Neuroprotection After Stroke by Targeting NOX4 As a Source of Oxidative Stress

Abstract

Significance: Stroke, a leading cause of death and disability, poses a substantial burden for patients, relatives, and our healthcare systems. Only one drug is approved for treating stroke, and more than 30 contraindications exclude its use in 90% of all patients. Thus, new treatments are urgently needed. In this review, we discuss oxidative stress as a pathomechanism of poststroke neurodegeneration and the inhibition of its source, type 4 nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX4), as a conceptual breakthrough in stroke therapy. Recent Advances: Among potential sources of reactive oxygen species (ROS), the NOXes stand out as the only enzyme family that is solely dedicated to forming ROS. In rodents, three cerebrovascular NOXes exist: the superoxide-forming NOX1 and 2 and the hydrogen peroxide-forming NOX4. Studies using NOX1 knockout mice gave conflicting results, which overall do not point to a role for this isoform. Several reports find NOX2 to be relevant in stroke, albeit to variable and moderate degrees. In our hands, NOX4 is, by far, the major source of oxidative stress and neurodegeneration on ischemic stroke. Critical Issues: We critically discuss the tools that have been used to validate the roles of NOX in stroke. We also highlight the relevance of different animal models and the need for advanced quality control in preclinical stroke research. Future Directions: The development of isoform-specific NOX inhibitors presents a precious tool for further clarifying the role and drugability of NOX homologues. This could pave the avenue for the first clinically effective neuroprotectant applied poststroke, and even beyond this, stroke could provide a proof of principle for antioxidative stress therapy.

Neuroprotective effect of apocynin nitrone in oxygen glucose deprivation-treated SH-SY5Y cells and rats with ischemic stroke

“…It brings irreversible injury of brain tissue if the cerebral blood vessel cannot be recanalized timely. Clinically, quick thrombolysis to restore blood flow as early as possible is recommended for the treatment of ischemic stroke [3]. The only proven thrombolytic therapy for acute ischemic stroke was achieved by intravenous use of t-PA.…”

“…It is one of the leading causes of death and disability worldwide. However, few therapeutic methods or drugs have adequate effects in the clinical treatment of ischemic stroke [2,3]. Timely recanalization of cerebral artery vessels and reintroduction of blood flow allow ischemic stroke-induced impairments to be arrested and reversed, thus, it is considered as an efficient therapy [3].…”

“…Timely recanalization of cerebral artery vessels and reintroduction of blood flow allow ischemic stroke-induced impairments to be arrested and reversed, thus, it is considered as an efficient therapy [3]. In ischemic cerebral injury, besides the ischemic infarction, the reperfusion after ischemia brings oxidative injury induced by reactive oxygen species (ROS) as well, which might cause delayed neuronal death [3]. To prevent irreversible ischemic injury, neuroprotection is essential [2][3][4].…”

“…In ischemic cerebral injury, besides the ischemic infarction, the reperfusion after ischemia brings oxidative injury induced by reactive oxygen species (ROS) as well, which might cause delayed neuronal death [3]. To prevent irreversible ischemic injury, neuroprotection is essential [2][3][4]. In ischemiareperfusion (I/R), superoxide anion is one of the most important ROS, as it contributes to oxidative injury in the progress of ischemic stroke [5].…”

New Insights onNOXEnzymes in the Central Nervous System

“…(86)] or NOX4 [comprehensively reviewed in ref. (137)] isoforms are the key pharmacological target for stroke. Interestingly, a recent report showed that deletion of the proton channel Hv1 significantly protected from brain damage caused by ischemic stroke (186).…”