtained by in vivo MRI. In conclusion, we were able to evaluate in vivo both lesion-induced damage and graft size in a 3-NP rat model of MSA using a conventional whole body 1.5 Tesla MRI scanner. Additionally, we obtained an excellent correlation between MRI and histological measurements.
Assuntos
Transplante de Tecido Encefálico , Transplante de Tecido Fetal , Imageamento por Ressonância Magnética/métodos , Degeneração Estriatonigral/patologia , Animais , Encéfalo/patologia , Ventrículos Cerebrais/patologia , Imuno-Histoquímica , Masculino , Mesencéfalo/transplante , Neostriado/patologia , Ratos , Ratos Wistar , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
In the present experiment we studied the ability of embryonic striatal grafts to protect against striatal quinolinic acid (QA)-induced excitotoxicity in a previously established double lesion rat model of striatonigral degeneration (SND), the neuropathological substrate of parkinsonism associated with multiple system atrophy (MSA). Male Wistar rats received under halothane inhalation anesthesia a 6-hydroxydopamine 6-OHDA injection into the left medial forebrain bundle. Four to 5 weeks later apomorphine-induced rotation behavior was tested. Rats were divided into two treatment groups receiving either embryonic striatal cell suspensions or sham injections. Apomorphine-induced rotation behavior was retested 2 and 4 weeks after the grafting procedure. Following the rotation test animals of the striatal and sham graft group received a stereotaxic injection of 150 nmol QA. Again rotation behavior was assessed 2 and 4 weeks after lesioning. Brains were then processed to dopamine reuptake ([(3)H]mazindol), dopamine D1 ([(3)H]SCH23390), and D2 ([(3)H]spiperone) receptor autoradiography. Gliosis was detected using [(3)H]PK11195, a marker for peripheral benzodiazepine binding sites. Behavioral and autoradiographic analysis failed to show striatal protection in 6-OHDA prelesioned animals receiving embryonic striatal grafts. These findings indicate that beneficial protective effects of striatal grafts implanted into host striatum prior to excitotoxic insults are abolished in the presence of severe dopaminergic denervation. Our present results are relevant to future applications of neural grafting in MSA-SND.
Assuntos
Transplante de Tecido Encefálico , Corpo Estriado/transplante , Transplante de Tecido Fetal , Atrofia de Múltiplos Sistemas/cirurgia , Animais , Apomorfina/farmacologia , Autorradiografia , Ligação Competitiva , Corpo Estriado/embriologia , Corpo Estriado/patologia , Modelos Animais de Doenças , Dopamina/deficiência , Agonistas de Dopamina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina , Masculino , Proteínas de Membrana/metabolismo , Atividade Motora/efeitos dos fármacos , Atrofia de Múltiplos Sistemas/patologia , Proteínas do Tecido Nervoso/metabolismo , Oxidopamina , Ácido Quinolínico , Ratos , Ratos Wistar , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Degeneração Estriatonigral/patologia , Degeneração Estriatonigral/cirurgia , Falha de TratamentoRESUMO
Multiple system atrophy (MSA) is a neurodegenerative disorder that occurs sporadically and causes parkinsonism, cerebellar, autonomic, urinary, and pyramidal dysfunction in many combinations. Progressive L-dopa-unresponsive parkinsonism due to underlying striatonigral degeneration dominates the clinical syndrome in the majority of cases (MSA-P subtype). MSA-P is characterized pathologically by degenerative changes in somatotopically related areas of the substantia nigra pars compacta and of the putamen. Furthermore, oligodendroglial cytoplasmic inclusions (GCIs) are observed throughout the cortico-striato-pallidocortical loops and may contribute to the basal ganglia dysfunction. Neurotransplantation strategies are of potential interest in this disease, which causes marked and early disability and dramatically reduces life expectancy. A number of experimental MSA-P models have been employed to evaluate neurotransplantation approaches. Sequential nigral and striatal lesions using 6-hydroxydopamine and quinolinic acid (double toxin-double lesion approach) indicate that apomorphine-induced contralateral rotation is abolished by a secondary striatal lesion. Intrastriatal injection of mitochondrial respiratory chain toxins produces secondary excitotoxic striatal lesions combined with retrograde nigral degeneration and therefore provides an alternative single toxin-double lesion approach. Neurotransplantation in MSA-P animal models has been used to improve functional deficits by replacing lost nigral and/or striatal circuitry (neuroregenerative approach). The available data indicate that embryonic mesencephalic grafts alone or combined with striatal grafts partially reverse drug-induced rotation asymmetries without improving deficits of complex motor function. The potential neuroprotective efficacy of embryonic striatal grafts against striatal excitotoxicity is presently under investigation in the double toxin-double lesion MSA-P rat model. Anecdotal clinical evidence in one MSA-P patient misdiagnosed as Parkinson's disease indicates that embryonic mesencephalic grafts produce incomplete clinical benefit. Striatal co-grafts may increase functional improvement. Further experimental studies are required prior to the clinical application of embryonic neurotransplantation in MSA-P. Future research strategies should explore the effect of neurotransplantation in partial MSA-P rat models with less severe nigral and striatal degeneration, the feasibility of a primate model closely mimicking the human disease, and the replication of oligodendroglial dysfunction.
