A Carbazole Derivative Protects Cells Against Endoplasmic Reticulum (ER) Stress and Glutathione Depletion

Hikari Miura; Katsura Takano; Yasuko Kitao; Satoshi Hibino; Tominari Choshi; Rika Murakami; Hiroto Suzuki; Masashi Yamada; Satoshi Ogawa; Osamu Hori

doi:10.1254/jphs.08136FP

Full Papers

A Carbazole Derivative Protects Cells Against Endoplasmic Reticulum (ER) Stress and Glutathione Depletion

Hikari Miura, Katsura Takano, Yasuko Kitao, Satoshi Hibino, Tominari Choshi, Rika Murakami, Hiroto Suzuki, Masashi Yamada, Satoshi Ogawa, Osamu Hori

Author information

Hikari Miura
Department of Neuroanatomy, Kanazawa University Graduate School of Medical Science, Japan
CREST, JST (Japan Science and Technology), Japan
Katsura Takano
Laboratory of Integrative Physiology in Veterinary Sciences, Osaka Prefecture University, Japan
Yasuko Kitao
Department of Neuroanatomy, Kanazawa University Graduate School of Medical Science, Japan
CREST, JST (Japan Science and Technology), Japan
Satoshi Hibino
Fukuyama University, Faculty of Pharmacy and Pharmaceutical Sciences, Japan
Tominari Choshi
Fukuyama University, Faculty of Pharmacy and Pharmaceutical Sciences, Japan
Rika Murakami
Meiji Dairies Corporation, Japan
Hiroto Suzuki
Meiji Dairies Corporation, Japan
Masashi Yamada
Taiho Pharmaceutical Co., Ltd., Japan
Satoshi Ogawa
Department of Neuroanatomy, Kanazawa University Graduate School of Medical Science, Japan
CREST, JST (Japan Science and Technology), Japan
Osamu Hori
Department of Neuroanatomy, Kanazawa University Graduate School of Medical Science, Japan
CREST, JST (Japan Science and Technology), Japan

Keywords: neuronal cell death, stress response, endoplasmic reticulum (ER), glutathione, neuroprotection

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Supplementary material

2008 Volume 108 Issue 2 Pages 164-171

DOI https://doi.org/10.1254/jphs.08136FP

View "Advance Publication" version (October 9, 2008).

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Abstract

Enhanced levels of intracellular stresses such as oxidative stress and endoplasmic reticulum (ER) stress are implicated in various neuropathological conditions including brain ischemia and neurodegeneration. During a search for compounds that regulate ER stress and ER stress-induced cell death, we identified a carbazole derivative 16-14 [9-(3-cyanobenzyl)-1,4-dimethylcarbazole] that protected against both ER stress and glutathione depletion. 16-14 suppressed tunicamycin (Tm)-induced cell death in both F9 Herp KO cells and PC12 cells, and its regulation of ER stress was associated with reduced levels of unfolded protein response (UPR) signaling. ER stress caused by overexpression of a fluorescent ER-resident protein, GFP-KDEL, was also attenuated by 16-14 without altering the expression levels of GFP-KDEL. 16-14 also prevented glutathione depletion-induced cell death caused by buthionine sulfoximine (BSO), but not likely via its anti-oxidative activity. Further analysis revealed that 16-14 suppressed increases in intracellular Ca²⁺ in response to thapsigargin (Tg). These results suggest that 16-14 may protect cells against different stresses via the maintenance of intracellular Ca²⁺ homeostasis.
[Supplementary Fig. 1: available only at http://dx.doi.org/10.1254/jphs.08136FP]

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