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

Protective Effects of Brain Infarction by N-Acetylcysteine Derivatives.

Author information

1
From the Amine Pharma Research Institute, Innovation Plaza at Chiba University, Japan (T.U., K.I.).
2
Department of Clinical and Analytical Biochemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Japan (K.W., K.K., K.H., N.K., M.K., H.T., T.T., K.I.).
3
Laboratory of Bioorganic Chemistry, Department of Pharmaceutical Technology, Josai University, Saitama, Japan (K.T., Y.S.).
4
Department of Clinical Biochemistry, Chiba Institute of Science, Japan (A.S., Y.T., K.K.).
5
From the Amine Pharma Research Institute, Innovation Plaza at Chiba University, Japan (T.U., K.I.) iga16077@faculty.chiba-u.jp.

Abstract

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

PMID:
29866754
DOI:
10.1161/STROKEAHA.118.021755
[Indexed for MEDLINE]

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