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

Exp Neurol. 2014 Jul;257:106-13. doi: 10.1016/j.expneurol.2014.04.020. Epub 2014 May 1.

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 15days 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 7days 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.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylcysteine / analogs & derivatives*
  • Acetylcysteine / therapeutic use
  • Aldehydes / metabolism
  • Animals
  • Brain Injuries / complications*
  • Brain Injuries / drug therapy*
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / pathology
  • Cerebral Cortex / ultrastructure
  • Disease Models, Animal
  • Double-Blind Method
  • Energy Metabolism / drug effects*
  • Glutathione / metabolism
  • Male
  • Maze Learning / drug effects*
  • Mitochondria / drug effects
  • Neuroprotective Agents / therapeutic use*
  • Oxidative Stress / drug effects
  • Oxygen Consumption / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Time Factors
  • Tyrosine / analogs & derivatives
  • Tyrosine / metabolism

Substances

  • Aldehydes
  • Neuroprotective Agents
  • 4-hydroxy-2-octenal
  • 3-nitrotyrosine
  • Tyrosine
  • N-Acetylcysteinamide
  • Glutathione
  • Acetylcysteine