Background and rationale: Parkinson’s disease (PD) is a progressive, degenerative disorder of the central nervous system and is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. The loss of functional dopamine in the striatum is thought to be responsible for the typical symptoms of PD. Cardinal features of PD include bradykinesia, muscular rigidity, resting tremor and impairment of postural balance. This study focuses on the inhibition of monoamine oxidase B (MAO-B) and antagonism of A2A receptors as therapeutic strategies for PD. Monoamine oxidase (MAO) is a flavin adenine dinucleotide (FAD)-containing mitochondrial bound isoenzyme which consists of two isoforms namely MAO-A and MAO-B. The primary function of MAO is to catalyze the oxidative deamination of dietary amines, monoamine neurotransmitters and hormones. MAO-A is responsible for the oxidative deamination of serotonin (5-HT) and norepinephrine (NE), while MAO-B is responsible for the oxidative deamination of dopamine (DA). The formation of DA takes place in the presynaptic neuron where it is stored in vesicles and released into the presynaptic cleft. The released DA then either binds to D1 and D2 receptors which results in an effector response. The excess DA in the presynaptic cleft is metabolized by MAO-B which may result in the formation of free radicals and a decrease in DA concentrations. Under normal physiological conditions free radicals are removed from the body via normal physiological processes, but in PD these normal physiological processes are thought to be unable to remove the radicals and this may lead to oxidative stress. Oxidative stress is believed to be one of the leading causes of neurodegeneration in PD. The rationale for the use of MAO-B inhibitors in PD would be to increase the natural DA levels in the brain and also diminish the likelihood of free radicals to be formed. Adenosine is an endogenous purine nucleoside and yields a variety of physiological effects. Four adenosine receptor subtypes have been characterized: A1, A2A, A2B and A3. They are all part of the G-protein-coupled receptor family and have seven transmembrane domains. The A2A receptor is highly concentrated in the striatum. There are two important pathways in the basal ganglia (BG) through which striatal information reaches the globus pallidus, namely the direct pathway containing A1 and D1 receptors and the indirect pathway containing A2A and D2 receptors. The direct pathway facilitates willed movement and the indirect pathway inhibits willed movement. A balance of the two pathways is necessary for normal movement. In PD, there is a decrease in DA in the striatum, thus leading to unopposed A2A receptor signaling and ultimately resulting in overactivity of the indirect pathway. Overactivity of the indirect pathway results in the locomotor symptoms associated with PD. Treatment with an A2A antagonist will block the A2A receptor, resulting in the restoration of balance between the indirect and direct pathways, thus leading to a decrease in locomotor symptoms. Aim: In this study, caffeine served as a lead compound for the design of dual-targeted drugs that are selective, reversible MAO-B inhibitors as well as A2A antagonists. Caffeine is a very weak MAO-B inhibitor and a moderately potent A2A antagonist. Substitution on the C8 position of caffeine yields compounds with good MAO-B inhibition activities and A2A receptor affinities. An example of this behaviour is found with (E)-8-(3-chlorostyryl)caffeine (CSC), which is not only a potent A2A antagonist but also a potent MAO-B inhibitor. The goal of this study was to identify and synthesize dual-targeted xanthine compounds. Recently Swanepoel and co-workers (2012) found that 8-phenoxymethyl substituted caffeines are potent reversible inhibitors of MAO-B. Therefore, this study focused on expanding the 8-(phenoxymethyl)caffeine series and evaluating the resulting compounds as both MAO-A and -B inhibitors as well as A2A antagonists. Synthesis: Two series were synthesized namely the 8-(phenoxymethyl)caffeines and 1,3-diethyl-7-methyl-8-(phenoxymethyl)xanthines. The analogues were synthesized according to the literature procedure. 1,3-Dimethyl-5,6-diaminouracil or 1,3-diethyl-5,6-diaminouracil were used as starting materials and were acylated with a suitable substituted phenoxyacetic acid in the presence of N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDAC) as an activating reagent. The intermediary amide was treated with sodium hydroxide, which resulted in ring closure to yield the corresponding 1,3-dimethyl-8-phenoxymethyl-7Hxanthinyl or 1,3-diethyl-8-phenoxymethyl-7H-xanthinyl analogues. These xanthines were 7-N-methylated in the presence of an excess of potassium carbonate and iodomethane to yield the target compounds. In vitro evaluation: A radioligand binding assay was performed to determine the affinities of the synthesized compounds for the A2A receptor. The MAO-B inhibition studies were carried out via a fluorometric assay where the MAO-catalyzed formation of H2O2 was measured. Results: Both series showed good to moderate MAO-B inhibition activities, while none of the compounds had activity towards MAO-A. Results were comparable to that of a known MAOB inhibitor lazabemide. For example, lazabemide (IC50 = 0.091 μM) was twice as potent as the most potent compound identified in this study, 8-(3-chlorophenoxymethyl)caffeine (compound 3; IC50 = 0.189 μM). Two additional compounds, 8-(4-iodophenoxymethyl)caffeine and 8-(3,4-dimethylphenoxymethyl) caffeine, also exhibited submicromolar IC50 values for the inhibition of MAO-B. The structure-activity relationships (SARs) indicated that 1,3-diethyl substitution resulted in decreased inhibition potency towards MAO-B and that 1,3-dimethyl substitution was a more suitable substitution pattern, leading to better inhibition potencies towards MAO-B. The compounds were also evaluated for A2A binding affinity, and relatively weak affinities were recorded with the most potent compound, 1,3-diethyl-7-methyl-8-[4-chlorophenoxymethyl]xanthine (compound 16), exhibiting a Ki value of 0.923 μM. Compared to KW-6002 (Ki = 7.94 nM), a potent reference A2A antagonist, compound 16 was 35-fold less potent. Comparing compound 16 to CSC [Ki(A2A) = 22.6 nM; IC50(MAO-B) = 0.146 nM], it was found that compound 16 is 31-fold less potent as an A2A antagonist and 21-fold less potent as a MAO-B inhibitor. Loss of MAO-B inhibition potency may be attributed to 1,3-diethyl substitution which correlates with similar conclusions reached in earlier studies. In addition, the replacement of the styryl functional group (as found with CSC and KW-6002) with the phenoxymethyl functional group (as found with the present series) may explain the general reduction in affinity for the A2A receptor. This suggests that the styryl side chain is more appropriate for A2A antagonism than the phenoxymethyl functional group. Conclusion: In this study two series of xanthine derivatives were successfully synthesized, namely the 8-(phenoxymethyl)caffeines and 1,3-diethyl-7-methyl-8-(phenoxymethyl)xanthines (11 compounds in total). Three of the newly synthesized compounds were found to act as potent inhibitors of MAO-B, with IC50 values in the submicromolar range. None of the compounds were however noteworthy MAO-A inhibitors. The most potent A2A antagonist among the examined compounds, compound 16, proved to be moderately potent compared to the reference antagonists, CSC and KW-6002. It may be concluded that the styryl functional group (as found with CSC and KW-6002) is more optimal than the phenoxymethyl functional group (as found with the present series) for A2A antagonism. 1,3-Diethyl substitution of the xanthine ring was found to be less optimal for MAO-B inhibition compared to 1,3-dimethyl substitution. These results together with known SARs provide valuable insight into the design of 8-(phenoxymethyl)caffeines as selective and potent MAO-B inhibitors. Such drugs may find application in the therapy of PD. / Thesis (MSc (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2013.

Currently L-DOPA is the drug most commonly used for the treatment of Parkinson’s disease (PD). However, the long-term use of L-DOPA is associated with the development of motor fluctuations and dyskinesias. Treatment mainly addresses the dopaminergic features of the disease and leaves its progressive course unaffected. An optimal treatment would be a combination of both motor and non-motor symptom relief with neuroprotective properties. Two drug targets have attracted the attention for PD treatment, namely monoamine oxidase B (MAOB) and adenosine A2A receptors. MAO-B inhibitors enhance the elevation of dopamine levels after L-DOPA treatment, improve motor functions and may also possess neuroprotective properties. The antagonistic interaction between A2A and dopamine receptors in the striatopallidal pathway, which modulates motor behaviour, has also become a potential strategy for PD treatment. Blockade of the A2A receptor exerts both anti-symptomatic and neuroprotective activities and offer benefit for motor symptoms and motor complications. This thesis seeks to synthesize novel drug treatments for PD by exploring both MAO-B inhibitors and adenosine A2A receptor antagonists and to assess the prospects for drug modification to increase activity. MAO-B inhibitors - Based on a recent report that the phthalimide moiety may be a useful scaffold for the design of potent MAO-B inhibitors, the present study examines a series of 5-sulfanylphthalimide analogues as potential inhibitors of both human MAO isoforms. The results document that 5- sulfanylphthalimides are highly potent and selective MAO-B inhibitors with all of the examined compounds possessing IC50 values in the nanomolar range. The most potent inhibitor, 5- (benzylsulfanyl)phthalimide, exhibits an IC50 value of 0.0045 μM for the inhibition of MAO-B with a 427–fold selectivity for MAO-B compared to MAO-A. We conclude that 5-sulfanylphthalimides represent an interesting class of MAO-B inhibitors and may serve as lead compounds for the design of antiparkinsonian therapy. It has recently been reported that nitrile containing compounds frequently act as potent MAO-B inhibitors. In an attempt to identify additional potent and selective inhibitors of MAO-B and to contribute to the known structure-activity relationships of MAO inhibition by nitrile containing compounds, the present study examined the MAO inhibitory properties of series of novel sulfanylphthalonitriles and sulfanylbenzonitriles. The