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

Bei Zhang, William M. Bailey, Anna Leigh McVicar, Andrew N. Stewart, Amy K. Veldhorst, John C. Gensel

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

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.

Original languageEnglish
Pages (from-to)139-150
Number of pages12
JournalBrain, Behavior, and Immunity
Volume76
DOIs
StatePublished - Feb 2019

Bibliographical note

Funding Information:
We would like to thank Katelyn McFarlane for technical support., This study was supported by the University of Kentucky and the Spinal Cord and Brain Injury Research Center, the Craig H. Neilsen Foundation (Postdoctoral fellowship to BZ), and NIH NINDS R01NS091582 (JCG)., The authors declare no competing financial interests.

Funding Information:
This study was supported by the University of Kentucky and the Spinal Cord and Brain Injury Research Center, the Craig H. Neilsen Foundation (Postdoctoral fellowship to BZ), and NIH NINDS R01NS091582 (JCG).

Publisher Copyright:
© 2018 The Authors

Keywords

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

ASJC Scopus subject areas

  • Immunology
  • Endocrine and Autonomic Systems
  • Behavioral Neuroscience

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