4-O-Methylhonokiol attenuates memory impairment in presenilin 2 mutant mice through reduction of oxidative damage and inactivation of astrocytes and the ERK pathway.
Presenilin 2 (PS2) mutation increases Aβ generation and neuronal cell death in the brains of Alzheimer disease (AD) patients. In a previous study, we showed that increased oxidative damage and activation of extracellular signal-regulated kinase (ERK) were associated with Aβ generation and neuronal cell death in neuronal cells expressing mutant PS2. In this study, we show that oral treatment with 4-O-methylhonokiol, a novel compound isolated from Magnolia officinalis, for 3 months (1.0mg/kg) prevented PS2 mutation-induced memory impairment and neuronal cell death accompanied by a reduction in Aβ(1-42) accumulation. We also found that 4-O-methylhonokiol inhibited PS2 mutation-induced activation of ERK and β-secretase, and oxidative protein and lipid damage, but recovered glutathione levels in the cortex and hippocampus of PS2 mutant mice. Additionally, 4-O-methylhonokiol prevented PS2 mutation-induced activation of astrocytes as well as production of TNF-α, IL-1β, reactive oxygen species (ROS), and nitric oxide (NO) in neurons. Generation of TNF-α, IL-1β, ROS, and NO and ERK activation in cultured astrocytes treated with lipopolysaccharide (1μg/ml) were also prevented by 4-O-methylhonokiol in a dose-dependent manner. These results suggest that the improving effects of 4-O-methylhonokiol on memory function may be associated with a suppression of the activation of ERK and astrocytes as well as a reduction in oxidative damage. Thus, 4-O-methylhonokiol may be useful in the prevention and treatment of AD.
College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 361-763, Korea.
Young Jung
YJ
Lee
Im Seop
IS
Choi
Mi Hee
MH
Park
Yuk Mo
YM
Lee
Ju Kyoung
JK
Song
Young Hee
YH
Kim
Ki Ho
KH
Kim
Dae Yeon
DY
Hwang
Jae Hwang
JH
Jeong
Yeo Pyo
YP
Yun
Ki-Wan
KW
Oh
Jae Kyung
JK
Jung
Sang Bae
SB
Han
Jin Tae
JT
Hong
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D017705:Lignans / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008569:Memory Disorders / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008954:Models, Biological; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D053766:Presenilin-2 / Q000235:genetics*
C542058:4-O-methylhonokiol; D000893:Anti-Inflammatory Agents; D001713:Biphenyl Compounds; D017705:Lignans; D053766:Presenilin-2; C095101:Psen2 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases