Extract of Danggui-Shaoyao-San ameliorates cognition deficits by regulating DHA metabolism in APP/PS1 mice

Abstract

Ethnopharmacological relevance: The traditional Chinese medicine formula Danggui-Shaoyao-San (DSS) has been reported to show therapeutic effect on alleviating the symptoms of Alzheimer's disease (AD).

Aim of the study: The present study aims to investigate the relation between DSS treatment of AD and DHA metabolism and evaluates its neuroprotective effect on cognitive in APP/PS1 mice.

Material and methods: DSS (1.6, 3.2, 6.4 g/kg/day) or Aricept (3 mg/kg/day) was orally administered (i.g.) to APP/PS1 mice, and saline was orally administered to Wild-type (WT) male mice as control group. Then, the Morris water maze (MWM) test, Y-maze spontaneous alternation test, open filed test and fear conditioning test were conducted for evaluation of learning and memory abilities. The DHA content was assessed by HPLC-MS/MS. Physiological indices were determined, including triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), ROS level, activity of superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), PEG2, TXB2 and LTB4. The expressions of COX-1, COX-2, cPLA2, iPLA2, 15-LOX, and were assessed by Western blot.

Results: APP/PS1 mice showed serious cognitive impairment in behavioral tests. However, treatment of DSS extract significantly ameliorated the cognitive deficits of APP/PS1 mice. Biochemical measurements showed the increases in TG, TC, LDL-c and the decrease in HDL-c in APP/PS1 mice compared with WT mice, and DSS extract significantly retarded these changes. Low content of DHA, low expression of iPLA2 and 15-LOX were observed both in hippocampus and cortex of APP/PS1 mice, while DSS extract significantly restored these changes. Additionally, the abnormal activity of SOD and ROS level, the decreased levels of MDA and GSH were observed in APP/PS1 mice, while DSS extract prominently lessened these changes. Moreover, DSS extract decreased the level of PEG2, TXB2 and LTB4 and also attenuated the expression of cPLA2, COX-1 and COX-2 in hippocampus as well as cortex of APP/PS1 mice.

Conclusions: Based on these results, we suggest that DSS play a positive effective role in increasing DHA content by up-regulating iPLA2 and 15-LOX, resulting in ameliorating oxidative stress and inflammation and finally ameliorating cognition deficits in APP/PS1 mice.

Keywords: Albiflorin; Alzheimer's disease (AD); Aricept; Benzoic acid; Danggui-Shaoyao-San (DSS); Docosahexaenoic acid (DHA); Ferulic acid; Gallic acid; Ligusticum lactone A; Ligusticum lactone Ⅰ; Lipid metabolism; Neuroinflammation; Oxidative stress; Paeoniflorin.