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

Abstract

Neurodegenerative disease are frequently characterized by microglia activation and/or leukocyte infiltration in the parenchyma of the central nervous system and at the molecular level by increased oxidative modifications of proteins, lipids and nucleic acids. NADPH oxidases (NOX) emerged as a novel promising class of pharmacological 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) and hydrogen peroxide (HO). However in the context of neuroinflammation, they present paradoxical features since O/HO generated by NOX and/or secondary reactive oxygen species (ROS) derived from O/HO can either lead to neuronal oxidative damage or resolution of inflammation. The role of NOX enzymes has been investigated in many models of neurodegenerative diseases by using either genetic or pharmacological approaches. In the present review we provide a critical assessment of recent findings related to the role of NOX in the CNS as well as how the field 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 neuroinflammation 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 inflammatory 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 efficacy 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.

Activation of nicotinamide adenine dinucleotide phosphate oxidase is the primary trigger of epileptic seizures in rodent models

“…24,25 In our experiments, a rise in extracellular glutamate preceding the SLE onset could be sufficient to activate NMDA receptors possessing high affinity to this neurotransmitter. 24,25 In our experiments, a rise in extracellular glutamate preceding the SLE onset could be sufficient to activate NMDA receptors possessing high affinity to this neurotransmitter.…”

Mitochondria and aging: A role for the mitochondrial transition pore?

“…Among the various enzymatic sources generating ROS, NADPH oxidase is an important contributor of Aβ peptide‐induced ROS (Abramov et al., 2004) and is considered as a common feature of neurodegenerative diseases. Whether this is a cause or a consequence of the neurodegenerative process remains questionable (Sorce et al., 2017). …”

Dihydroceramide desaturase regulates the compartmentalization of Rac1 for neuronal oxidative stress

“…NOX is one of the major sources of ROS, and previous studies have shown a connection between NOX-dependent oxidative stress and neural disorders (Sorce et al, 2017). However, the subcellular site of NOX action remained ambiguous.…”

“…An elevated level of ROS in ifc-KO photoreceptors causes morphological and functional defects that can be ameliorated by panantioxidant AD4 , but the source of ROS was unknown. The major sources of ROS include mitochondrial electron transport chain, NADPH oxidases (NOXs), xanthine oxidases, peroxisomal acyl-coenzyme A oxidase 1, and nitric oxide synthase, all of which have been linked to neuronal oxidative stress in different pathological contexts (Angelova and Abramov, 2018;Chung et al, 2020;Dawson and Dawson, 2018;Honorat et al, 2013;Sorce et al, 2017). Of note, pan-antioxidants therapies were promising in preclinical models but had no significant effects in clinical trials.…”