N-acetylcysteine amide confers neuroprotection, improves bioenergetics and behavioral outcome following TBI

Jignesh D. Pandya, Ryan D. Readnower, Samir P. Patel, Heather M. Yonutas, James R. Pauly, Glenn A. Goldstein, Alexander G. Rabchevsky, Patrick G. Sullivan

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

Abstract

Traumatic brain injury (TBI) has become a growing epidemic but no approved pharmacological treatment has been identified. Our previous work indicates that mitochondrial oxidative stress/damage and loss of bioenergetics play a pivotal role in neuronal cell death and behavioral outcome following experimental TBI. One tactic that has had some experimental success is to target glutathione using its precursor N-acetylcysteine (NAC). However, this approach has been hindered by the low CNS bioavailability of NAC. The current study evaluated a novel, cell permeant amide form of N-acetylcysteine (NACA), which has high permeability through cellular and mitochondrial membranes resulting in increased CNS bioavailability. Cortical tissue sparing, cognitive function and oxidative stress markers were assessed in rats treated with NACA, NAC, or vehicle following a TBI. At 15. days post-injury, animals treated with NACA demonstrated significant improvements in cognitive function and cortical tissue sparing compared to NAC or vehicle treated animals. NACA treatment also was shown to reduce oxidative damage (HNE levels) at 7. days post-injury. Mechanistically, post-injury NACA administration was demonstrated to maintain levels of mitochondrial glutathione and mitochondrial bioenergetics comparable to sham animals. Collectively these data provide a basic platform to consider NACA as a novel therapeutic agent for treatment of TBI.

Original languageEnglish
Pages (from-to)106-113
Number of pages8
JournalExperimental Neurology
Volume257
DOIs
StatePublished - Jul 2014

Bibliographical note

Funding Information:
This work was supported by NIH/NINDS R01 NS062993 (JWG and PGS), R01NS069633 (AGR and PGS), NIH/NINDS P30NS051220 and funding from the Kentucky Spinal Cord and Head Injury Research Trust. We would like to thank Andrea Sebastian for expert technical assistance.

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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