Assuntos
Transplante de Tecido Encefálico , Transplante de Tecido Fetal , Atrofia de Múltiplos Sistemas/cirurgia , Animais , Modelos Animais de Doenças , Humanos , Atrofia de Múltiplos Sistemas/etiologia , Atrofia de Múltiplos Sistemas/fisiopatologia , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/fisiopatologia , Transtornos Parkinsonianos/cirurgia , RatosRESUMO
The influence of embryonic mesencephalic, striatal and mesencephalic/striatal co-grafts on amphetamine- and apomorphine-induced rotation behaviour was assessed in a rat model of multiple system atrophy/striatonigral degeneration type using dopamine D1 ([3H]SCH23390) and D2 ([3H]spiperone) receptor and dopamine re-uptake ([3H]mazindol) autoradiography. Male Wistar rats subjected to a sequential unilateral 6-hydroxydopamine lesion of the medial forebrain bundle followed by a quinolinic acid lesion of the ipsilateral striatum were divided into four treatment groups, receiving either mesencephalic, striatal, mesencephalic/striatal co-grafts or sham grafts. Amphetamine- and apomorphine-induced rotation behaviour was recorded prior to and up to 10 weeks following transplantation. 6-Hydroxydopamine-lesioned animals showed ipsiversive amphetamine-induced and contraversive apomorphine-induced rotation behaviour. Amphetamine-induced rotation rates persisted after the subsequent quinolinic acid lesion, whereas rotation induced by apomorphine was decreased. In 11 of 14 animals receiving mesencephalic or mesencephalic/striatal co-grafts, amphetamine-induced rotation scores were decreased by >50% at the 10-week post-grafting time-point. In contrast, only one of 12 animals receiving non-mesencephalic (striatal or sham) grafts exhibited diminished rotation rates at this time-point. Apomorphine-induced rotation rates were significantly increased following transplantation of mesencephalic, striatal or sham grafts. The largest increase of apomorphine-induced rotation rates approaching post-6-hydroxydopamine levels were observed in animals with striatal grafts. In contrast, in the co-graft group, there was no significant increase of apomorphine-induced rotation compared to the post-quinolinic acid time-point. Morphometric analysis revealed a 63-74% reduction of striatal surface areas across the treatment groups. Striatal [3H]mazindol binding on the lesioned side (excluding the demarcated graft area) revealed a marked loss of dopamine re-uptake sites across all treatment groups, indicating missing graft-induced dopaminergic re-innervation of the host. In eight (73%) of the 11 animals with mesencephalic grafts and reduced amphetamine-induced circling, discrete areas of [3H]mazindol binding ("hot spots") were observed, indicating graft survival. Dopamine D1 and D2 receptor binding was preserved in the remaining lesioned striatum irrespective of treatment assignment, except for a significant reduction of D2 receptor binding in animals receiving mesencephalic grafts. "Hot spots" of dopamine D1 and D2 receptor binding were observed in 10 (83%) and nine (75%) of 12 animals receiving striatal grafts or co-grafts, consistent with survival of embryonic primordial striatum grafted into a severely denervated and lesioned striatum. Our study confirms that functional improvement may be obtained from embryonic neuronal grafts in a double-lesion rat model of multiple system atrophy/striatonigral degeneration type. Co-grafts appear to be required for reversal of both amphetamine- and apomorphine-induced rotation behaviour in this model. We propose that the partial reversal of amphetamine-induced rotation asymmetry in double-lesioned rats receiving mesencephalic or mesencephalic/striatal co-grafts reflects non-synaptic graft-derived dopamine release. The changes of apomorphine-induced rotation following transplantation are likely to reflect a complex interaction of graft- and host-derived striatal projection pathways and basal ganglia output nuclei. Further studies in a larger number of animals are required to determine whether morphological parameters and behavioural improvement in the neurotransplantation multiple system atrophy rat model correlate.
