A carbazole derivative protects cells against endoplasmic reticulum (ER) stress and glutathione depletion.
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 Ca(2+) in response to thapsigargin (Tg). These results suggest that 16-14 may protect cells against different stresses via the maintenance of intracellular Ca(2+) homeostasis. [Supplementary Fig. 1: available only at http://dx.doi.org/10.1254/jphs.08136FP].
Department of Neuroanatomy, Kanazawa University Graduate School of Medical Science, 13-1 Takara-Machi, Kanazawa, Ishikawa, Japan.
Hikari
H
Miura
Katsura
K
Takano
Yasuko
Y
Kitao
Satoshi
S
Hibino
Tominari
T
Choshi
Rika
R
Murakami
Hiroto
H
Suzuki
Masashi
M
Yamada
Satoshi
S
Ogawa
Osamu
O
Hori
D000818:Animals; D019328:Buthionine Sulfoximine / Q000633:toxicity; D002118:Calcium / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D054278:Embryonal Carcinoma Stem Cells / Q000187:drug effects* / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D018384:Oxidative Stress / Q000187:drug effects; D016716:PC12 Cells; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects*; D019284:Thapsigargin / Q000494:pharmacology; D014415:Tunicamycin / Q000633:toxicity
D002227:Carbazoles; D011993:Recombinant Fusion Proteins; D014415:Tunicamycin; D019328:Buthionine Sulfoximine; D019284:Thapsigargin; D005978:Glutathione; D002118:Calcium