results document that the evaluated compounds are potent and selective MAO-B inhibitors with most homologues possessing IC50 values in the nanomolar range. In general, the sulfanylphthalonitriles exhibited higher binding affinities for MAO-B than the corresponding sulfanylbenzonitrile homologues. Among the compounds evaluated, 4-[(4-bromobenzyl)sulfanyl]phthalonitrile is a particularly promising inhibitor since it displayed a high degree of selectivity (8720-fold) for MAO-B over MAO-A, and potent MAO-B inhibition (IC50 = 0.025 μM). Based on these observations, this structure may serve as a lead for the development of therapies for neurodegenerative disorders such as Parkinson’s disease. Adenosine A2A receptor antagonism - Most adenosine A2A receptor antagonists belong to two different chemical classes, the xanthine derivatives and the amino-substituted heterocyclic compounds. In an attempt to discover high affinity A2A receptor antagonists for PD and to further explore the structure-activity relationships of A2A antagonism by the xanthine class of compounds, this study examines the A2A antagonistic properties of series of (E)-8-styrylxanthine, 8-(phenoxymethyl)xanthine and 8-(3- phenylpropyl)xanthine derivatives. The results document that among these series, the (E)-8- styrylxanthines are the most potent antagonists with the most potent homologue, (E)-1,3-dietyl- 7-methyl-8-[(3-trifluoromethyl)styryl]xanthine, exhibiting a Ki value of 11.9 nM. This compound was also effective in reversing haloperidol-induced catalepsy in rats. The importance of substitution at C8 with the styryl moiety was demonstrated by the finding that none of the 8- (phenoxymethyl)xanthines and 8-(3-phenylpropyl)xanthines exhibited high binding affinities for the A2A receptor. It was also concluded that (E)-8-styrylxanthines are potent A2A antagonists with particularly the 1,3-dietyl-7-methylxanthine substitution pattern being most appropriate for high affinity binding. Conclusion - The results of these studies have established that all of the sulfanylphthalimides, sulfanylphthalonitriles and sulfanylbenzonitriles examined display significant MAO-B inhibitory properties in vitro with IC50 values in the low μM to nM range. Good A2A receptor affinity was demonstrated by the xanthines containing a styryl moiety, while the phenoxymethyl and phenylpropyl xanthines exhibited poor activity. / Thesis (PhD (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2013

Background and rationale: Parkinson’s disease (PD) is a progressive, degenerative disorder of the central nervous system and is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. The loss of functional dopamine in the striatum is thought to be responsible for the typical symptoms of PD. Cardinal features of PD include bradykinesia, muscular rigidity, resting tremor and impairment of postural balance. This study focuses on the inhibition of monoamine oxidase B (MAO-B) and antagonism of A2A receptors as therapeutic strategies for PD. Monoamine oxidase (MAO) is a flavin adenine dinucleotide (FAD)-containing mitochondrial bound isoenzyme which consists of two isoforms namely MAO-A and MAO-B. The primary function of MAO is to catalyze the oxidative deamination of dietary amines, monoamine neurotransmitters and hormones. MAO-A is responsible for the oxidative deamination of serotonin (5-HT) and norepinephrine (NE), while MAO-B is responsible for the oxidative deamination of dopamine (DA). The formation of DA takes place in the presynaptic neuron where it is stored in vesicles and released into the presynaptic cleft. The released DA then either binds to D1 and D2 receptors which results in an effector response. The excess DA in the presynaptic cleft is metabolized by MAO-B which may result in the formation of free radicals and a decrease in DA concentrations. Under normal physiological conditions free radicals are removed from the body via normal physiological processes, but in PD these normal physiological processes are thought to be unable to remove the radicals and this may lead to oxidative stress. Oxidative stress is believed to be one of the leading causes of neurodegeneration in PD. The rationale for the use of MAO-B inhibitors in PD would be to increase the natural DA levels in the brain and also diminish the likelihood of free radicals to be formed. Adenosine is an endogenous purine nucleoside and yields a variety of physiological effects. Four adenosine receptor subtypes have been characterized: A1, A2A, A2B and A3. They are all part of the G-protein-coupled receptor family and have seven transmembrane domains. The A2A receptor is highly concentrated in the striatum. There are two important pathways in the basal ganglia (BG) through which striatal information reaches the globus pallidus, namely the direct pathway containing A1 and D1 receptors and the indirect pathway containing A2A and D2 receptors. The direct pathway facilitates willed movement and the indirect pathway inhibits willed movement. A balance of the two pathways is necessary for normal movement. In PD, there is a decrease in DA in the striatum, thus leading to unopposed A2A receptor signaling and ultimately resulting in overactivity of the indirect pathway. Overactivity of the indirect pathway results in