Protective Effects of Brain Infarction by N-Acetylcysteine Derivatives

Stroke. 2018 Jul;49(7):1727-1733. doi: 10.1161/STROKEAHA.118.021755. Epub 2018 Jun 4.


Background and purpose: We recently found that acrolein (CH2=CH-CHO) is more strongly involved in brain infarction compared with reactive oxygen species. In this study, we looked for acrolein scavengers with less side effects.

Methods: Photochemically induced thrombosis model mice were prepared by injection of Rose Bengal. Effects of N-acetylcysteine (NAC) derivatives on brain infarction were evaluated using the public domain National Institutes of Health image program.

Results: NAC, NAC ethyl ester, and NAC benzyl ester (150 mg/kg) were administered intraperitoneally at the time of induction of ischemia, or these NAC derivatives (50 mg/kg) were administered 3× at 24-h intervals before induction of ischemia and 1 more administration at the time of induction of ischemia. The size of brain infarction decreased in the order NAC benzyl ester>NAC ethyl ester>NAC in both experimental conditions. Detoxification of acrolein occurred through conjugation of acrolein with glutathione, which was catalyzed by glutathione S-transferases, rather than direct conjugation between acrolein and NAC derivatives. The level of glutathione S-transferases at the locus of brain infarction was in the order of administration of NAC benzyl ester>NAC ethyl ester>NAC>no NAC derivatives, suggesting that NAC derivatives stabilize glutathione S-transferases.

Conclusions: The results indicate that detoxification of acrolein by NAC derivatives is caused through glutathione conjugation with acrolein catalyzed by glutathione S-transferases, which can be stabilized by NAC derivatives. This is a new concept of acrolein detoxification by NAC derivatives.

Keywords: acetylcysteine; acrolein; brain glutathione transferase; infarction; mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / pharmacology
  • Acetylcysteine / therapeutic use*
  • Acrolein / metabolism
  • Animals
  • Brain / drug effects*
  • Brain / metabolism
  • Brain Infarction / drug therapy*
  • Brain Infarction / metabolism
  • Cell Line, Tumor
  • Disease Models, Animal
  • Glutathione / metabolism
  • Mice
  • Neuroprotective Agents / therapeutic use*
  • Oxidative Stress / drug effects*
  • Reactive Oxygen Species / metabolism


  • Neuroprotective Agents
  • Reactive Oxygen Species
  • Acrolein
  • Glutathione
  • Acetylcysteine