Idiopathic Parkinson??s disease (PD) and the atypical parkinsonian syndromes progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) have substantial overlap in clinical features, with parkinsonian and cerebellar phenotypes identified. Pathologically, reactive glial changes occur in overlapping pathways in these disorders. Recent findings that glia concentrate proteins associated with genetic forms of PD, suggest a more significant role for these cells in the pathogenesis of these disorders. This study is the first to comparatively assess glial abnormalities in PD, PSP and MSA. Cases were clinically and pathologically characterised to establish correlates to prominent glial changes. The three main types of glia (astrocytes, oligodendroglia and microglia) were characterised by morphological features and protein expression (using immunohistochemical techniques) for correlations with disease indices. Tissue features measured included subregional volumes, nigral cell loss, characteristic disease inclusions, and the densities of glia. Using these techniques, the parkin co-regulated gene protein was found to be a novel constituent protein in protoplasmic astrocytes, facilitating the assessment of glial subtypes. The data show that distinct glial abnormalities associate with each parkinsonian syndrome. The most marked differences were observed in the astrocytic reaction in each disorder. In PD, protoplasmic astrocytes accumulated non-fibrillar -synuclein and degenerated over time, relating to a loss of levodopa responsiveness. In PSP, there was a marked protoplasmic astrogliosis (with these reactive glia strongly expressing parkin) that related to PSP-prominent clinical symptoms. In MSA, there was a marked fibrous astrogliosis and a loss of protoplasmic astrocytes in association with early changes in constituent myelin and oligodendroglial proteins. In contrast, similar microglial activation was observed across all disorders, with phagocytes concentrating in the substantia nigra, while non-phagocytic reactive microglia expressed parkin and associated with inclusion formation in each disorder. Overall, the glial reactions were considered to be either contributing to or ameliorating (neuroprotective) the neurodegenerative processes, and the timing of these reactions assessed with respect to indices of disease progression. The novel findings of this thesis show that glial abnormalities are prominent but distinct, and occur early in these parkinsonian syndromes. Suggestions on how these findings may translate into future therapeutic targets are given.

Idiopathic Parkinson??s disease (PD) and the atypical parkinsonian syndromes progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) have substantial overlap in clinical features, with parkinsonian and cerebellar phenotypes identified. Pathologically, reactive glial changes occur in overlapping pathways in these disorders. Recent findings that glia concentrate proteins associated with genetic forms of PD, suggest a more significant role for these cells in the pathogenesis of these disorders. This study is the first to comparatively assess glial abnormalities in PD, PSP and MSA. Cases were clinically and pathologically characterised to establish correlates to prominent glial changes. The three main types of glia (astrocytes, oligodendroglia and microglia) were characterised by morphological features and protein expression (using immunohistochemical techniques) for correlations with disease indices. Tissue features measured included subregional volumes, nigral cell loss, characteristic disease inclusions, and the densities of glia. Using these techniques, the parkin co-regulated gene protein was found to be a novel constituent protein in protoplasmic astrocytes, facilitating the assessment of glial subtypes. The data show that distinct glial abnormalities associate with each parkinsonian syndrome. The most marked differences were observed in the astrocytic reaction in each disorder. In PD, protoplasmic astrocytes accumulated non-fibrillar -synuclein and degenerated over time, relating to a loss of levodopa responsiveness. In PSP, there was a marked protoplasmic astrogliosis (with these reactive glia strongly expressing parkin) that related to PSP-prominent clinical symptoms. In MSA, there was a marked fibrous astrogliosis and a loss of protoplasmic astrocytes in association with early changes in constituent myelin and oligodendroglial proteins. In contrast, similar microglial activation was observed across all disorders, with phagocytes concentrating in the substantia nigra, while non-phagocytic reactive microglia expressed parkin and associated with inclusion formation in each disorder. Overall, the glial reactions were considered to be either contributing to or ameliorating (neuroprotective) the neurodegenerative processes, and the timing of these reactions assessed with respect to indices of disease progression. The novel findings of this thesis show that glial abnormalities are prominent but distinct, and occur early in these parkinsonian syndromes. Suggestions on how these findings may translate into future therapeutic targets are given.

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published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

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A Doença de Parkinson (DP) caracteriza-se por sintomas motores típicos e déficits proprioceptivos. Considerando-se o papel do estresse oxidativo na doença, o uso de agentes antioxidantes pode ter potencial terapêutico. Depois de uma revisão sobre déficits proprioceptivos na DP, esta dissertação apresenta um estudo empírico sobre o efeito da epicatequina (EC), sobre o modelo animal da 6- hidroxidopamina (6-OHDA). Ratos (n = 75) infundidos unilateralmente com 6- OHDA na via nigroestriatal receberam, após 24h, infusões intracerebrais de EC no estriado (0,031mg/mL, 0,1mg/mL, 0,31mg/mL, 1mg/mL ou veículo). O tratamento foi avaliado através dos testes de rotações induzidas por metilfenidato (40mg/kg) e apomorfina (1mg/kg), teste de motricidade sobre grade e teste da fita adesiva, além de imunoistoquímica. Os resultados mostraram que não houve diferenças entre os grupos em nenhuma das avaliações. Com base nesses resultados, concluímos que a EC, nas concentrações e condições empregadas, não foi capaz de retardar a lesão nigroestriatal ou recuperá-la. / Besides the typical motor symptoms, Parkinson´s disease (PD) is characterized by deficits in proprioception. Considering the putative role of oxidative stress in PD, antioxidants might have therapeutic value. After a review on proprioception in PD, this dissertation presents an empirical study based on the evaluation of epicatechin (EC), in 6-hydroxidopamine (6-0HDA) model of Parkinsonism. Rats (n=75) where unilaterally lesioned into the nigrostriatal pathway and treated 24h later with intracerebral infusions of EC in the striatum (0.031mg/mL, 0.1mg/mL, 0.31mg/mL, 1mg/mL or vehicle). The behavioral effects were assessed through methylphenidate (40 mg/kg) and apomorphine (1 mg/kg)-induced rotations, footfault and stick-tape tests; and brain tissue was analyzed by imunohistochemistry. There were no significant differences between groups neither in the behavioral assessments nor the histological analyses. These results showed that EC was incapable to act on either the reversal or retardation of the lesion in the nigrostriatal pathway.

