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Previous issue date: 2014-09-26 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico - CNPq / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / A Doen?a de Parkinson (DP) est? associada a sintomas motores e ? perda de neur?nios dopamin?rgicos na via nigroestriatal. A prote?na alfa-sinucle?na ? o principal componente dos corpos de Lewy, marcadores biol?gicos da doen?a, e tem sido associada a casos de Parkinson heredit?rio. Recentemente, a estimula??o da medula espinhal (EME) tem se mostrado um m?todo de neuromodula??o efetivo em aliviar os sintomas parkinsonianos em modelos animais e pacientes humanos da DP. Nesse projeto, caracterizamos os efeitos motores e eletrofisiol?gicos da express?o de alfa-sinucle?na na subst?ncia nigra de ratos. Al?m disso, investigamos os efeitos da administra??o de AMPT, L-dopa e da aplica??o de EME nesse modelo. M?todo: Ratos Sprague-Dawley receberam inje??o unilateral de vetor viral vazio ou para expressar alfa-sinucle?na na subst?ncia nigra e foram avaliados semanalmente na tarefa do campo aberto e do cilindro. Um grupo separado de animais implantados com matrizes bilaterais de eletrodos no c?rtex motor e no estriado foram registrados semanalmente no campo aberto, durante as sess?es de EME e nos experimentos farmacol?gicos. Resultados: A express?o de alfa-sinucle?na resultou em assimetria motora, observada na redu??o do uso da pata contralateral na tarefa do cilindro. Os animais apresentaram aumento da atividade de potencial de campo local estriatal em beta ap?s tr?s e quatro semanas de express?o de alfa-sinucle?na, que desapareceu a partir da quinta semana. A administra??o de AMPT resultou em um quadro parkinsoniano severo, com redu??o da atividade locomotora e significativo aparecimento do pico de atividade oscilat?ria em beta no estriado e no cortex desse modelo. A EME mostrou-se efetiva em aliviar a assimetria motora em longo prazo, mas n?o reduziu as oscila??es corticostriatais de baixa frequ?ncia observadas 24 hs ap?s a administra??o de AMPT. Essas oscila??es foram atenuadas pela administra??o de L-dopa que, de forma semelhante ? EME, n?o foi efetiva em restaurar a atividade locomotora dos animais durante esse quadro de deple??o severa de dopamina. Discuss?o: O modelo alfa-sinucle?na da DP reproduz o preju?zo motor e a condi??o progressiva do processo neurodegenerativo. N?s demonstramos, pela primeira vez, que esse modelo apresenta tamb?m aumento da atividade corticostriatal oscilat?ria na banda beta compat?vel com as caracter?sticas da doen?a e que a EME tem efeito terap?utico sobre o sintoma motor desse modelo. / Parkinson disease (PD) is associated with motor symptoms and dopaminergic cell loss in the nigrostriatal pathway. Alpha-synuclein is the major component of the Lewy bodies, the biological hallmarks of disease, and has been associated with familial cases of PD. Recently, the spinal cord stimulation (SCS) showed to be effective to alleviate the Parkinson symptoms in animal models and human patients. In this project, we characterized the motor and electrophysiological effects of alpha-synuclein overexpression in the substantia nigra of rats. We further investigated the effects of spinal electrical stimulation, AMPT and L-dopa administration in this model. Method: Sprague-Dawley rats were injected with empty viral vector or the vector carrying the gene for alpha-synuclein in the substantia nigra, and were tested weekly for 10 weeks in the open field and cylinder tests. A separated group of animals implanted with bilateral electrode arrays in the motor cortex and the striatum were recorded in the open field, during the SCS sessions and the pharmacological experiments. Results: Alpha-synuclein expression resulted in motor asymmetry, observed as the reduction in use of contralateral forepaw in the cylinder test. Animals showed an increase of local field potential activity in beta band three and four weeks after the virus injection, that was not evident after the 5th week. AMPT resulted in a sever parkinsonian state, with reduction in the locomotor activity and significant peak of oscillatory activity in cortex and striatum. SCS was effective to alleviate the motor asymmetry at long term, but did not reduce the corticostriatal low frequency oscillations observed 24 hs after the AMPT administration. These oscillations were attenuated by L-dopa that, even as SCS, was not effective to restore the locomotor activity during the severe dopaminergic depletion period. Discussion: The alpha-synuclein model reproduces the motor impairment and the progressive neurodegenerative process of PD. We demonstrated, by the first time, that this model also presents the increase in low frequency oscillatory activity in the corticostriatal circuit, compatible with parkinsonian condition; and that SCS has a therapeutic effect on motor symptom of this model.
| Identifer | oai:union.ndltd.org:IBICT/oai:repositorio.ufrn.br:123456789/19589 |
| Date | 26 September 2014 |
| Creators | Brys, Ivani |
| Contributors | 25715330297, http://lattes.cnpq.br/1402289786010170, Godeiro J?nior, Clecio de Oliveira, 00931137497, http://lattes.cnpq.br/6861574542099266, Ara?jo, Mariana Ferreira Pereira de, 13556119897, http://lattes.cnpq.br/8680061079519776, Moioli, Renan Cipriano, 30911587802, http://lattes.cnpq.br/3898958813303048, Fuentes, R?mulo, Pereira J?nior, Antonio |
| Publisher | Universidade Federal do Rio Grande do Norte, PROGRAMA DE P?S-GRADUA??O EM PSICOBIOLOGIA, UFRN, Brasil |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/doctoralThesis |
| Source | reponame:Repositório Institucional da UFRN, instname:Universidade Federal do Rio Grande do Norte, instacron:UFRN |
| Rights | info:eu-repo/semantics/openAccess |
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