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Expert Opin Ther Targets. 2009 Mar;13(3):319-29. doi: 10.1517/13543780802716501 .

The transcription factor Nrf2 as a new therapeutic target in Parkinson's disease.

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1
Instituto de Investigaciones Biomédicas Alberto Sols UAM-CSIC, Ciber de Enfermedades Neurodegenerativas, Departamento de Bioquímica, Facultad de Medicina Universidad Autónoma de Madrid, Madrid, Spain. antonio.cuadrado@uam.es

Abstract

In recent years, it has been accepted that oxidative stress is critically involved in the etiopathology of Parkinson's disease (PD) and as a result new therapeutic targets for reduction of oxidant injury and neuroprotection can be defined. Here we discuss the potential use of the transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2), as a pharmacological target for neuroprotective therapy in PD. Data generated by various groups indicate that Nrf2 induces the expression of a group of cytoprotective, antixenobiotic and antioxidant enzymes that include heme oxygenase-1, NAD(P)H:quinone oxidoreductase and enzymes of glutathione (GSH) metabolism such as gamma-glutamyl cysteine ligase, GSH transferases and so on. Two strategies are known to increase Nrf2 transcriptional activity in PD: i) use of certain catechol-derived quinones for selective inhibition of the Nrf2 repressor Kelch-like ECH-associated protein to increase of Nrf2 protein levels; and ii) use of glycogen synthase kinase 3beta inhibitors to maintain high protein and activity levels of Nrf2 in the nucleus. This review provides a rationale for drug design of appropriate molecules that might endorse a neuroprotective strategy to PD on the basis of attenuation of oxidative stress.

PMID:
19236154
DOI:
10.1517/13543780802716501
[Indexed for MEDLINE]

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