Protective Effects of 4-Phenylbutyrate Derivatives on the Neuronal Cell Death and Endoplasmic Reticulum Stress
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概要
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Endoplasmic reticulum (ER) stress responses play an important role in neurodegenerative diseases. Sodium 4-phenylbutyrate (4-PBA) is a terminal aromatic substituted fatty acid that has been used for the treatment of urea cycle disorders. 4-PBA possesses in vitro chemical chaperone activity and reduces the accumulation of Parkin-associated endothelin receptor-like receptor (Pael-R), which is involved in autosomal recessive juvenile parkinsonism (AR-JP). In this study, we show that terminal aromatic substituted fatty acids, including 3-phenylpropionate (3-PPA), 4-PBA, 5-phenylvaleric acid, and 6-phenylhexanoic acid, prevented the aggregation of lactalbumin and bovine serum albumin. Aggregation inhibition increased relative to the number of carbons in the fatty acids. Moreover, these compounds protected cells against ER stress-induced neuronal cell death. The cytoprotective effect correlated with the in vitro chemical chaperone activity. Similarly, cell viability decreased on treatment with tunicamycin, an ER stress inducer, and was dependent on the number of carbons in the fatty acids. Moreover, the expression of glucose-regulated proteins 94 and 78 (GRP94, 78) decreased according to the number of carbons in the fatty acids. Furthermore, we investigated the effects of these compounds on the accumulation of Pael-R in neuroblastoma cells. 3-PPA and 4-PBA significantly suppressed neuronal cell death caused by ER stress induced by the overexpression of Pael-R. Overexpressed Pael-R accumulated in the ER of cells. With 3-PPA and 4-PBA treatment, the localization of the overexpressed Pael-R shifted away from the ER to the cytoplasmic membrane. These results suggest that terminal aromatic substituted fatty acids are potential candidates for the treatment of neurodegenerative diseases.
著者
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OKUMA Yasunobu
Departmen of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University
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Kawada Koichi
Department Of Mathematics Faculty Of Education Iwate University
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Ozawa Koichiro
Department Of Pharmacotherapy Division Of Clinical Pharmacotherapeutics Programs For Applied Biomedi
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Hamana Hiroshi
Department Of Applied Chemistry Faculty Of Engineering Saitama Institute Of Technology
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HOSOI Toru
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University
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Kaneko Masayuki
Department Of Dental Radiology Health Sciences University Of Hokkaido
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Nomura Yasuyuki
Laboratory Of Pharmacotherapeutics Yokohama College Of Pharmacy
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Mimori Seisuke
Department of Pharmaceutical Chemistry, Chiba Institute of Science
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Kaneko Masayuki
Department of Cardiology, Cardiovascular Center, Oita Oka Hospital
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Hamana Hiroshi
Department of Pharmaceutical Chemistry, Chiba Institute of Science
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Hosoi Toru
Department of Pharmacotherapy, Graduate School of Biomedical Sciences, Hiroshima University
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Kawada Koichi
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Chiba Institute of Science
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