the locomotor symptoms associated with PD. Treatment with an A2A antagonist will block the A2A receptor, resulting in the restoration of balance between the indirect and direct pathways, thus leading to a decrease in locomotor symptoms. Aim: In this study, caffeine served as a lead compound for the design of dual-targeted drugs that are selective, reversible MAO-B inhibitors as well as A2A antagonists. Caffeine is a very weak MAO-B inhibitor and a moderately potent A2A antagonist. Substitution on the C8 position of caffeine yields compounds with good MAO-B inhibition activities and A2A receptor affinities. An example of this behaviour is found with (E)-8-(3-chlorostyryl)caffeine (CSC), which is not only a potent A2A antagonist but also a potent MAO-B inhibitor. The goal of this study was to identify and synthesize dual-targeted xanthine compounds. Recently Swanepoel and co-workers (2012) found that 8-phenoxymethyl substituted caffeines are potent reversible inhibitors of MAO-B. Therefore, this study focused on expanding the 8-(phenoxymethyl)caffeine series and evaluating the resulting compounds as both MAO-A and -B inhibitors as well as A2A antagonists. Synthesis: Two series were synthesized namely the 8-(phenoxymethyl)caffeines and 1,3-diethyl-7-methyl-8-(phenoxymethyl)xanthines. The analogues were synthesized according to the literature procedure. 1,3-Dimethyl-5,6-diaminouracil or 1,3-diethyl-5,6-diaminouracil were used as starting materials and were acylated with a suitable substituted phenoxyacetic acid in the presence of N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDAC) as an activating reagent. The intermediary amide was treated with sodium hydroxide, which resulted in ring closure to yield the corresponding 1,3-dimethyl-8-phenoxymethyl-7Hxanthinyl or 1,3-diethyl-8-phenoxymethyl-7H-xanthinyl analogues. These xanthines were 7-N-methylated in the presence of an excess of potassium carbonate and iodomethane to yield the target compounds. In vitro evaluation: A radioligand binding assay was performed to determine the affinities of the synthesized compounds for the A2A receptor. The MAO-B inhibition studies were carried out via a fluorometric assay where the MAO-catalyzed formation of H2O2 was measured. Results: Both series showed good to moderate MAO-B inhibition activities, while none of the compounds had activity towards MAO-A. Results were comparable to that of a known MAOB inhibitor lazabemide. For example, lazabemide (IC50 = 0.091 μM) was twice as potent as the most potent compound identified in this study, 8-(3-chlorophenoxymethyl)caffeine (compound 3; IC50 = 0.189 μM). Two additional compounds, 8-(4-iodophenoxymethyl)caffeine and 8-(3,4-dimethylphenoxymethyl) caffeine, also exhibited submicromolar IC50 values for the inhibition of MAO-B. The structure-activity relationships (SARs) indicated that 1,3-diethyl substitution resulted in decreased inhibition potency towards MAO-B and that 1,3-dimethyl substitution was a more suitable substitution pattern, leading to better inhibition potencies towards MAO-B. The compounds were also evaluated for A2A binding affinity, and relatively weak affinities were recorded with the most potent compound, 1,3-diethyl-7-methyl-8-[4-chlorophenoxymethyl]xanthine (compound 16), exhibiting a Ki value of 0.923 μM. Compared to KW-6002 (Ki = 7.94 nM), a potent reference A2A antagonist, compound 16 was 35-fold less potent. Comparing compound 16 to CSC [Ki(A2A) = 22.6 nM; IC50(MAO-B) = 0.146 nM], it was found that compound 16 is 31-fold less potent as an A2A antagonist and 21-fold less potent as a MAO-B inhibitor. Loss of MAO-B inhibition potency may be attributed to 1,3-diethyl substitution which correlates with similar conclusions reached in earlier studies. In addition, the replacement of the styryl functional group (as found with CSC and KW-6002) with the phenoxymethyl functional group (as found with the present series) may explain the general reduction in affinity for the A2A receptor. This suggests that the styryl side chain is more appropriate for A2A antagonism than the phenoxymethyl functional group. Conclusion: In this study two series of xanthine derivatives were successfully synthesized, namely the 8-(phenoxymethyl)caffeines and 1,3-diethyl-7-methyl-8-(phenoxymethyl)xanthines (11 compounds in total). Three of the newly synthesized compounds were found to act as potent inhibitors of MAO-B, with IC50 values in the submicromolar range. None of the compounds were however noteworthy MAO-A inhibitors. The most potent A2A antagonist among the examined compounds, compound 16, proved to be moderately potent compared to the reference antagonists, CSC and KW-6002. It may be concluded that the styryl functional group (as found with CSC and KW-6002) is more optimal than the phenoxymethyl functional group (as found with the present series) for A2A antagonism. 1,3-Diethyl substitution of the xanthine ring was found to be less optimal for MAO-B inhibition compared to 1,3-dimethyl substitution. These results together with known SARs provide valuable insight into the design of 8-(phenoxymethyl)caffeines as selective and potent MAO-B inhibitors. Such drugs may find application in the therapy of PD. / Thesis (MSc (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2013.

Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy are disorders featuring accumulation of Lewy bodies in brain. The main component of these large insoluble intracellular inclusions is the presynaptic protein alpha-synuclein (α-synuclein). It is generally believed that α-synuclein monomers adopt an abnormal conformation that favors the formation of soluble oligomers or protofibrils and, eventually, insoluble fibrils depositing as Lewy bodies. Notably, the intermediately sized oligomers/protofibrils seem to have particular neurotoxic effects. Several factors may influence the formation of α-synuclein oligomers/protofibrils, e.g. the reactive aldehydes 4-hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE) formed during oxidative stress. The overall aims of this thesis were to investigate biophysical and biochemical properties of in vitro generated α-synuclein oligomers, characterize their functional effects on cell and animal disease models as well as to explore whether their formation could be prevented in a cell culture model for oligomerization.  Here, it was found that α-synuclein rapidly formed oligomers after incubation with both ONE and HNE. The resulting oligomers were stable and did not continue to form insoluble fibrils. By comparing HNE- and ONE induced α-synuclein oligomers biochemically they were both found to exhibit extensive β-beta sheet structure and had a molecular size of ~2000 kDa. However, they differed in morphology; the ONE induced α-synuclein oligomers described round amorphous species whereas the HNE induced α-synuclein oligomers appeared as elongated protofibril-like structures. Both these oligomers were cell internalized to varying degrees and induced toxicity in neuroblastoma cells. In addition, the ONE induced α-synuclein oligomers seemed to initiate aggregation of monomeric α-synuclein in vitro, but failed to do so in vivo. Finally, treatment of α-synuclein overexpressing cells with monoclonal antibodies specific for α-synuclein significantly reduced aggregation and lowered levels of the protein, suggesting increased turnover in these cells.  To conclude, this thesis has characterized different oligomeric α-synuclein species, which may have properties similar to soluble species central to the pathogenesis of Parkinson’s disease and other disorders with α-synuclein pathology. For therapeutic strategies it is important to selectively target such harmful protein species and avoid interaction with other forms of α-synuclein, which may have vital physiological cellular functions.

No description available.

Introdução: apesar de depressão e dor serem altamente prevalentes em pacientes com Doença de Parkinson (DP), há poucos estudos sobre a relação entre esses fatores, apesar da já bem descrita potencial modulação da dor por estados emocionais. Objetivo: avaliar a percepção termoalgésica de calor e dor em método quantitativo e correlacioná-la com sintomas psiquiátricos e da Doença de Parkinson. Método: realizamos um estudo transversal avaliando características clínicas e dados psicofísicos em 31 pacientes com DP sob efeito da medicação dopaminérgica (estado “on”). Verificamos as características da DP utilizando a escala Hoehn and Yahr, realizamos uma avaliação psiquiátrica usando as escalas Inventário de Depressão de Beck (Inventário de Depressão de Beck - IDB), Mini International Neuropsychiatric Interview (MINI) de acordo com os critérios do DSM IV, e Mini Mental State Evaluation (MMSE), avaliamos queixas de dor nos últimos 90 dias usando uma escala visual analógica para dor (EVA – Escala Visual Analógica) e medimos a percepção termoalgésica através do Teste Quantitativo Sensitivo (TQS) para percepção de calor e de dor. Resultados: 31 pacientes foram avaliados. Surpreendentemente, não houve associação entre a percepção termoalgésica e as queixas de dor ou sintomas da DP. Entretanto, houve uma correlação moderada mas significativa entre sintomas depressivos medidos pela BDI e os limiares de calor e de dor (r=0.54 para calor p<0.05 e r=0.47 p<0.05 para dor). Pacientes com sintomas depressivos significativos tiveram limiares de calor e de dor maiores comparados aos sem sintomas depressivos. Esse achado se manteve após correção estatística para severidade dos sintomas da DP. Conclusão: processamento termoalgésico em pacientes com DP é mais influenciado por depressão do que pela severidade da Doença de Parkinson ou pelo nível da dor em si. Essa informação tem implicações importantes para o diagnóstico e abordagem terapêutica para pacientes com DP e dor e/ou depressão. Por exemplo, a depressão poderia ser mais sistematicamente rastreada e tratada em pacientes com DP com processamento de dor alterado. / Introduction: Although depression and pain are highly prevalent in Parkinson’s Disease (PD) patients, there is a lack of studies in their relationship, even though it is well-known that pain is potentially modulated by emotional state. Aims: To assess warm and heat pain perception in a quantitative method and correlate it with psychiatric and parkinsonian symptoms. Methods: We carried out a transversal study assessing clinical and psychophysical data in 31 patients with PD during the effect of dopaminergic medication (on state). We assessed the clinical characteristics of Parkinson's using Hoehn and Yahr (HY), performed a psychiatric evaluation using Beck Depression Inventory (BDI), Mini International Neuropsychiatric Interview (MINI) according to the DSM IV criteria and Mini Mental State Evaluation (MMSE), evaluated pain complaints in the last 90 days using a visual analogue scale for pain (VAS) and measured pain perception by means of quantitative sensory testing (QST) for warm and heat pain perception. Results: 31 patients were evaluated. Surprisingly, there was no association between thermoalgesic perception with pain complaints or parkinsonian symptoms. However, there was a moderate but significant correlation between depressive symptoms measured by BDI and warm sensation and heat pain thresholds(r=0.54 for warm p<0.05 and r=0.47 p<0.05 for heat pain). Patients with significant depressive symptoms had higher warm and heat pain thresholds compared to those without depression. This finding was maintained after statistical correction for the PD symptoms severity. Conclusion: Thermoalgesic processing in PD patients is more influenced by depression than by PD severity or level of pain itself. This information has important implications for diagnostic and therapeutic approaches for patients with PD and pain and/or depression. For instance, depression might be more systematically screened and treated in PD patients with altered pain processing.

