Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Deep brain stimulation (DBS) has emerged as a potential intervention for treatment-resistant tardive dyskinesia (TD). Despite promising case reports, no consensus exists regarding optimal stimulation parameters, neuroanatomical target for DBS in TD, or mechanisms underlying its anti-dyskinetic effects. We used vacuous chewing movements (VCMs) in rats treated chronically with haloperidol (HAL) as a TD model to address some of these issues. We show that acute DBS applied to the subthalamic nucleus (STN) or the entopeduncular nucleus (EPN) suppresses VCMs without affecting locomotor activity. Using immediate early gene mapping with zif268 as an index of neuronal activity, we found that STN-DBS induced decreases in activity throughout the basal ganglia, whereas EPN-DBS increased activity in projection regions. While chemical inactivation of the STN or EPN with the GABAA agonist muscimol also suppressed VCMs, muscimol infusion did not mimic the changes in neuronal activity induced by DBS, suggesting that DBS is not equivalent to functional inactivation. We next examined the contribution of serotonin (5-HT) and dopamine (DA) to the anti-dyskinetic effects of DBS. Decreasing 5-HT transmission pharmacologically or with serotonergic lesions decreased VCMs. Using microdialysis and zif268 mapping, we determined that STN- but not EPN-DBS decreased 5-HT release and activity of raphe neurons. However, when the decrease in 5-HT induced by STN-DBS was prevented by pre-treating rats with fluoxetine or fenfluramine, we found that decreasing 5-HT is not necessary for the anti-dyskinetic effects of DBS. STN-DBS transiently increased striatal DA release in intact rats only, whereas EPN-DBS had no effect on DA release. Moreover, pharmacologically elevating DA levels did not suppress VCMs. Together these findings lead us to conclude that increased DA release does not contribute to the anti-dyskinetic effects of DBS. Finally, we compared depressive- and anxiety-like behaviours induced by chronic DBS of the EPN and STN, since adverse psychiatric effects of DBS have become a significant clinical concern. STN-DBS but not EPN-DBS induced depressive-like behaviour in a learned helplessness task. We established that the chronic HAL VCM model preparation may be used to explore mechanisms underlying anti-dyskinetic and psychiatric effects of DBS, and provided the first investigations into these mechanisms.

Thesis (MSc)--University of Stellenbosch, 2007. / Bibliography. Also available via the Internet.

FundaÃÃo de Amparo à Pesquisa do Estado do Cearà / CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / Sleep disturbances are common in Parkinsonâs disease (PD) and are associated with worse quality of life in those patients. Insomnia described as difficulty initiating and maintaining sleep, excessive daytime sleepiness and abnormal behavior during sleep are some of the most frequently described symptoms. Melatonin has been shown to improve sleep in many other clinical conditions. The main objective of this study was to evaluate the effect of four weeks melatonin administration, 3 mg one hour before bedtime, on sleep and motor disability in PD. This was a randomized, double blind placebo controlled study. We have studied 18 patients of either gender with a clinical diagnosis of PD (Hoehn and Yahr I to III). Patients were evaluated before and after treatment with the Pittsburgh sleep quality index questionnaire (PSQI), with the Epworth sleepiness scale (ESS) with the Unified ParkinsonÂs disease rating scale (UPDRS) and with all night polysomnography. Melatonin treatment did not influence motor disability as informed by the patient (UPDRS II, p=0,58) or by the examiner (UPDRS III, p=0,94). Also, complications related to treatment were not different after melatonin administration (UPDRS IV, p=0,897). Excessive daytime sleepiness as evaluated by the ESS was not modified by melatonin treatment (p=0,84). Sleep