Differential effects of NOX2 and NOX4 inhibition after rodent spinal cord injury

PLOS ONE, 2023 · DOI: https://doi.org/10.1371/journal.pone.0281045 · Published: March 10, 2023

Simple Explanation

Spinal cord injury (SCI) leads to inflammation and oxidative stress, hindering recovery. Reactive oxygen species (ROS) contribute to this, with NADPH oxidase (NOX) enzymes being key ROS sources. This study explores the roles of NOX2 and NOX4 after SCI in mice. The researchers used NOX2 knockout mice and a NOX4 inhibitor (GKT137831) to examine the effects of blocking these enzymes after SCI. They assessed motor function, inflammation, and oxidative stress. Genetic removal of NOX2 improved motor recovery and reduced oxidative stress long-term. Blocking NOX4 acutely reduced ROS but didn't lead to lasting improvements in motor function.

Study Duration

28 Days

Participants

82 male mice (NOX2 KO n = 16, WT n = 53, WT naïve n = 3)

Evidence Level

Not specified

Key Findings

1
NOX2 knockout mice showed significantly improved motor function at 7, 14, and 28 days post-injury compared to wild-type mice.
2
Both NOX2 knockout and GKT137831 treatment significantly reduced ROS production and oxidative stress markers.
3
NOX2 knockout mice exhibited a shift in microglial activation toward a more neuroprotective, anti-inflammatory state at 7 days post-injury and a reduction of microglial markers at 28 days.

Research Summary

This study investigated the differential effects of NOX2 and NOX4 inhibition after spinal cord injury (SCI) in rodents, using NOX2 knockout mice and a NOX4 inhibitor (GKT137831). Genetic ablation of NOX2 resulted in improved motor function, reduced oxidative stress, and a shift towards anti-inflammatory microglial activation, while acute NOX4 inhibition only provided temporary reductions in ROS without sustained functional benefits. The findings suggest that targeting NOX2 may have therapeutic benefits for SCI, whereas a single dose of NOX4 inhibitor is less effective in promoting long-term recovery.

Practical Implications

Therapeutic Potential of NOX2 Inhibition

Targeting NOX2 after SCI may offer therapeutic benefits for improving motor function and reducing oxidative stress and inflammation.

Limited Efficacy of Acute NOX4 Inhibition

A single dose of a NOX4 inhibitor may not be sufficient for promoting long-term recovery after SCI, suggesting the need for alternative treatment strategies.

Microglial Modulation

NOX2 knockout can modulate microglial activation towards a neuroprotective phenotype, highlighting the importance of microglial polarization in SCI recovery.

Study Limitations

1
GKT137831 inhibits both NOX1 and NOX4, making it difficult to isolate the specific effect of NOX4 inhibition.
2
The study only evaluated responses in male rodents, and limited information is available on the influence of sex on NOX2 or 4 expression or impact in the injured spinal cord.
3
The study only used a single dose of NOX4 inhibitor.

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