A infusão de 6-hidroxidopamina (6-OHDA) na via nigroestriatal em ratos é um modelo da Doença de Parkinson (DP). O Teste de Motricidade sobre Grade (TMG ou, em inglês, footfault test) é um teste comportamental utilizado para avaliar a função motora em ratos. Observamos que animais lesionados unilateralmente com 6-OHDA mostram atividade rotacional ipsilateral induzida pelo contexto quando colocados no aparato do TMG por 3 minutos e isso pode ser utilizado como índice para detectar animais lesionados. Nossos resultados mostraram que o TMG tem sensibilidade e especificidade de 100% para lesões maiores que 94 e 64%, respectivamente (Curva Operacional Característica: Área sob a curva = 0,988). Um modelo de regressão logística binária mostrou exp(B)= 1,116 (95% CI, 1,007-1,236) e C = -9,081 ± 4,554 (p = 0,046) utilizando a imunoistoquímica para tirosina-hidroxilase como técnica padrão (cada unidade representa 10% de lesão). Além disso, o TMG foi mais sensível que o teste de atividade rotacional induzida por apomorfina 1mg/kg quando os testes foram realizados em dias diferentes e foi menos sensível que o teste de atividade rotacional induzida por metilfenidato 40mg/kg (Teste do Sinal, p < 0,05). Portanto, o TMG pode ser bastante útil nesse modelo animal de DP para triagem de animais, uma vez que é um teste rápido, simples e não requer drogas para indução de atividade rotacional. / The administration of 6-hydroxydopamine (6-OHDA) into the nigrostriatal pathway is a rat model of Parkinson’s Disease (PD). The footfault test is a behavioural task in which rodents have their motor functions assessed. Here, we observed that unilaterally 6-OHDA-lesioned animals show a context-induced ipsilateral rotational behaviour when placed on the footfault apparatus for 3 minutes and this may be used as index to detect lesioned animals. Our results showed a sensitivity and specificity of 100% for lesions higher than 94 and 64%, respectively (ROC curve: AUC = 0.988). A binary logistic regression model showed an exp(B)= 1.116 (95% CI, 1.007-1.236) and C = -9.081 ± 4.554 (p = 0.046) using the nigral tirosine hidroxylase immunocontent as standard (each unit represents a 10%-lesion extension). Additionally, the footfault test was more sensitive than apomorphine challenging at 1 mg/kg when these tests were carried out days apart and it was less sensitive than methylphenidate at 40 mg/kg (Sign Test, p < 0.05). Therefore, the footfault test may be very useful in the PD animal model for screening animals since it is fast and simple and it does not require a drug to induce rotational activity.

197f. / Submitted by Suelen Reis (suziy.ellen@gmail.com) on 2013-04-03T17:21:02Z No. of bitstreams: 1 Isleide%20Santos.pdf: 18785907 bytes, checksum: e3d6e94309c3734c7b9268260e53fd18 (MD5) / Approved for entry into archive by Rodrigo Meirelles(rodrigomei@ufba.br) on 2013-04-09T17:39:34Z (GMT) No. of bitstreams: 1 Isleide%20Santos.pdf: 18785907 bytes, checksum: e3d6e94309c3734c7b9268260e53fd18 (MD5) / Made available in DSpace on 2013-04-09T17:39:34Z (GMT). No. of bitstreams: 1 Isleide%20Santos.pdf: 18785907 bytes, checksum: e3d6e94309c3734c7b9268260e53fd18 (MD5) Previous issue date: 2009 / Esta dissertação apresenta, através da história oral temática, os relatos de pessoas idosas com doença de Parkinson (DP). Estabeleceu-se como objetivo geral analisar as concepções de pessoas idosas com DP sobre a doença e o cuidado familiar, a partir das experiências vivenciadas e narradas pelos mesmos. Como objetivos específicos, foram delimitados: descrever as concepções que as pessoas idosas com DP têm da doença e do cuidado familiar; identificar o impacto da DP em suas vidas e em suas relações intrafamiliares. A metodologia envolveu investigação com abordagem qualitativa, descritiva, em que foram entrevistadas 13 pessoas idosas com doença de Parkinson, no período de março a junho de 2008, as quais participam do Grupo de Ajuda Mútua de Parkinson da Universidade Estadual do Sudoeste da Bahia, Jequié-BA. Utilizou-se como instrumento de coleta de dados, a entrevista