Assuntos
Transplante de Tecido Encefálico , Corpo Estriado/transplante , Dopamina/metabolismo , Transplante de Tecido Fetal , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Substância Negra/transplante , Anfetamina/metabolismo , Anfetamina/farmacologia , Animais , Apomorfina/farmacologia , Atrofia , Autorradiografia , Comportamento Animal/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Agonistas de Dopamina/farmacologia , Inibidores da Captação de Dopamina/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Masculino , Mazindol/metabolismo , Mazindol/farmacologia , Degeneração Neural/induzido quimicamente , Degeneração Neural/metabolismo , Neurônios/química , Neurônios/metabolismo , Oxidopamina , Ácido Quinolínico , Ratos , Ratos Wistar , Receptores de Dopamina D1/análise , Receptores de Dopamina D2/análise , Rotação , Substância Negra/metabolismo , Substância Negra/patologia , Simpatolíticos , TrítioRESUMO
Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) are increasingly recognized as alpha-synucleinopathies, i.e. neurodegenerative disorders that share a common subcellular pathology characterized by alpha-synuclein abnormal aggregation. In the present review we focus on depression in alpha-synucleinopathies, discussing epidemiological, pathophysiological and treatment aspects of this frequently disabling clinical feature which may occur in PD, DLB and MSA alike.
Assuntos
Transtorno Depressivo , Doença por Corpos de Lewy/psicologia , Atrofia de Múltiplos Sistemas/psicologia , Proteínas do Tecido Nervoso/metabolismo , Doença de Parkinson/psicologia , Animais , Antidepressivos/uso terapêutico , Encéfalo/fisiopatologia , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/epidemiologia , Transtorno Depressivo/fisiopatologia , Diagnóstico Diferencial , Humanos , Prevalência , Sinucleínas , alfa-SinucleínaRESUMO
Multiple system atrophy of the striatonigral degeneration (MSA-SND) type is increasingly recognized as major cause of neurodegenerative parkinsonism. Due to combined degeneration of substantia nigra pars compacta (SNC) and of striatum, antiparkinsonian therapy based on levodopa substitution eventually fails in more than 90% of patients. Animal models of MSA-SND are urgently required as test-bed for the evaluation of novel therapeutic interventions in this disorder such as neurotrophic factor delivery and neuronal transplantation. A number of well established rodent and primate models of Parkinson's (PD) and Huntington's (HD) disease replicate either nigral ("PD-like") or striatal ("HD-like") pathology and may therefore provide a useful baseline for the development of MSA-SND models. Previous attempts to mimick MSA-SND pathology in rodents have included sequential injections of 6-hydroxydopamine (6OHDA) and quinolinic acid (QA) into medial forebrain bundle and ipsilateral striatum, respectively ("double toxin-double lesion" approach). Preliminary evidence in rodents subjected to such lesions indicates that embryonic transplantation may partially reverse behavioural abnormalities. Intrastriatal injections of mitochondrial toxins such as 3-nitropropionic acid (3NP) and 1-methyl-4-phenylpyridinium (MPP+) in rodents result in (secondary) excitotoxic striatal lesions and subtotal neuronal degeneration of ipsilateral SNC, thus producing MSA-SND-like pathology by a simplified "single toxin-double lesion" approach. Comparative studies of human SND pathology and rodent striatonigral lesions are required in order to determine the rodent model(s) most closely mimicking the human disease process.