The 1027th target candidate in stroke: Will NADPH oxidase hold up?

Area of Science:

• Biomedical Science
• Neuroscience
• Pharmacology

Background:

• 1026 neuroprotective drug candidates for stroke have failed clinical translation.
• Preclinical research quality and publication bias are identified as key failure reasons.
• Understanding neuronal death mechanisms post-stroke is crucial for developing new therapies.

Purpose of the Study:

• To review the state-of-the-art of NADPH oxidases (NOX) as a therapeutic target in ischemic stroke.
• To highlight the role of oxidative stress and NOX isoforms in stroke-induced neuronal death.
• To identify open questions for the clinical translation of NOX-targeting therapies.

Main Methods:

• Review of existing literature on neuroprotection in stroke.
• Analysis of data from NOX knockout mouse models in ischemic stroke.
• Discussion of the role of oxidative stress and reactive oxygen species (ROS) in stroke.

Main Results:

• NADPH oxidases (NOX1-5) are key enzymatic sources of ROS, implicated in cellular death.
• NOX4 appears to be the most relevant NOX isoform in the context of ischemic stroke.
• Despite established quality control guidelines, a gap in understanding stroke mechanisms persists.

Conclusions:

• Oxidative stress, mediated by NOX enzymes, is a promising target for neuroprotection in stroke.
• NOX4 warrants further investigation as a potential therapeutic target for stroke treatment.
• Addressing open questions regarding NOX4 function and inhibition is essential for clinical translation.