Am J Physiol Cell Physiol AJP: Heart and Circulatory Physiology
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Am J Physiol Cell Physiol 293: C1884-C1894, 2007. First published October 3, 2007; doi:10.1152/ajpcell.00305.2007
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NERVOUS SYSTEM CELL BIOLOGY

A dibenzoylmethane derivative protects dopaminergic neurons against both oxidative stress and endoplasmic reticulum stress

Katsura Takano,1,3 Yasuko Kitao,1 Yoshiyuki Tabata,1,2 Hikari Miura,1 Kosuke Sato,4 Kazuhiro Takuma,4 Kiyofumi Yamada,4 Satoshi Hibino,5 Tominari Choshi,5 Munekazu Iinuma,6 Hiroto Suzuki,7 Rika Murakami,7 Masashi Yamada,7 Satoshi Ogawa,1 and Osamu Hori1

1Department of Neuroanatomy and 2Department of Molecular Pharmacology, Kanazawa University Graduate School of Medical Science, Kanazawa City; 3Laboratory of Molecular Pharmacology and 4Laboratory of Neuropsychopharmacology, Kanazawa University Graduate School of Natural Science and Technology, Kanazawa City, Ishikawa; 5Fukuyama University, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama, Hiroshima; 6Gifu Pharmaceutical University, Gifu City, Gifu; and 7Meiji Dairies Corporation, Tokyo, Japan

Submitted 18 July 2007 ; accepted in final form 1 October 2007

The enhancement of intracellular stresses such as oxidative stress and endoplasmic reticulum (ER) stress has been implicated in several neurodegenerative disorders including Parkinson's disease (PD). During a search for compounds that regulate ER stress, a dibenzoylmethane (DBM) derivative 14-26 (2,2'-dimethoxydibenzoylmethane) was identified as a novel neuroprotective agent. Analysis in SH-SY5Y cells and in PC12 cells revealed that the regulation of ER stress by 14-26 was associated with its anti-oxidative property. 14-26 prevented the production of reactive oxygen species (ROS) when the cells were exposed to oxidants such as hydrogen peroxide and 6-hydroxydopamine (6-OHDA) or an ER stressor brefeldin A (BFA). 14-26 also prevented ROS-induced damage in both the ER and the mitochondria, including the protein carbonylation in the microsome and the reduction of the mitochondrial membrane potential. Further examination disclosed the presence of the iron-chelating activity in 14-26. In vivo, 14-26 suppressed both oxidative stress and ER stress and prevented neuronal death in the substantia nigra pars compacta (SNpc) after injection of 6-OHDA in mice. These results suggest that 14-26 is an antioxidant that protects dopaminergic neurons against both oxidative stress and ER stress and could be a therapeutic candidate for the treatment of PD.

neuronal cell death; stress response; Parkinson's disease


Address for reprint requests and other correspondence: O. Hori, Dept. of Neuroanatomy, Kanazawa Univ. Graduate School of Medical Science, 13-1 Takara-Machi, Kanazawa City, Ishikawa, 920-8640, Japan (e-mail: osamuh{at}nanat.m.kanazawa-u.ac.jp)






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