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Brain Behav Immun. 2019 Feb;76:139-150. doi: 10.1016/j.bbi.2018.11.013. Epub 2018 Nov 16.

Reducing age-dependent monocyte-derived macrophage activation contributes to the therapeutic efficacy of NADPH oxidase inhibition in spinal cord injury.

Author information

1
Spinal Cord and Brain Injury Research Center (SCoBIRC), Department of Physiology, University of Kentucky, Lexington, KY 40536, United States; College of Public Health, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi 712046 PR China. Electronic address: bei.zhang@uky.edu.
2
Spinal Cord and Brain Injury Research Center (SCoBIRC), Department of Physiology, University of Kentucky, Lexington, KY 40536, United States. Electronic address: william.bailey@uky.edu.
3
Spinal Cord and Brain Injury Research Center (SCoBIRC), Department of Physiology, University of Kentucky, Lexington, KY 40536, United States.
4
Spinal Cord and Brain Injury Research Center (SCoBIRC), Department of Physiology, University of Kentucky, Lexington, KY 40536, United States. Electronic address: andrew.n.stewart@uky.edu.
5
Spinal Cord and Brain Injury Research Center (SCoBIRC), Department of Physiology, University of Kentucky, Lexington, KY 40536, United States. Electronic address: amy.veldhorst@uky.edu.
6
Spinal Cord and Brain Injury Research Center (SCoBIRC), Department of Physiology, University of Kentucky, Lexington, KY 40536, United States. Electronic address: gensel.1@uky.edu.

Abstract

OBJECTIVE:

The average age at the time of spinal cord injury (SCI) has increased to 43 years old. Middle-aged mice (14 months old, MO) exhibit impaired recovery after SCI with age-dependent increases in reactive oxygen species (ROS) production through NADPH oxidase (NOX) along with pro-inflammatory macrophage activation. Despite these aging differences, clinical therapies are being examined in individuals regardless of age based upon preclinical data generated primarily using young animals (∼4 MO). Our objective is to test the extent to which age affects SCI treatment efficacy. Specifically, we hypothesize that the effectiveness of apocynin, a NOX inhibitor, is age-dependent in SCI.

METHODS:

Apocynin treatment (5 mg/kg) or vehicle was administered 1 and 6 h after moderate T9 contusion SCI (50kdyn IH) and then daily for 1 week to 4 and 14 MO mice. Locomotor and anatomical recovery was evaluated for 28 days. Monocyte-derived macrophage (MDM) and microglial activation and ROS production were evaluated at 3 and 28 days post-injury.

RESULTS:

Apocynin improved functional and anatomical recovery in 14 but not 4 MO SCI mice. Apocynin-mediated recovery was coincident with significant reductions in MDM infiltration and MDM-ROS production in 14 MO SCI mice. Importantly, microglial activation was unaffected by treatment.

CONCLUSION:

These results indicate that apocynin exhibits age-dependent neuroprotective effects by blocking excessive neuroinflammation through NOX-mediated ROS production in MDMs. Further, these data identify age as a critical regulator for SCI treatment efficacy and indicate that pharmacologically reduced macrophage, but not microglia, activation and ROS production reverses age-associated neurological impairments.

KEYWORDS:

Age; Apocynin; Macrophage; Microglia; Monocyte; NADPH oxidase; Neuroinflammation; Reactive oxygen species; Spinal cord injury

PMID:
30453022
PMCID:
PMC6348135
[Available on 2020-02-01]
DOI:
10.1016/j.bbi.2018.11.013
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