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.
Lee
Young Jung
YJ
College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 361-763, Korea.
Choi
Im Seop
IS
Park
Mi Hee
MH
Lee
Yuk Mo
YM
Song
Ju Kyoung
JK
Kim
Young Hee
YH
Kim
Ki Ho
KH
Hwang
Dae Yeon
DY
Jeong
Jae Hwang
JH
Yun
Yeo Pyo
YP
Oh
Ki-Wan
KW
Jung
Jae Kyung
JK
Han
Sang Bae
SB
Hong
Jin Tae
JT
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