Simple ortho- and para-hydroquinones as compounds neuroprotective against oxidative stress in a manner associated with specific transcriptional activation.
Electrophilic compounds protect neurons through the activation of the Keap1/Nrf2 pathway and the induction of phase-2 enzymes [T. Satoh, S.A. Lipton, Redox regulation of neuronal survival by electrophilic compounds, Trends Neurosci. 30 (2007) 38-45; T. Satoh, S. Okamoto, J. Cui, Y. Watanabe, K. Furuta, M. Suzuki, K. Tohyama, S.A. Lipton, Activation of the Keap1/Nrf2 pathway for neuroprotection by electrophilic phase II inducers. Proc. Natl. Acad. Sci. USA 103 (2006) 768-773]. Hydroquinone-type electrophilic compounds such as tert-butyl hydroquinone (TBHQ) and carnosic acid (CA) have attracted special attention, because the oxidative conversion of "hydroquinone" to "quinone" is essential for the transcriptional activation of the above-mentioned enzymes [T. Satoh, K. Kosaka, K. Itoh, A. Kobayashi, M. Yamamoto, Y. Shimojo, C. Kitajima, J. Cui, J. Kamins, S. Okamoto, T. Shirasawa, S.A. Lipton, Carnosic acid, a catechol-type electrophilic compound, protect neurons both in vitro and in vivo through activation of the Keap1/Nrf2 pathway via S-alkylation of specific cysteine, J. Neurochem. 104 (2008) 1161-1131; A.D. Kraft, D.A. Johnson, J.A. Johnson, Nuclear factor E2-related factor 2-dependent antioxidant response element activation by tert-butylhydroquinone and sulforaphane occurring preferentially in astrocytes conditions neurons against oxidative insult, J. Neurosci. 24 (2004) 1101-1112]. In the present study, we examined the relationship between electrophilicity and the protective effects afforded by electrophilic compounds. Electrophilicity was assessed in terms of the ability of a compound to bind to a cysteine on bovine serum albumin, by which we found that neuroprotective hydroquinones [TBHQ (para-) and CA (ortho-)] had distinctive patterns of cysteine binding compared with other electrophilic compounds. Further, we found that isomers of simple ortho- and para-hydroquinones such as 2-methylhydroquinone (para-) and 4-methyl-catechol (ortho-) [not in abstract] had similar properties of cysteine binding as TBHQ and CA, which compounds were associated with the transcriptional activation and an increase in the level of reduced glutathione. These results suggest that para- and ortho-dihydroquinones may be neuroprotective compounds active against oxidative stress.
Satoh
Takumi
T
Department of Welfare Engineering, Faculty of Engineering, Iwate University, Ueda 4-3-5, Morioka, Iwate 020-8551, Japan. tsatoh@iwate-u.ac.jp
Saitoh
Sachie
S
Hosaka
Manami
M
Kosaka
Kunio
K
D045784:Abietanes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002417:Cattle; D002460:Cell Line; D003545:Cysteine / Q000378:metabolism; D005456:Fluorescent Dyes / Q000737:chemistry / Q000378:metabolism; D005978:Glutathione / Q000096:biosynthesis; D006801:Humans; D006873:Hydroquinones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008301:Maleimides / Q000737:chemistry / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D010936:Plant Extracts / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020218:Response Elements / Q000187:drug effects; D012710:Serum Albumin, Bovine / Q000737:chemistry / Q000378:metabolism; D015533:Transcriptional Activation
D045784:Abietanes; D000975:Antioxidants; D005456:Fluorescent Dyes; D006873:Hydroquinones; D008301:Maleimides; D018696:Neuroprotective Agents; D010936:Plant Extracts; C043592:maleimide; D012710:Serum Albumin, Bovine; C018855:2-tert-butylhydroquinone; D005978:Glutathione; D003545:Cysteine; C018381:salvin