measures evaluated by polysomnography were also not altered by melatonin treatment. Patients treated with melatonin showed improvement in sleep measures as evaluated by the PSQI (ANCOVA, p=0,03). In summary, 3 mg of melatonin, one hour before bedtime significantly improved quality of sleep and was not associated with worsening of motor disability in PD. / DistÃrbios do sono sÃo comuns na doenÃa de Parkinson (DP) e estÃo associados a piora da qualidade de vida nesses pacientes. Os sintomas mais freqÃentemente relatados sÃo a dificuldade de iniciar e de manter o sono, sonolÃncia excessiva diurna e parassonia. A melatonina tem mostrado melhorar o sono em diversas condiÃÃes clÃnicas. O principal objetivo desse estudo foi avaliar o uso da melatonina na dose de 3mg, durante quatro semanas, no sono e na funÃÃo motora em pacientes com DP. O estudo foi randomizado, duplo-cego, controlado com placebo e paralelo. A amostra final foi composta de dezoito pacientes, de ambos os sexos, com diagnÃstico clÃnico da DP ( Hoehn e Yahr I a III ). Os pacientes foram avaliados antes e apÃs o tratamento pelo o Ãndice de Qualidade de Sono de Pittsburgh ( IQSP ), Escala de SonolÃncia de Epworth ( ESE ), Unified Parkinson`s Disease Rating Scale ( UPDRS ) partes II, III, IV e atravÃs de polissonografia. O tratamento com a melatonina nÃo influenciou a avaliaÃÃo do desempenho motor conforme o paciente ( UPDRS II, p=0,58 ) ou conforme o examinador ( UPDRS III, p=0,94 ), apÃs quatro semanas. TambÃm nÃo houve diferenÃa quanto as complicaÃÃes motoras ( UPDRS IV, p=0,897 ). ApÃs o tratamento, nenhuma diferenÃa significativa foi observada em relaÃÃo ao estado de sonolÃncia diurna conforme avaliado pela ESE ( p=0,84 ). As medidas de sono avaliadas atravÃs de polissonografia tambÃm nÃo foram modificadas pelo o tratamento com melatonina. Os pacientes tratados com melatonina apresentaram melhora de qualidade de sono avaliada pelo IQSP (p=0,03). Em conclusÃo, a melatonina na dose de 3mg, administrada 1 hora antes de deitar, melhora a qualidade do sono em pacientes com DP e nÃo se associa a piora da funÃÃo motora nesses pacientes.

A doença de Parkinson (DP) é a segunda doença neurodegenerativa mais comum do mundo, e seu tratamento atual se baseia principalmente no uso de medicações que facilitam a transmissão dopaminérgica nos núcleos da base. A L-DOPA é a principal medicação usada no tratamento da DP, contudo seu uso crônico está associado ao surgimento de complicações motoras, como as discinesias induzidas por L-DOPA (DIL). As DIL ocorrem em cerca de 50% dos pacientes com DP que usaram LDOPA por cerca de 4 a 6 anos, e podem causar uma série de impactos negativos aos pacientes. Pela incapacidade adicional que esta complicação traz aos pacientes com DP, a definição de fatores que possam predizer o surgimento das DIL é de importância direta para o clínico que prescreve L-DOPA rotineiramente. O objetivo deste estudo foi determinar os principais fatores de risco clínicos e genéticos para o desenvolvimento de DIL em uma casuística de pacientes brasileiros com DP. Um estudo transversal foi realizado em pacientes brasileiros de dois centros (Ribeirão Preto e São Paulo) como parte do projeto \"Latin American Research Consortium on the Genetics of PD\" (LARGE-PD), incluindo apenas pacientes com DP e em uso de L-DOPA. A avaliação foi baseada em um exame neurológico completo e em uma entrevista semi-estruturada feita por um médico neurologista especialista em Distúrbios de Movimentos. A presença de DIL foi considerada se a pontuação fosse >= 1 no item 32 da Parte IV na MDS-UPDRS. Baseados em estudos prévios, nós escolhemos oito polimorfismos tipo single nucleotide polymorphism (SNP) nestes genes: COMT, MAOB, ANKK1, DRD3, DAT1, BDNF, ADORA2A and NOS1. A genotipagem foi realizada através de ensaios TaqMan SNP. Foram realizados modelos de regressão logística e análises de sobrevivência para identificarmos os fatores de risco clínicos e genéticos associados ao surgimento de DIL. Ao