A Doença de Parkinson (DP) caracteriza-se por sintomas motores típicos e déficits proprioceptivos. Considerando-se o papel do estresse oxidativo na doença, o uso de agentes antioxidantes pode ter potencial terapêutico. Depois de uma revisão sobre déficits proprioceptivos na DP, esta dissertação apresenta um estudo empírico sobre o efeito da epicatequina (EC), sobre o modelo animal da 6- hidroxidopamina (6-OHDA). Ratos (n = 75) infundidos unilateralmente com 6- OHDA na via nigroestriatal receberam, após 24h, infusões intracerebrais de EC no estriado (0,031mg/mL, 0,1mg/mL, 0,31mg/mL, 1mg/mL ou veículo). O tratamento foi avaliado através dos testes de rotações induzidas por metilfenidato (40mg/kg) e apomorfina (1mg/kg), teste de motricidade sobre grade e teste da fita adesiva, além de imunoistoquímica. Os resultados mostraram que não houve diferenças entre os grupos em nenhuma das avaliações. Com base nesses resultados, concluímos que a EC, nas concentrações e condições empregadas, não foi capaz de retardar a lesão nigroestriatal ou recuperá-la. / Besides the typical motor symptoms, Parkinson´s disease (PD) is characterized by deficits in proprioception. Considering the putative role of oxidative stress in PD, antioxidants might have therapeutic value. After a review on proprioception in PD, this dissertation presents an empirical study based on the evaluation of epicatechin (EC), in 6-hydroxidopamine (6-0HDA) model of Parkinsonism. Rats (n=75) where unilaterally lesioned into the nigrostriatal pathway and treated 24h later with intracerebral infusions of EC in the striatum (0.031mg/mL, 0.1mg/mL, 0.31mg/mL, 1mg/mL or vehicle). The behavioral effects were assessed through methylphenidate (40 mg/kg) and apomorphine (1 mg/kg)-induced rotations, footfault and stick-tape tests; and brain tissue was analyzed by imunohistochemistry. There were no significant differences between groups neither in the behavioral assessments nor the histological analyses. These results showed that EC was incapable to act on either the reversal or retardation of the lesion in the nigrostriatal pathway.

A Doença de Parkinson (DP) caracteriza-se por sintomas motores típicos e déficits proprioceptivos. Considerando-se o papel do estresse oxidativo na doença, o uso de agentes antioxidantes pode ter potencial terapêutico. Depois de uma revisão sobre déficits proprioceptivos na DP, esta dissertação apresenta um estudo empírico sobre o efeito da epicatequina (EC), sobre o modelo animal da 6- hidroxidopamina (6-OHDA). Ratos (n = 75) infundidos unilateralmente com 6- OHDA na via nigroestriatal receberam, após 24h, infusões intracerebrais de EC no estriado (0,031mg/mL, 0,1mg/mL, 0,31mg/mL, 1mg/mL ou veículo). O tratamento foi avaliado através dos testes de rotações induzidas por metilfenidato (40mg/kg) e apomorfina (1mg/kg), teste de motricidade sobre grade e teste da fita adesiva, além de imunoistoquímica. Os resultados mostraram que não houve diferenças entre os grupos em nenhuma das avaliações. Com base nesses resultados, concluímos que a EC, nas concentrações e condições empregadas, não foi capaz de retardar a lesão nigroestriatal ou recuperá-la. / Besides the typical motor symptoms, Parkinson´s disease (PD) is characterized by deficits in proprioception. Considering the putative role of oxidative stress in PD, antioxidants might have therapeutic value. After a review on proprioception in PD, this dissertation presents an empirical study based on the evaluation of epicatechin (EC), in 6-hydroxidopamine (6-0HDA) model of Parkinsonism. Rats (n=75) where unilaterally lesioned into the nigrostriatal pathway and treated 24h later with intracerebral infusions of EC in the striatum (0.031mg/mL, 0.1mg/mL, 0.31mg/mL, 1mg/mL or vehicle). The behavioral effects were assessed through methylphenidate (40 mg/kg) and apomorphine (1 mg/kg)-induced rotations, footfault and stick-tape tests; and brain tissue was analyzed by imunohistochemistry. There were no significant differences between groups neither in the behavioral assessments nor the histological analyses. These results showed that EC was incapable to act on either the reversal or retardation of the lesion in the nigrostriatal pathway.