title: Dl-3-n-butylphthalide-induced upregulation of antioxidant defense is involved in the enhancement of cross talk between CREB and Nrf2 in an Alzheimer's disease mouse model.
abstract: Synapse impairment in the Alzheimer's disease (AD) brain is an early event leading to cognitive dysfunction. Most oxidative stress localizes to the synapse, and synapse loss is the basis of cognitive decline in AD. Dl-3-n-butylphthalide (Dl-NBP), a small molecule compound has been shown to ameliorate oxidative stress. We evaluated the effects of a 5-month oral delivery with Dl-NBP on oxidative stress and cognitive function in APP/PS1 transgenic mice. Dl-NBP treatment reduced oxidative stress in the APP/PS1 mouse brain and alleviated learning and memory deficits. Dl-NBP supplementation meliorated synaptic plasticity, diminished soluble amyloid beta and amyloid beta oligomer in the APP/PS1 mouse brain. Dl-NBP administration caused an increase of cyclic adenosine monophosphate-response element binding protein (CREB)-binding protein (CBP)-associated Ser133-phosphorylated CREB (p-CREB) protein. Chromatin immunoprecipitation analysis revealed that Dl-NBP increased the recruitment of CBP to the promoters of best-characterized genes downstream of nuclear factor erythroid 2-related factor 2, nicotinamide adenine dinucleotide phosphate (NADPH) quinone oxidoreductase 1, and γ-glutamylcysteine synthetase modifier subunit. We demonstrate that the Dl-NBP-triggered upregulation of antioxidant defenses is involved in the enhancement of cross talk between CREB and nuclear factor erythroid 2-related factor 2 via CBP. Our results suggest that Dl-NBP may be a useful agent for the treatment of AD.
authors.affiliation: Medical Research Laboratory, Jilin Medical University, Jilin, China; College of Life and Health Sciences, Northeastern University, Shenyang, China; Department of Surgery, Jilin Medical University, Jilin, China.
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Wang
authors.affiliation: College of Life and Health Sciences, Northeastern University, Shenyang, China.
authors.forename: Zhan-You
authors.initials: ZY
authors.lastname: Wang
authors.affiliation: Department of Pathophysiology, China Medical University, Shenyang, China.
authors.forename: Jing-Wei
authors.initials: JW
authors.lastname: Xie
authors.affiliation: College of Life and Health Sciences, Northeastern University, Shenyang, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Histology and Embryology, Liaoning University of Traditional Chinese Medicine, Shenyang, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Medical Research Laboratory, Jilin Medical University, Jilin, China. Electronic address: xuye_9707@163.com.
authors.forename: Ye
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Surgery, Jilin Medical University, Jilin, China. Electronic address: jlmpc.cjh@163.com.
authors.forename: Jian-Hui
authors.initials: JH
authors.lastname: Cai
mesh_terms: D000284:Administration, Oral; D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics* / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology*; D001572:Benzofurans / Q000008:administration & dosage / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D003071:Cognition / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004195:Disease Models, Animal; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D001572:Benzofurans; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C027125:3-n-butylphthalide
keywords: Alzheimer's disease; CREB; Cognitive dysfunction; Dl-NBP; Nrf2; Oxidative stress