Tags

Type your tag names separated by a space and hit enter

A novel glycogen synthase kinase-3 inhibitor 2-methyl-5-(3-{4-[(S)-methylsulfinyl]phenyl}-1-benzofuran-5-yl)-1,3,4-oxadiazole decreases tau phosphorylation and ameliorates cognitive deficits in a transgenic model of Alzheimer's disease.
J Neurochem. 2011 Dec; 119(6):1330-40.JN

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder leading to a progressive loss of cognitive function and is pathologically characterized by senile plaques and neurofibrillary tangles. Glycogen synthase kinase-3 (GSK-3) is involved in AD pathogenesis. GSK-3 is reported not only to phosphorylate tau, a major component of neurofibrillary tangles, but also to regulate the production of amyloid β, which is deposited in senile plaques. Therefore, pharmacological inhibition of GSK-3 is considered an attractive therapeutic approach. In this study, we report the pharmacological effects of a novel GSK-3 inhibitor, 2-methyl-5-(3-{4-[(S)-methylsulfinyl]phenyl}-1-benzofuran-5-yl)-1,3,4-oxadiazole (MMBO), which displays high selectivity for GSK-3 and brain penetration following oral administration. MMBO inhibited tau phosphorylation in primary neural cell culture and also in normal mouse brain. When administered to a transgenic mouse model of AD, MMBO significantly decreased hippocampal tau phosphorylation at GSK-3 sites. Additionally, chronic MMBO administration suppressed tau pathology as assessed by AT8-immunoreactivity without affecting amyloid β pathology. Finally, in behavioral assessments, MMBO significantly improved memory and cognitive deficits in the Y-maze and in novel object recognition tests in the transgenic AD mouse model. These results indicate that pharmacological GSK-3 inhibition ameliorates behavioral dysfunction with suppression of tau phosphorylation in an AD mouse model, and that MMBO might be beneficial for AD treatment.

Authors+Show Affiliations

Pharmacology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited, Juso-Honmachi, Yodogawa, Osaka, Japan. Oonishi_Tomohiro@takeda.co.jpNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21992552

Citation

Onishi, Tomohiro, et al. "A Novel Glycogen Synthase Kinase-3 Inhibitor 2-methyl-5-(3-{4-[(S)-methylsulfinyl]phenyl}-1-benzofuran-5-yl)-1,3,4-oxadiazole Decreases Tau Phosphorylation and Ameliorates Cognitive Deficits in a Transgenic Model of Alzheimer's Disease." Journal of Neurochemistry, vol. 119, no. 6, 2011, pp. 1330-40.
Onishi T, Iwashita H, Uno Y, et al. A novel glycogen synthase kinase-3 inhibitor 2-methyl-5-(3-{4-[(S)-methylsulfinyl]phenyl}-1-benzofuran-5-yl)-1,3,4-oxadiazole decreases tau phosphorylation and ameliorates cognitive deficits in a transgenic model of Alzheimer's disease. J Neurochem. 2011;119(6):1330-40.
Onishi, T., Iwashita, H., Uno, Y., Kunitomo, J., Saitoh, M., Kimura, E., Fujita, H., Uchiyama, N., Kori, M., & Takizawa, M. (2011). A novel glycogen synthase kinase-3 inhibitor 2-methyl-5-(3-{4-[(S)-methylsulfinyl]phenyl}-1-benzofuran-5-yl)-1,3,4-oxadiazole decreases tau phosphorylation and ameliorates cognitive deficits in a transgenic model of Alzheimer's disease. Journal of Neurochemistry, 119(6), 1330-40. https://doi.org/10.1111/j.1471-4159.2011.07532.x
Onishi T, et al. A Novel Glycogen Synthase Kinase-3 Inhibitor 2-methyl-5-(3-{4-[(S)-methylsulfinyl]phenyl}-1-benzofuran-5-yl)-1,3,4-oxadiazole Decreases Tau Phosphorylation and Ameliorates Cognitive Deficits in a Transgenic Model of Alzheimer's Disease. J Neurochem. 2011;119(6):1330-40. PubMed PMID: 21992552.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A novel glycogen synthase kinase-3 inhibitor 2-methyl-5-(3-{4-[(S)-methylsulfinyl]phenyl}-1-benzofuran-5-yl)-1,3,4-oxadiazole decreases tau phosphorylation and ameliorates cognitive deficits in a transgenic model of Alzheimer's disease. AU - Onishi,Tomohiro, AU - Iwashita,Hiroki, AU - Uno,Yumiko, AU - Kunitomo,Jun, AU - Saitoh,Morihisa, AU - Kimura,Eiji, AU - Fujita,Hisashi, AU - Uchiyama,Noriko, AU - Kori,Masakuni, AU - Takizawa,Masayuki, Y1 - 2011/11/02/ PY - 2011/10/14/entrez PY - 2011/10/14/pubmed PY - 2012/1/27/medline SP - 1330 EP - 40 JF - Journal of neurochemistry JO - J. Neurochem. VL - 119 IS - 6 N2 - Alzheimer's disease (AD) is a neurodegenerative disorder leading to a progressive loss of cognitive function and is pathologically characterized by senile plaques and neurofibrillary tangles. Glycogen synthase kinase-3 (GSK-3) is involved in AD pathogenesis. GSK-3 is reported not only to phosphorylate tau, a major component of neurofibrillary tangles, but also to regulate the production of amyloid β, which is deposited in senile plaques. Therefore, pharmacological inhibition of GSK-3 is considered an attractive therapeutic approach. In this study, we report the pharmacological effects of a novel GSK-3 inhibitor, 2-methyl-5-(3-{4-[(S)-methylsulfinyl]phenyl}-1-benzofuran-5-yl)-1,3,4-oxadiazole (MMBO), which displays high selectivity for GSK-3 and brain penetration following oral administration. MMBO inhibited tau phosphorylation in primary neural cell culture and also in normal mouse brain. When administered to a transgenic mouse model of AD, MMBO significantly decreased hippocampal tau phosphorylation at GSK-3 sites. Additionally, chronic MMBO administration suppressed tau pathology as assessed by AT8-immunoreactivity without affecting amyloid β pathology. Finally, in behavioral assessments, MMBO significantly improved memory and cognitive deficits in the Y-maze and in novel object recognition tests in the transgenic AD mouse model. These results indicate that pharmacological GSK-3 inhibition ameliorates behavioral dysfunction with suppression of tau phosphorylation in an AD mouse model, and that MMBO might be beneficial for AD treatment. SN - 1471-4159 UR - https://www.unboundmedicine.com/medline/citation/21992552/A_novel_glycogen_synthase_kinase_3_inhibitor_2_methyl_5__3_{4_[_S__methylsulfinyl]phenyl}_1_benzofuran_5_yl__134_oxadiazole_decreases_tau_phosphorylation_and_ameliorates_cognitive_deficits_in_a_transgenic_model_of_Alzheimer's_disease_ L2 - https://doi.org/10.1111/j.1471-4159.2011.07532.x DB - PRIME DP - Unbound Medicine ER -