Protective Effects of Brain Infarction by N-Acetylcysteine Derivatives

You likely want this followed up with human testing since acrolein is implicated in Parkinsons. That followup is your doctor and stroke hospitals responsibility. Not doing so is pure incompetency.

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Protective Effects of Brain Infarction by N-Acetylcysteine Derivatives

Takeshi Uemura, Kenta Watanabe, Kenta Ko, Kyohei Higashi, Noriyuki Kogure, Mariko Kitajima, Hiromitsu Takayama, Koichi Takao, Yoshiaki Sugita, Akihiko Sakamoto, Yusuke Terui, Toshihiko Toida, Keiko Kashiwagi, Kazuei Igarashi

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https://doi.org/10.1161/STROKEAHA.118.021755

Stroke. 2018;49:1727-1733

Originally published June 4, 2018

Takeshi Uemura

From the Amine Pharma Research Institute, Innovation Plaza at Chiba University, Japan (T.U., K.I.)

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Kenta Ko

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.)

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Kyohei Higashi

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.)

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Noriyuki Kogure

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.)

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Mariko Kitajima

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.)

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Hiromitsu Takayama

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.)

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Koichi Takao

Laboratory of Bioorganic Chemistry, Department of Pharmaceutical Technology, Josai University, Saitama, Japan (K.T., Y.S.)

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Yoshiaki Sugita

Laboratory of Bioorganic Chemistry, Department of Pharmaceutical Technology, Josai University, Saitama, Japan (K.T., Y.S.)

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Akihiko Sakamoto

Department of Clinical Biochemistry, Chiba Institute of Science, Japan (A.S., Y.T., K.K.).

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Yusuke Terui

Department of Clinical Biochemistry, Chiba Institute of Science, Japan (A.S., Y.T., K.K.).

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Toshihiko Toida

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.)

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Keiko Kashiwagi

Department of Clinical Biochemistry, Chiba Institute of Science, Japan (A.S., Y.T., K.K.).

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Kazuei Igarashi

From the Amine Pharma Research Institute, Innovation Plaza at Chiba University, Japan (T.U., K.I.)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.)

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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 estergt;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 estergt;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.