title: Ursolic acid improves domoic acid-induced cognitive deficits in mice.
abstract: Our previous findings suggest that mitochondrial dysfunction is the mechanism underlying cognitive deficits induced by domoic acid (DA). Ursolic acid (UA), a natural triterpenoid compound, possesses many important biological functions. Evidence shows that UA can activate PI3K/Akt signaling and suppress Forkhead box protein O1 (FoxO1) activity. FoxO1 is an important regulator of mitochondrial function. Here we investigate whether FoxO1 is involved in the oxidative stress-induced mitochondrial dysfunction in DA-treated mice and whether UA inhibits DA-induced mitochondrial dysfunction and cognitive deficits through regulating the PI3K/Akt and FoxO1 signaling pathways. Our results showed that FoxO1 knockdown reversed the mitochondrial abnormalities and cognitive deficits induced by DA in mice through decreasing HO-1 expression. Mechanistically, FoxO1 activation was associated with oxidative stress-induced JNK activation and decrease of Akt phosphorylation. Moreover, UA attenuated the mitochondrial dysfunction and cognitive deficits through promoting Akt phosphorylation and FoxO1 nuclear exclusion in the hippocampus of DA-treated mice. LY294002, an inhibitor of PI3K/Akt signaling, significantly decreased Akt phosphorylation in the hippocampus of DA/UA mice, which weakened UA actions. These results suggest that UA could be recommended as a possible candidate for the prevention and therapy of cognitive deficits in excitotoxic brain disorders.
authors.affiliation: School of Environment and Spatial Informatics, China University of Mining and Technology, Xuzhou 221008, Jiangsu Province, PR China.
authors.forename: Dong-mei
authors.initials: DM
authors.lastname: Wu
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.forename: Yan-qiu
authors.initials: YQ
authors.lastname: Zhang
authors.forename: Yuan-lin
authors.initials: YL
authors.lastname: Zheng
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.forename: Wei
authors.initials: W
authors.lastname: Cheng
authors.forename: Zi-feng
authors.initials: ZF
authors.lastname: Zhang
authors.forename: Meng-qiu
authors.initials: MQ
authors.lastname: Li
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D003072:Cognition Disorders / Q000139:chemically induced* / Q000517:prevention & control* / Q000523:psychology; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D000229:Dependovirus; D005455:Fluorescent Antibody Technique; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005822:Genetic Vectors; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007608:Kainic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000633:toxicity; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D028361:Mitochondrial Diseases / Q000139:chemically induced / Q000517:prevention & control; D009467:Neuromuscular Depolarizing Agents / Q000009:adverse effects* / Q000633:toxicity*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011597:Psychomotor Performance / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014315:Triterpenes / Q000627:therapeutic use*; D000097245:Ursolic Acid
chemical_list: D016861:Cyclooxygenase Inhibitors; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D007608:Kainic Acid; D009467:Neuromuscular Depolarizing Agents; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D014315:Triterpenes; D000097245:Ursolic Acid; C467200:Foxo1 protein, mouse; C012301:domoic acid
keywords: 2′7′-dichlorodihydrofluorescein diacetate; 2′7′-dichlorofluorescein; AAV; AP; APR; ATP production rate; Cognitive deficits; DA; DCF; DCFH-DA; DV; Domoic acid; EGFP; ETC; Forkhead box protein O1; FoxO1; FoxO1 knockdown; HO-1; IOD; JNK; ML; MWM; Mitochondrial dysfunction; Morris water maze; OCT; RCR; ROI; ROS; UA; Ursolic acid; adeno-associated viral; anterior-posterior; c-Jun N-terminal kinase; domoic acid; dorsal–ventral; electron transport chain; enhanced green fluorescent protein; heme oxygenase 1; i.c.v; integral optical density; intracerebroventricular; medial–lateral; optimal cutting temperature medium; reactive oxygen species; region of interest; respiratory control ratio; ursolic acid