Nobiletin restoring beta-amyloid-impaired CREB phosphorylation rescues memory deterioration in Alzheimer's disease model rats.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive and memory deterioration. Production and accumulation of beta-amyloid peptide (Abeta) is central to the pathogenesis of AD. Recent studies have demonstrated that PKA/CREB-dependent signaling pathway and long-term potentiation are inhibited by sublethal concentrations of Abeta(1-42) in cultured hippocampus neurons. Here, we examined the effects of nobiletin on the Abeta-induced inhibition of CREB phosphorylation in cultured rat hippocampus neurons. A sublethal concentration of Abeta(1-42) or Abeta(1-40) decreased glutamate-induced CREB phosphorylation, whereas pretreatment with nobiletin reversed the Abeta-induced decrease in CREB phosphorylation. The effects of nobiletin on impairment of learning ability were also examined in chronically Abeta(1-40) infused AD model rats using the eight-arm radial maze. In the AD model rats, nobiletin showed protective effects on Abeta(1-40)-induced impairment of learning ability. These results suggest that nobiletin has the potential for becoming a novel lead compound for drug development for AD.
Matsuzaki
Kentaro
K
Department of Pharmaceutical Molecular Biology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
Yamakuni
Tohru
T
Hashimoto
Michio
M
Haque
Abdul Md
AM
Shido
Osamu
O
Mimaki
Yoshihiro
Y
Sashida
Yutaka
Y
Ohizumi
Yasushi
Y
D000544:Alzheimer Disease / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism*; D016229:Amyloid beta-Peptides; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D050882:CREB-Binding Protein / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D047309:Flavones / Q000008:administration & dosage*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008569:Memory Disorders / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control*; D010446:Peptide Fragments; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D047309:Flavones; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C008661:nobiletin; D050882:CREB-Binding Protein; C494365:Crebbp protein, rat