todo, foram analisados 199 pacientes (sexo masculino - 59%; idade média 61.8 anos), sendo 96 indivíduos (48.2%) com DIL. Através de um modelo de regressão logística multivariado com 7 variáveis independentes, o fenótipo clínico motor do tipo postural instability with gait disorder (PIGD) (OR 0.17, IC 95% 0.07-0.39; p < 0.001), longos períodos de tratamento com L-DOPA (OR 1.31, IC 95% 1.17-1.47; p < 0.001), altas doses diárias equivalentes de L-DOPA (OR 1.00, IC 95% 1.000-1.002; p = 0.04) e a início precoce dos sintomas da 11 DP (OR 1.04, IC 95% 1.01-1.07; p = 0.009) foram os fatores de risco clínicos mais associados ao surgimento de DIL. Dentre os fatores de risco genéticos, apenas o alelo T do SNP rs1799836 no gene da MAOB esteve associado ao aumento na chance de surgimento de DIL (OR 1.51, IC 95% 1.00-2.28; p = 0.05). Nossos resultados mostraram que a predição de surgimento de DIL em pacientes com DP em uso de L-DOPA pode ser feita através de alguns fatores de risco clínicos (fenótipo clínico motor, duração do tratamento com L-DOPA, dose diária equivalente de L-DOPA e idade de início de sintomas) e genéticos, como o SNPrs1799836 no gene da MAOB. Novos estudos com amostras maiores e desenhos prospectivos longitudinais são necessários para se explorar a associação entre estes preditores e o surgimento de DIL. / Parkinson\'s disease (PD) is the second most common neurodegenerative disease in the world, and its treatment is mainly based on drugs involved on dopaminergic neurotransmission in basal ganglia. L-DOPA is the major medication used on the management of PD, but its chronic use is associated with the onset of motor complications, as L-DOPA-induced dyskinesias (LID). LID occur in approximately 50% of patients using L-DOPA over 4 and 6 years, and they cause negative impacts on the quality of life of patients PD. To predict the onset of LID based on clinical and genetic risk may be an useful tool for clinicians which prescribe L-DOPA. The aim of this study was to determinate the main clinical and genetic risk factors for the onset of LID in Brazilian PD patients. A cross-sectional study was conducted with Brazilian PD patients from two centers (Ribeirao Preto and Sao Paulo) as part of the Latin American Research consortium on the Genetics of PD (LARGE-PD), which enrolled only PD patients using L-DOPA. PD patients were submitted to neurological examination and semi-structured interviews performed by movement disorders specialists. Presence of LID was confirmed if UPDRS Part IV had a score >= 1 on item 32. Based on previous studies, we chose eight Single Nucleotide Polymorphisms (SNP) in the following genes: COMT, MAOB, ANKK1, DRD3, DAT1, BDNF, ADORA2A and NOS1. Genotyping was performed using TaqMan SNP genotyping assays. We performed logistic regression and survival analysis to identify clinical and genetic risk factors associated with LID onset We enrolled 199 PD patients (males - 59%; mean age 61.8 years), and 96 patients (48.2%) had LID. At a multivariate model with 7 independent variables, postural instability with gait disorder (PIGD) clinical phenotype (OR 0.17, CI 95% 0.07-0.39; p < 0.001), longer duration of L-DOPA therapy (OR 1.31, Cl 95% 1.17-1.47; p < 0.001), higher L-DOPA equivalent daily doses (OR 1.00, CI 95% 1.000-1.002; p = 0.04), as also as early onset of PD (OR 1.04, CI 95% 1.01-1.07; p = 0.009) were the clinical risk factor more associated with onset of LID. Regarding genetic risk factors, only MAOB SNP rs1799836 was associated with LID, with the T allele increasing the risk of developing LIDs (OR 1.51, CI 95% 1.00-2.28; p = 0.05). Our results showed onset of LID can be predicted based on some clinical (motor clinical phenotype, duration of L-DOPA therapy, L-DOPA equivalent daily dose and age at PD onset) and genetic risk factors, as MAOB SNP rs1799836. Further studies in larger samples, using longitudinal and prospective designs, are needed to explore the association between these predictors and onset of LID.

