N-acetylcysteine amide preserves mitochondrial bioenergetics and improves functional recovery following spinal trauma

Samir P. Patel, Patrick G. Sullivan, Jignesh D. Pandya, Glenn A. Goldstein, Jenna L. VanRooyen, Heather M. Yonutas, Khalid C. Eldahan, Johnny Morehouse, David S.K. Magnuson, Alexander G. Rabchevsky

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

Abstract

Mitochondrial dysfunction is becoming a pivotal target for neuroprotective strategies following contusion spinal cord injury (SCI) and the pharmacological compounds that maintain mitochondrial function confer neuroprotection and improve long-term hindlimb function after injury. In the current study we evaluated the efficacy of cell-permeating thiol, N-acetylcysteine amide (NACA), a precursor of endogenous antioxidant glutathione (GSH), on mitochondrial function acutely, and long-term tissue sparing and hindlimb locomotor recovery following upper lumbar contusion SCI. Some designated injured adult female Sprague-Dawley rats (n = 120) received either vehicle or NACA (75, 150, 300 or 600. mg/kg) at 15. min and 6. h post-injury. After 24. h the total, synaptic, and non-synaptic mitochondrial populations were isolated from a single 1.5 cm spinal cord segment (centered at injury site) and assessed for mitochondrial bioenergetics. Results showed compromised total mitochondrial bioenergetics following acute SCI that was significantly improved with NACA treatment in a dose-dependent manner, with maximum effects at 300. mg/kg (n = 4/group). For synaptic and non-synaptic mitochondria, only 300. mg/kg NACA dosage showed efficacy. Similar dosage (300 mg/kg) also maintained mitochondrial GSH near normal levels. Other designated injured rats (n = 21) received continuous NACA (150 or 300. mg/kg/day) treatment starting at 15. min post-injury for one week to assess long-term functional recovery over 6. weeks post-injury. Locomotor testing and novel gait analyses showed significantly improved hindlimb function with NACA that were associated with increased tissue sparing at the injury site. Overall, NACA treatment significantly maintained acute mitochondrial bioenergetics and normalized GSH levels following SCI, and prolonged delivery resulted in significant tissue sparing and improved recovery of hindlimb function.

Original languageEnglish
Pages (from-to)95-105
Number of pages11
JournalExperimental Neurology
Volume257
DOIs
StatePublished - Jul 2014

Bibliographical note

Funding Information:
Special thanks to Dr. David Powell for technical expertise in MRI analysis and Mr. Taylor Smith for helping with MRI scanning. This study was supported by NIH/NINDS R01NS069633 (A.G.R. and P.G.S.), The Craig H. Neilsen Foundation # 190115 (A.G.R.), NIH/NINDS P30 NS051220 (UK) and NIH/NIGMS P30 GM103507 (UofL).

Keywords

  • Contusion spinal cord injury
  • Gait analysis
  • N-acetylcysteine amide (NACA)
  • Neuroprotective agent
  • Therapeutics

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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