The transcription factor Nrf2 as a new therapeutic target in Parkinson's disease.
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.
Cuadrado
Antonio
A
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
Moreno-Murciano
Paz
P
Pedraza-Chaverri
José
J
D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000187:drug effects* / Q000235:genetics; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D010300:Parkinson Disease / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D000978:Antiparkinson Agents; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species