Planta Med 2010; 76(7): 683-688
DOI: 10.1055/s-0029-1240622
Pharmacology
Original Papers
© Georg Thieme Verlag KG Stuttgart · New York

Activated Glutathione Metabolism Participates in Protective Effects of Carnosic Acid against Oxidative Stress in Neuronal HT22 Cells

Yosei Tamaki1 , Takahito Tabuchi1 , Toshiyuki Takahashi1 , Kunio Kosaka2 , Takumi Satoh1
  • 1Department of Welfare Engineering, Faculty of Engineering, Iwate University, Morioka, Iwate, Japan
  • 2Research and Development Center, Nagase Co., Ltd., Kobe, Hyogo, Japan
Further Information

Publication History

received August 7, 2009 revised October 19, 2009

accepted October 26, 2009

Publication Date:
25 November 2009 (online)

Abstract

In our previous studies, we have reported that carnosic acid (CA) and carnosol (CS) originating from rosemary protects cortical neurons by inducing phase 2 enzymes, the induction of which was initiated by activation of the Keap1/Nrf2 pathway [1], [2], [3]. In the present study we address the nature of the effector of these neuroprotective effects downstream of the phase 2 enzyme induction. From our results we conclude that activated glutathione (GSH) metabolism may participate in these protective effects. First, we performed cDNA microarray analysis in order to identify the gene(s) responsible for the actions and found that various enzymes involved in the metabolism of GSH (glutathione S-transferase, alpha 4; glutathione S-transferase, alpha 2; and formylglutathione hydrolase) constituted 3 of the top 5 CA-induced genes. The other 2 genes encoded phase 2 enzymes [NAD(P)H-quinone oxidoreductase1and aldehyde dehydrogenase family 3, subfamily A1]. Next, we compared the physiologically-active compounds originating from rosemary (CA, CS, luteolin, genkwanin, rosmarinic acid, caffeic acid, and verbenone) by 3 criteria (enhancement of total glutathione levels, transcriptional activation, neuroprotective effects). By all of these criteria, CA and CS were the most active. In contrast, the other compounds were only weakly active or totally inactive. These results suggest that pro-electrophilic compounds such as CA and CS may protect cortical neurons by causing the following sequential events: S-alkylation → activation of the Keap1/Nrf2 pathway → transcriptional activation → induction of phase 2 enzymes → activation of GSH metabolism → neuroprotection.

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Prof. Dr. Takumi Satoh

Department of Welfare Engineering
Faculty of Engineering
Iwate University

Ueda 4–3–5

Morioka

020–8551 Iwate

Japan

Phone: + 81 1 96 21 60 39

Fax: + 81 1 96 21 63 14

Email: tsatoh@iwate-u.ac.jp