semiestruturada, que foi gravada e submetida à Análise de Conteúdo de Bardin. As categorias de análise foram agrupadas em três temas: as concepções das pessoas idosas sobre a doença; mudanças ocorridas em suas vidas após o adoecimento e, as concepções das pessoas idosas com DP sobre o cuidado familiar. Os resultados mostraram que a doença foi percebida como: degeneração da saúde; produção de dependência; limitação do viver cotidiano; tratamento; constrangimento e instabilidade emocional. As mudanças significativas aconteceram no contexto do trabalho; da família e sociocultural. Os significados do cuidado familiar foram relatados como: satisfação e gratidão; obrigação/ reciprocidade; segurança no ambiente doméstico; impaciência; e, suporte físico, emocional e financeiro. Portanto, concluímos que a doença tem significados negativos, para os idosos e o impacto maior, em suas vidas, foi na perda da capacidade para o trabalho, entretanto a família desempenha papel fundamental no cuidado dos idosos. Desse modo o idoso e família precisam da implementação das Políticas Públicas de Assistência à saúde, com enfoque preventivo e de promoção da qualidade de vida para um envelhecimento bem sucedido. Neste sentido, esta investigação pode subsidiar o planejamento do cuidado à pessoa idosa com DP, na perspectiva da integralidade, interdisciplinaridade e humanização considerando a produção de vida, mesmo na presença de limitações impostas pela progressão da doença. / Salvador

A infusão de 6-hidroxidopamina (6-OHDA) na via nigroestriatal em ratos é um modelo da Doença de Parkinson (DP). O Teste de Motricidade sobre Grade (TMG ou, em inglês, footfault test) é um teste comportamental utilizado para avaliar a função motora em ratos. Observamos que animais lesionados unilateralmente com 6-OHDA mostram atividade rotacional ipsilateral induzida pelo contexto quando colocados no aparato do TMG por 3 minutos e isso pode ser utilizado como índice para detectar animais lesionados. Nossos resultados mostraram que o TMG tem sensibilidade e especificidade de 100% para lesões maiores que 94 e 64%, respectivamente (Curva Operacional Característica: Área sob a curva = 0,988). Um modelo de regressão logística binária mostrou exp(B)= 1,116 (95% CI, 1,007-1,236) e C = -9,081 ± 4,554 (p = 0,046) utilizando a imunoistoquímica para tirosina-hidroxilase como técnica padrão (cada unidade representa 10% de lesão). Além disso, o TMG foi mais sensível que o teste de atividade rotacional induzida por apomorfina 1mg/kg quando os testes foram realizados em dias diferentes e foi menos sensível que o teste de atividade rotacional induzida por metilfenidato 40mg/kg (Teste do Sinal, p < 0,05). Portanto, o TMG pode ser bastante útil nesse modelo animal de DP para triagem de animais, uma vez que é um teste rápido, simples e não requer drogas para indução de atividade rotacional. / The administration of 6-hydroxydopamine (6-OHDA) into the nigrostriatal pathway is a rat model of Parkinson’s Disease (PD). The footfault test is a behavioural task in which rodents have their motor functions assessed. Here, we observed that unilaterally 6-OHDA-lesioned animals show a context-induced ipsilateral rotational behaviour when placed on the footfault apparatus for 3 minutes and this may be used as index to detect lesioned animals. Our results showed a sensitivity and specificity of 100% for lesions higher than 94 and 64%, respectively (ROC curve: AUC = 0.988). A binary logistic regression model showed an exp(B)= 1.116 (95% CI, 1.007-1.236) and C = -9.081 ± 4.554 (p = 0.046) using the nigral tirosine hidroxylase immunocontent as standard (each unit represents a 10%-lesion extension). Additionally, the footfault test was more sensitive than apomorphine challenging at 1 mg/kg when these tests were carried out days apart and it was less sensitive than methylphenidate at 40 mg/kg (Sign Test, p < 0.05). Therefore, the footfault test may be very useful in the PD animal model for screening animals since it is fast and simple and it does not require a drug to induce rotational activity.