Orientador: Elizabeth Maria Aparecida Barasnevicius Quagliato / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-19T22:19:48Z (GMT). No. of bitstreams: 1 Letro_GraceHelena_D.pdf: 960474 bytes, checksum: 73209cd37ac6132633ef6ce1d577cd77 (MD5) Previous issue date: 2012 / Resumo: Estudar as complicações motoras e não motoras em um grupo de pacientes com DP em tratamento com levodopa (LD). Complicações motoras e não motoras foram avaliadas em 61 pacientes (22 mulheres e 39 homens) com DP usando LD. As escalas Unified Parkinson's Disease Rating Scale (UPDRS), estágio da doença Hoehn & Yahr e Schwab & England foram usadas para avaliar os pacientes nos períodos "on/off". Wearing-off motor e não motor foram identificados pelo Cartão Questionário de Wearing-off (QC). A depressão foi avaliada pelo Inventário de Depressão de Beck, e a percepção da qualidade de vida, pelo questionário de Qualidade de Vida na DP (PDQ-39). A média do tempo de doença foi de 7.82±3.16 anos. A idade de início dos sintomas foi de 56.70±9.38 anos, e a média de tempo de tratamento com LD foi de 5.33±3.16 anos. Flutuações motoras (FM) e discinesias foram observadas nos pacientes com DP em 78.6% e 45.9%, respectivamente. Os melhores preditores para as FM foram o tempo de tratamento com LD, UPDRS motor "on" e desconforto corporal (PDQ-39). O melhor preditor para as discinesias foi o tempo de doença. As FM foram mais bem identificadas pelo QC. Os sintomas não motores (FNM) mais frequentes foram ansiedade, alterações do humor, sensação dolorosa e dor e apareceram juntamente com as flutuações motoras. Conclusão: As flutuações motoras foram relacionadas com maior comprometimento motor, desconforto corporal e tempo de tratamento com LD. As discinesias foram correlacionadas com tempo de doença. As flutuações não motoras ocorreram simultaneamente às FM / Abstract: Study the motor and non-motor complications in a group of patients with Parkinson's disease (PD) treated with levodopa (LD). Motor and non-motor complications were assessed in 61 patients (22 women and 39 men) with PD using LD. The Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn & Yahr staging and Schwab & England ADL scale were used to assess the patients "on/off" period. Motor and non-motor wearing-off effects were identified by the Wearing-off Questionnaire Card (QC). Depression was assessed by the Beck Depression Inventory and the perception of quality of life by the PD Quality of Life questionnaire (PDQ-39). The mean disease duration was 7.82±3.16 years. The mean age at onset was 56.70±9.38 years and the mean duration of levodopa (LD) treatment was 5.33±3.16 years. Motor fluctuations (MF) and dyskinesias were observed in 78.6% and 45.9%, respectively, of PD patients. The prevalence of MF was best predicted by the duration of levodopa treatment, the UPDRS "on" motor score and bodily discomfort (PDQ-39). The prevalence of dyskinesias was best predicted by disease duration. Motor symptoms were best identified by the QC. The most frequent nonmotor symptoms were anxiety, mood changes, aching and pain. Non-motor symptoms appeared along with motor symptoms. Conclusion: Motor fluctuations were related with greater motor impairment, bodily discomfort and duration of LD treatment. In addition, a correlation was found between dyskinesias and disease duration. Non-motor fluctuations occurred simultaneously with MF / Doutorado / Neurologia / Doutor em Ciências Médicas

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Reserpine treatment is a putative animal model of orofacial dyskinesia, tremor, and Parkinsonism. Here, we examined the effects of resveratrol, a polyphenol with neuroprotective properties primarily contained in red grapes and red wine, in an animal model of vacuous chewing movements (VCM) induced by treatment with reserpine in mice. Mice were treated with reserpine (1 mg/kg, subcutaneously administered on days 1 and 3) and/or resveratrol (5 mg/kg, intraperitonealy administered 3 consecutive days). VCM, locomotor, and exploratory performance were evaluated. It was also analysed nonproteic thiol groups and Vitamin C levels in cortex and region containing both substantia nigra and striatum as antioxidant defense parameters. Reserpine