title: Racemic oleracein E increases the survival rate and attenuates memory impairment in D-galactose/NaNO₂-induced senescent mice.
abstract: BACKGROUND
  Compounds that possess a pyrrolidone skeleton are a rich resource for the discovery of nootropic drugs. Oleracein E (OE), which possesses both tetrahydroisoquinoline and pyrrolidone skeletons, was first isolated from the medicinal plant Portulaca oleracea L. and was thought to be an active component in the cognition-improvement effect induced by this herb. The aim of this study was to investigate the effect of OE on cognitive impairment in senescent mice and its underlying mechanism of action.
  
  
  METHODS
  Senescent Kunming mice were established by the intraperitoneal injection of D-galactose (D-gal, 1250 mg/kg/d) and NaNO2 (90 mg/kg/d) for 8 weeks. OE (3 mg/kg/d, 15 mg/kg/d) was orally administered for 8 weeks, and the nootropic drug piracetam (PA, 400 mg/kg/d) was used as a positive control. A Morris water maze was used to assess cognitive ability. GSH and MDA levels and T-AOC, SOD, and CAT activities in the brain or plasma were determined. Hippocampal morphology was observed by HE staining, and expression of the anti-apoptotic protein Bcl-2 and the pro-apoptotic proteins Bax and Caspase-3 was observed by immunohistochemical staining.
  
  
  RESULTS
  Large-dosage treatments with D-gal/NaNO2 for 8 weeks significantly reduced survival, impaired spatial memory capacity, compensatorily up-regulated GSH level and T-AOC and SOD activities, decreased CAT activity, and induced hippocampal neuronal damage and apoptosis as reflected by the apparent low expression of Bcl-2 and high expression of Bax and Caspase-3. OE significantly prolonged lifespan and was more potent than PA. Similar to PA, OE at 15 mg/kg/d improved memory capacity. The underlying mechanism of action was related to the reversal of abnormal brain antioxidant biomarkers (GSH, T-AOC, and SOD) to normal levels and the inhibition of hippocampal neuronal apoptosis.
  
  
  CONCLUSIONS
  OE from P. oleracea is an active compound for improving cognitive function and is also a candidate nootropic drug for the treatment of age-related dementia.
authors.affiliation: School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China; Suzhou Psychiatric Hospital, Suzhou 215008, China.
authors.forename: Pei-Pei
authors.initials: PP
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
authors.forename: Hong-Xiang
authors.initials: HX
authors.lastname: Sun
authors.affiliation: Jinan Hongjitang Pharmaceutical Co. Ltd, Jinan 250100, China.
authors.forename: Ce-Jia
authors.initials: CJ
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
authors.forename: Ming-Hong
authors.initials: MH
authors.lastname: Hu
authors.affiliation: School of Medicine, Shandong University, Jinan 250012, China.
authors.forename: Xiu-Quan
authors.initials: XQ
authors.lastname: He
authors.affiliation: School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
authors.forename: Su
authors.initials: S
authors.lastname: Yue
authors.affiliation: School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
authors.forename: Ze-Zhao
authors.initials: ZZ
authors.lastname: Jiao
authors.affiliation: School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China. Electronic address: xianglan02@sdu.edu.cn.
authors.forename: Lan
authors.initials: L
authors.lastname: Xiang
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D003071:Cognition / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy; D005690:Galactose / Q000009:adverse effects; D006624:Hippocampus / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy*; D051379:Mice; D018697:Nootropic Agents / Q000494:pharmacology*; D010636:Phenols / Q000494:pharmacology*; D010889:Piracetam / Q000494:pharmacology; D031822:Portulaca / Q000737:chemistry; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012977:Sodium Nitrite / Q000009:adverse effects; D013482:Superoxide Dismutase / Q000378:metabolism; D015996:Survival Rate; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000470:Alkaloids; D000975:Antioxidants; C494827:Bax protein, mouse; D018697:Nootropic Agents; D010636:Phenols; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C542300:oleracein E; C052617:Bcl2 protein, mouse; D008315:Malondialdehyde; D013482:Superoxide Dismutase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D012977:Sodium Nitrite; D005690:Galactose; D010889:Piracetam
keywords: D-galactose/NaNO(2); Nootropic; Oleracein E; Portulaca oleracea; Senescent mice