Made available in DSpace on 2015-12-06T23:46:42Z (GMT). No. of bitstreams: 0 Previous issue date: 2014 / A doenca de Parkinson e uma das doencas neurologicas mais prevalentes. Diversos deficits motores estao presentes nestes pacientes, entre eles os disturbios da marcha e equilibrio. Alem das terapias convencionais, tem se utilizado com frequencia, pistas (tambem chamados de feedback extrinseco) para melhora destes deficits. Objetivos: Avaliar a efetividade e seguranca do uso de pistas na marcha de pacientes com Doenca de Parkinson. Assim como verificar se a mudanca na marcha provocada auxilia na melhora da qualidade de vida e do desempenho psicomotor, e diminuicao do freezing. Por fim, com os objetivos anteriores respondidos, analisar qual tipo de pista externa provoca ganhos mais expressivos em todos os desfechos analisados. Metodos de busca: As bases de dados eletronicas analisadas foram: Cochrane Library, Pubmed, Embase, Lilacs, Pedro, e Sumsearch. Tambem foram analisados artigos das referencias bibliograficas dos artigos coletados, assim como busca manual nas Revistas Movement Disorders e Physical Therapy, alem de anais de congressos principalmente da Movement Disorders Society. As seguintes palavras chaves foram utilizadas: Parkinson disease, feedback, biofeedback, neurofeedback, psychology biofeedback, cue, cues, cueing, rehabilitation, physical therapy, physiotherapy, exercise, locomotion, gait, neurologic gait disorders, optical flow field, visual, auditory, sensory, tactile. Criterios de inclusao: Ensaios clinicos randomizados e quasi randomizados que analisaram marcha, freezing, qualidade de vida e desempenho psicomotor foram analisados. Coleta e analise de dados: Os dados destes estudos foram analisados por meio de um formulario padronizado por dois revisores. Resultados: Dos 259 artigos localizados, apenas sete estudos se enquadraram nos criterios de inclusao e de qualidade metodologica desta revisao. Deste total, dois estudos utilizaram pistas visuais, dois pistas auditivas, um analisou o uso de instrucoes verbais, um utilizou pistas combinadas e por fim, um utilizou pistas sensoriais (proprioceptivas). Em geral, o uso de pistas resultou em melhoras no comprimento do passo (p < 0,0001), velocidade (p < 0,00001), cadencia (p < 0,001), comprimento da passada (p < 0,00001). As pistas visuais provocaram melhorias significantes na velocidade (p < 0,00001), cadencia (p < 0,00001) e comprimento do passo (p = 0,0004), enquanto as auditivas foram efetivas no aumento do comprimento do passo (p = 0,03) e velocidade (p < 0,00001); o estudo incluido que avaliou o uso da instrucao verbal apenas analisou comprimento do passo, porem, esta intervencao nao mostrou diferenca estatisticamente significante para este desfecho (p = 0,16). A pista sensorial (proprioceptiva) mostrou beneficios significantes na velocidade (p = 0,01), cadencia e comprimento da passada (p < 0,00001), enquanto que com o uso de pistas combinadas (visual + auditiva) houve maiores ganhos na UPDRS III (p = 0,009) do que na velocidade (p = 0,01). Conclusao: Esta revisao sistematica apresenta nivel de evidencia 1A, com base na classificacao de oOxford Centre for Evidence-based Medicineo. Conclui-se que o uso de pistas externas e efetivo para a melhora dos parametros de marcha de pacientes com Doenca de Parkinson, havendo melhora do freezing, do desempenho psicomotor avaliados pelo FOGQ e UPDRS III, respectivamente / Parkinson's disease (PD) is one of the most prevalent neurological diseases. Several motor deficits are present in patients with this disease, including gait and balance disturbances. In addition to onventional therapies, it has been used frequently in the current studies, cues (also called extrinsic feedback) to improve gait and balance in PD patients.Objectives: Evaluate the effectiveness and safety of using cues on gait in patients with PD. As well as verify if this improvement on gait generates increase in quality of life, decrease freezing and improve psychomotor performance on this population. Finally, with the previous goals answered, to analyze which type of cues cause more significant gains in all outcomes assessed. Search methods: Electronic databases analyzed: Cochrane Library, Pubmed, Embase, Lilacs, Pedro and Sumsearch. It was also analyzed the articles references, as well as manual search on Movement Disorders and Physical Therapy journals, in addition to the annals of the Movement Disorders Society. The following key words were used: Parkinson disease, feedback, biofeedback, neurofeedback, biofeedback, psychology cue, cues, cueing, rehabilitation, physical therapy, physiotherapy, exercise, locomotion, gait, gait disorders, neurologic optical flow field, visual, auditory, sensory, proprioceptive and tactile. Inclusion criteria: Randomized and quasi randomized clinical trials that assessed gait, freezing, quality of life and psychomotor performance were analyzed. Data collection and analysis: two reviewers analyzed the data with a standardized form. Results: Of 259 articles collected, just 07 fit the inclusion and methodological quality criteria of this review. Of this total, two studies used visual cues, two auditory cues, one used verbal instructions, one used combined cues and finally, one used sensory cues (proprioceptive). In general, the use of cues led improves with statistically significant difference in step length (p < 0,0001), speed (p < 0,00001), cadence (p < 0,001), stride length (p < 0,00001). Moreover, visual cues were most effective in improving speed (p < 0,00001), cadence (p < 0,00001) and step length (p = 0,0004), while the auditory cues cause more impact in step length (p = 0,03) and speed (p < 0,00001). Verbal instruction did not show statistically significant difference for any outcome (p = 0,16). The sensory (proprioceptive) cues showed significant improvements in speed (p = 0,01), cadence and stride length (p < 0,00001), while with combined cues (visual + auditory) there was greater gains in UPDRS III (p = 0,009) than in speed (p = 0,01). Conclusion: this systematic review has evidence level 1A based on the “Oxford Centre for Evidence-based Medicine”. It was proved that the use of external cues is effective to improve gait parameters of patients with Parkinson's disease, with improvements on freezing and psychomotor performance, evaluated by FOGQ and UPDRS III, respectively. / BV UNIFESP: Teses e dissertações