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Advisor(s)
Abstract(s)
A doença de Parkinson é a segunda doença neurodegenerativa mais
comum, depois do Alzheimer, e caracteriza-se principalmente pela perda
progressiva de neurónios dopaminérgicos na Substantia Nigra. Numerosos
trabalhos reportaram a maior prevalência e incidência desta doença no sexo
masculino, relativamente ao sexo feminino. Estudos envolvendo a reposição
com estrogénios em ratos fêmea ovariectomizados, atribuíram esta diferença
de incidências ao efeito neuroprotectivo do estrogénio. No entanto, o grau de
protecção exercida por níveis fisiológicos desta hormona permanece
desconhecido.
Os estrogénios também têm sido implicados na regulação da expressão
de factores neurotróficos, o que pode estar na origem dos seus efeitos
neuroprotectores. O factor neurotrófico derivado de uma linha de células da glia
(GDNF) é um dos factores neurotróficos regulados pelo estrogénio, que foi
implicado na neuroprotecção e regeneração na via nigroestriatal, actuando
como um potente factor de sobrevivência para os neurónios dopaminérgicos,
que são alvo de degeneração na doença de Parkinson.
De forma a esclarecer o papel dos níveis endógenos de estrogénio na
protecção da via nigroestriatal, utilizámos como modelo da doença de
Parkinson a 6-hidroxidopamina, e estudámos de que forma a remoção dos
ovários em fêmeas férteis interferiu com a extenção da lesão dopaminérgica
induzida pela toxina. As fêmeas Wistar foram ovariectomizadas e 3 semanas
após a cirurgia os animais foram injectados estereotaxicamente, no estriado, com 6-hidroxidopamina. A extensão da lesão foi avaliada através da contagem
de células que expressavam o marcador dopaminérgico tirosina hidroxilase,
por imunohistoquimica, assim como pelos níveis de expressão desta proteína,
por western blot, tanto na Substantia Nigra como no estriado. Os níveis
plasmáticos de estradiol também foram quantificados. De forma a determinar a
a existência de relação entre os níveis de estradiol, a expressão de GDNF e a
extensão da lesão dopaminérgica, também foi estudada a expressão do factor
neurotrófico GDNF.
Os nossos resultados sugerem fortemente que o estrogénio produzido
endogenamente, assim como o GDNF, estão associados com níveis
aumentados de tirosina hidroxilase estriatal, um marcador de sobrevivência da
célula dopaminérgica.
Parkinson´s disease is the second most common neurodegenerative disorder after Alzheimer and is mainly characterized by a progressive and selective depletion of dopamine neurons in the Substantia Nigra. Numerous studies have reported a greater prevalence and incidence of PD in men than in women. Studies involving estrogen treatment of ovariectomised rodents attribute this largely to the neuroprotective effets of estrogen. However, a neuroprotective role for physiologic levels of circulating estrogen in females is less clear. Estrogens have also been shown to regulate the expression of neurotrophic factors, like glial cell line-derived neurotrophic factor (GDNF), which might mediate their neuroprotective effects. GDNF produces neuroprotective and regenerative effects in the nigrostriatal pathways, acting as a potent survival factor for dopaminergic neurons that degenerate in Parkinson’s disease. In order to clarify the role of endogenous levels of estrogens in protecting the nigrostriatal pathway, we used the 6-hydroxydopamine (6-OHDA) model of Parkinson’s disease and tested how the removal of ovaries in fertile females interferes with extent of the dopaminergic lesion induced by 6-OHDA. Female Wistar rats were ovariectomised and 3 weeks after the surgery the animals were stereotaxically injected in the striatum with 6-OHDA. The extent of the lesion was assessed by counting the cells expressing the dopaminergic marker tyrosine hydroxylase by imunohistochemistry and also the expression levels of this protein by Western blot in both the Substantia Nigra and the striatum. The plasma levels of estradiol were also quantified. To determine if there was a relationship between estradiol levels, the expression of GDNF and the extent of the dopaminergic lesion, we also studied the expression of the neurotrophic factor GDNF. Our findings strongly suggest that endogenously produced estrogens and GDNF are associated with increased levels of striatal tyrosine hydroxylase, a marker of dopaminergic cell survival.
Parkinson´s disease is the second most common neurodegenerative disorder after Alzheimer and is mainly characterized by a progressive and selective depletion of dopamine neurons in the Substantia Nigra. Numerous studies have reported a greater prevalence and incidence of PD in men than in women. Studies involving estrogen treatment of ovariectomised rodents attribute this largely to the neuroprotective effets of estrogen. However, a neuroprotective role for physiologic levels of circulating estrogen in females is less clear. Estrogens have also been shown to regulate the expression of neurotrophic factors, like glial cell line-derived neurotrophic factor (GDNF), which might mediate their neuroprotective effects. GDNF produces neuroprotective and regenerative effects in the nigrostriatal pathways, acting as a potent survival factor for dopaminergic neurons that degenerate in Parkinson’s disease. In order to clarify the role of endogenous levels of estrogens in protecting the nigrostriatal pathway, we used the 6-hydroxydopamine (6-OHDA) model of Parkinson’s disease and tested how the removal of ovaries in fertile females interferes with extent of the dopaminergic lesion induced by 6-OHDA. Female Wistar rats were ovariectomised and 3 weeks after the surgery the animals were stereotaxically injected in the striatum with 6-OHDA. The extent of the lesion was assessed by counting the cells expressing the dopaminergic marker tyrosine hydroxylase by imunohistochemistry and also the expression levels of this protein by Western blot in both the Substantia Nigra and the striatum. The plasma levels of estradiol were also quantified. To determine if there was a relationship between estradiol levels, the expression of GDNF and the extent of the dopaminergic lesion, we also studied the expression of the neurotrophic factor GDNF. Our findings strongly suggest that endogenously produced estrogens and GDNF are associated with increased levels of striatal tyrosine hydroxylase, a marker of dopaminergic cell survival.
Description
Keywords
Estrogénios Estrogénios - Factor neurotrófico - GDNF Estrogénios - Neuroprotecção - GDNF Estrogénios - Doença de Parkinson
Citation
Publisher
Universidade da Beira Interior