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Authors
Abstract(s)
A doença de Parkinson (DP) é a segunda doença neurodegenerativa mais comum do
sistema nervoso central (SNC). Patologicamente, é caracterizada pela perda progressiva de
neurónios dopaminérgicos na substantia nigra pars compacta (SNpc) e pela formação de
corpos de Lewy. Estas alterações patológicas estão subjacentes aos sintomas motores e não
motores, que incluem o comprometimento cognitivo, definindo a doença de Parkinson com
demência (DPD). A DPD envolve mecanismos moleculares patológicos, como o stress oxidativo (SO) e o envolvimento da a-sinucleína e da ß-amilóide, que está associado ao estado
cognitivo. As NADPH oxidases (NOX), responsáveis pela produção de espécies reativas de
oxigénio (ROS), estão envolvidas nos mecanismos moleculares patológicos, afetando uma
variedade de funções cognitivas. Particularmente, a Nox4 tem vindo a ser implicada na progressão da patologia. Assim, este projeto pretendeu investigar se um inibidor das isoformas
1 e 4 das NOX, formulado em líquido iónico (N1(4)inh-IL), seria capaz de contrariar o contributo patológico da deposição proteica anormal num modelo animal da DP. Para isso, foram avaliados os níveis de a-sinucleína, de ß-amilóide e de oligómero A11 na região da substantia nigra (SN) e do hipocampo (HC). Os resultados demonstraram uma redução dos
níveis de agregação proteica destas proteínas no grupo de animais que foram tratados com
o N1(4)inh-IL. Estes resultados sugerem que ao inibir a Nox4, a deposição e agregação anormal de proteínas na SN e no HC são prevenidas. Tal formulação poderá ser utilizada futuramente para terapias que envolvam a inibição das NOX, no controlo da produção excessiva
de ROS.
Parkinson's disease is the second most common neurodegenerative disease of the central nervous system. Pathologically, it is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the formation of Lewy bodies. These pathological changes underlie motor symptoms and non-motor symptoms, which include cognitive impairment, defining Parkinson’s disease with dementia (PDD). PDD involves pathological molecular mechanisms, such as oxidative stress and the involvement of a-synuclein and ß-amyloid, which is associated with cognitive status. NADPH oxidases (NOX), responsible for the production of reactive oxygen species (ROS), are involved in pathological molecular mechanisms, affecting a variety of cognitive functions. In particular, Nox4 has been implicated in the progression of pathology. Therefore, this project aimed to investigate whether an inhibitor of NOX isoforms 1 and 4, formulated in ionic liquid (N1(4)- inh-IL), would be able to counteract the pathological contribution of abnormal protein deposition in an animal model of PD. To this end, the levels of-synuclein, ß-amyloid and A11 oligomer in the substantia nigra (SN) and hippocampus (HC) were assessed. The results showed a reduction in the levels of protein aggregation of these proteins in the group of animals that were treated with N1(4)inh-IL. These results suggest that by inhibiting Nox4, the deposition and abnormal aggregation of proteins in the SN and HC are prevented. Such a formulation could be used in the future for therapies involving NOX inhibition to control excessive ROS production.
Parkinson's disease is the second most common neurodegenerative disease of the central nervous system. Pathologically, it is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the formation of Lewy bodies. These pathological changes underlie motor symptoms and non-motor symptoms, which include cognitive impairment, defining Parkinson’s disease with dementia (PDD). PDD involves pathological molecular mechanisms, such as oxidative stress and the involvement of a-synuclein and ß-amyloid, which is associated with cognitive status. NADPH oxidases (NOX), responsible for the production of reactive oxygen species (ROS), are involved in pathological molecular mechanisms, affecting a variety of cognitive functions. In particular, Nox4 has been implicated in the progression of pathology. Therefore, this project aimed to investigate whether an inhibitor of NOX isoforms 1 and 4, formulated in ionic liquid (N1(4)- inh-IL), would be able to counteract the pathological contribution of abnormal protein deposition in an animal model of PD. To this end, the levels of-synuclein, ß-amyloid and A11 oligomer in the substantia nigra (SN) and hippocampus (HC) were assessed. The results showed a reduction in the levels of protein aggregation of these proteins in the group of animals that were treated with N1(4)inh-IL. These results suggest that by inhibiting Nox4, the deposition and abnormal aggregation of proteins in the SN and HC are prevented. Such a formulation could be used in the future for therapies involving NOX inhibition to control excessive ROS production.
Description
Keywords
Agregação Proteica Anormal Doença de Parkinson com Demência Inibidor Nox Nadph Oxidases