treatment produced an increase in VCM intensity, which was significantly reduced by resveratrol co-treatment. Reserpine also decreased locomotor and exploratory activity in the open field test. However, resveratrol co-treatment was not able to protect against these effects. We did not find any statistical differences among the groups when antioxidant defense parameters were evaluated. The data suggest that resveratrol could be a promising pharmacological tool for treating VCM in rodents. However, further investigations are needed to understand the exact mechanisms involved in the neuroprotective effects of resveratrol. / A administração de reserpina consiste num modelo animal de discinesia orofacial, tremor e parkinsonismo. Neste trabalho, investigamos o efeito do resveratrol, um polifenol com propriedades neuroprotetoras encontrado principalmente em frutas vermelhas e no vinho tinto, em um modelo animal de movimentos de mascar no vazio induzidos (MMVs) por tratamento com reserpina em camundongos. Os camundongos foram tratados com reserpina (1 mg/kg, administrado subcutaneamente nos dias 1 e 3) e/ou resveratrol (5 mg/kg, administrado intraperitonealmente durante 3 dias consecutivos). Foram avaliados os MMVs, atividade locomotora e exploratória. Também analisamos os níveis de tióis nãoprotéicos e de ácido ascórbico em córtex e região contendo ambos, substância negra e estriado, como parâmetros de defesa antioxidante. O tratamento com reserpina produziu um aumento na intensidade dos MMVs, os quais foram significativamente reduzidos pelo cotratamento com resveratrol. A reserpina também diminuiu a atividade locomotora e exploratória no teste de campo aberto. Contudo, o co-tratamento com resveratrol não foi capaz de modificar estes efeitos. Não foram encontradas diferenças estatisticamente significativas entre os grupos quando os parâmetros de defesa antioxidantes foram avaliados. Os dados obtidos sugerem que o resveratrol poderia ser um agente promissor no tratamento de MMVs em camundongos. Contudo, investigações adicionais são necessárias para entender os exatos mecanismos envolvidos nos efeitos neuroprotetores do resveratrol.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder producing a clinical syndrome of bradykinesia, rigidity and resting tremor. These motor symptoms appear due to the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) and loss of dopamine in the striatum, which subsequently leads to an imbalance of the basal ganglia motor circuit. The most effective pharmacological treatment for PD is L-3,4-dihydroxyphenylalanine (L-DOPA), the immediate metabolic precursor of dopamine, which effectively restores motor function. L-DOPA is catabolised into dopamine and replaces neurotransmitter loss in PD. However, long-term L-DOPA treatment leads to abnormal involuntary movements (AIMs), such as L-DOPA-induced dyskinesia (LID), which reduces the quality of life in PD patients. Currently, there are no reliable pharmacological treatments for these motor complications. Clinical and preclinical studies have shown that development and expression of LID is linked to unregulated dopamine release and plasticity-induced changes of striatal dopaminergic and non-dopaminergic signalling pathways. The activities of these pathways can be modulated by neurotransmitter receptors of a specific classification, the G-protein-coupled receptor (GPCR) family. In turn, GPCRs are regulated by certain endogenous proteins, the regulators of G-protein signalling (RGS) proteins. Numerous RGS protein subtypes are expressed in the striatum but their roles in PD and LID remain poorly understood. Given the modulatory function of RGS proteins in the striatum, these endogenous factors may have pathophysiological roles in the expression of motor symptoms in PD and LID. The studies presented in this thesis investigated the roles of RGS proteins in the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD and LID. Rats received unilateral 6-OHDA lesions of the right medial forebrain bundle to induce severe dopamine denervation. L-DOPA/benserazide (6/15 mg/kg) was then administered once daily for at least 21 days to induce stable abnormal involuntary movements (AIMs). In Chapter 