NADPH oxidases as drug targets and biomarkers in neurodegenerative diseases: What is the evidence?

Neurodegenerative disease are frequently characterized by microglia activation and/or leukocyte in fi ltration in the parenchyma of the central nervous system and at the molecular level by increased oxidative modi fi cations of proteins, lipids and nucleic acids. NADPH oxidases (NOX) emerged as a novel promising class of pharmacolo- gical targets for the treatment of neurodegeneration due to their role in oxidant generation and presumably in regulating microglia activation. The unique function of NOX is the generation of superoxide anion (O 2 •– ) and hydrogen peroxide (H 2 O 2 ). However in the context of neuroin fl ammation, they present paradoxical features since O 2 •– /H 2 O 2 generated by NOX and/or secondary reactive oxygen species (ROS) derived from O 2 •– /H 2 O 2 can either lead to neuronal oxidative damage or resolution of in fl ammation. The role of NOX enzymes has been investigated in many models of neurodegenerative diseases by using either genetic or pharmacological ap- proaches. In the present review we provide a critical assessment of recent fi ndings related to the role of NOX in the CNS as well as how the fi eld has advanced over the last 5 years. In particular, we focus on the data derived from the work of a consortium (Neurinox) funded by the European Commission's Programme 7 (FP7). We discuss the evidence gathered from animal models and human samples linking NOX expression/activity with neuroin- fl ammation in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Creutzfeldt – Jakob disease as well as autoimmune demyelinating diseases like multiple sclerosis (MS) and chronic in fl ammatory demyelinating polyneuropathy (CIDP). We address the possibility to use measurement of the activity of the NOX2 isoform in blood samples as biomarker of disease severity and treatment e ffi cacy in neurodegenerative disease. Finally we clarify key controversial aspects in the field of NOX, such as NOX cellular expression in the brain, measurement of NOX activity, impact of genetic deletion of NOX in animal models of neurodegeneration and specificity of NOX inhibitors.