2 of this thesis, increased levels of RGS2 and RGS4 mRNA were found in the rostral striatum of the unilateral 6-OHDA-lesioned rat model of LID. Moreover, elevated levels of RGS4 mRNA were specific to sensorimotor regions and positively correlated with AIMs severity. These molecular and behavioural data suggest that RGS4 proteins are involved in the expression of LID. In Chapters 3 and 4, behavioural studies conducted in the unilateral 6-OHDA-lesioned rat model of LID showed that acute inhibition of striatal RGS4 proteins reduced the expression of AIMs and improved overall motor function. Moreover, repeated de novo treatment with RGS4 protein inhibitors, in combination with L-DOPA, attenuated the development of AIMs and reduced the overexpression of preproenkephalin-B, a molecular marker of LID. These behavioural and molecular data suggest that blockade of RGS4 proteins can reduce the induction of LID. In Chapter 5, in vivo microdialysis conducted in the unilateral 6-OHDA-lesioned rat model of LID showed that systemic administration of RGS4 protein inhibitors, in combination with L-DOPA, attenuated unregulated striatal dopamine efflux. These data suggest that RGS4 proteins may regulate specific G-protein coupled receptors, such as 5-HT1A receptors, that modulate striatal dopamine release. In conclusion, the work presented in this thesis shows that RGS4 proteins play a pathophysiological role in the expression and development of LID. These proteins could mediate regulation of key neurotransmitter receptors involved in LID, making them a potential therapeutic target for the development of future treatments.

Neonatal 6-hydroxydopamine (6-OHDA) treatment of rats is associated with supersensitization of the dopamine D1 agonist induction of oral activity. The present study was conducted to determine whether induced oral responses to serotonin (5-HT) agonists would be similarly altered in this rat model. At 3 days after birth, rats received desipramine HCl (20 mg/kg, IP) 1 h before 6-OHDA HBr (100 μg in each lateral ventricle) or saline-ascorbic acid (0.1%) vehicle. At approximately 9 mo, rats were challenged with the mixed 5-HT1C and 5-HT2 receptor agonist, m-chlorophenylpiperazine diHCl (m-CPP 2HCl; 0.30-6.0 mg/kg, IP) and were then observed for 1 min every 10 min over a 60-min period. m-CPP induced oral activity in both the vehicle and 6-OHDA groups, with the responses of the 6-OHDA group being much greater. An m-CPP dose of 3.0 mg/kg produced a maximal response of 63.6 ± 3.2 oral movements in the 6-OHDA group. A bell-shaped response curve was obtained, with lower and higher doses of m-CPP producing less of an effect. Attenuation of the m-CPP-induced response by the 5-HT receptor antagonist, mianserin HCl (1.0 mg/kg, IP, 30 min before m-CPP), indicates that the m-CPP effect is receptor mediated. These findings demonstrate that neonatal 6-OHDA treatment produces ontogenic long-lived supersensitization of a 5-HT receptor system in rats.

Enhanced oral responses have been observed in rats that are treated shortly after birth with 6-hydroxydopamine (6-OHDA). A series of studies was conducted to characterize this effect. A dose-response curve demonstrated that the dopamine D1 receptor agonist, SKF 38393, produced a maximal response in 6-OHDA-treated rats at a dose of 0.10 mg/kg (IP). With the D2 receptor antagonist, spiperone, a bell-shaped dose-response curve was seen, with a maximal effect in the 6-OHDA group occurring at 80 μg/kg. There were only slight increases in oral activity with different SKF 38393 or spiperone doses in the saline group, indicating that there was an overt supersensitization of D1 receptors in the 6-OHDA-treated rats. The D1 antagonist SCH 23390 (0.30 mg/kg, IP) attenuated the response to both SKF 38393 and spiperone. The oral response to the D2 agonist, quinpirole (0.10 mg/kg, IP) was not preferentially increased in the 6-OHDA group of rats. These findings indicate that the enhanced oral response in neonatal 6-OHDA-treated rats is mediated by supersensitive dopamine D1 receptors. The persistence of the enhanced oral ersponse in 6-OHDA-treated rats at 8 months demonstrates that this sensitization of D1 receptors is a long-lived phenomenon.