Schisandrin ameliorates cognitive impairment and attenuates Aβ deposition in APP/PS1 transgenic mice: involvement of adjusting neurotransmitters and their metabolite changes in the brain

Abstract

Neurotransmitters (NTs) in the brain are involved in neurodegenerative diseases, such as Alzheimer's disease (AD). Schisandrin is a major ingredient of Schisandra chinensis (Turcz.) Baill and has been used for the treatment of AD. In this study we examined the therapeutic effects of schisandrin in APP/PS1 transgenic mice, and correlated the beneficial effects on cognitive impairment with the adjustments in NTs and their metabolites in the mouse brains. APP/PS1 mice were treated with schisandrin (2 mg·kg^-1·d^-1, ip) for 2 weeks. In Morris Water Maze test; untreated APP/PS1 mice displayed significant cognitive impairment compared with normal mice; schisandrin administration ameliorated the cognitive impairment and significantly decreased Aβ deposition in the hippocampus. In order to assess the effects of schisandrin on NTs and their metabolites, we developed a rapid and sensitive UPLC-MS/MS method for simultaneous determination of serotonin, 5-hydroxyindole acetic acid, dopamine, norepinephrine, γ-aminobutyric acid, glutamic acid, homovanillic acid, 3,4-dihydroxyphenylacetic acid and acetylcholine in mouse brains. This method conformed to methodology validation requirements. We found that there were statistically significant differences in these NTs and their metabolites between untreated APP/PS1 mice and normal mice, whereas schisandrin administration restored the abnormal NTs and their metabolites levels. These results suggest that schisandrin could alter the levels of these NTs and their metabolites in the brain, thus ameliorating learning and memory impairments in APP/PS1 mice.

Figure 1

Chemical structures and MS/MS scan product ion spectrums of the NTs and their metabolites investigated together and internal standard. GABA (A), Glu (B), NE (C), ACh (D), DA (E), 5-HT (F), HVA (G) 5-HIAA (H), DOPAC (I) and DHBA (J; IS).

Figure 2

Schisandrin (SIN) treatment improved the escape latency (A) and path length (B) in the navigation test and improved performance of the probe trial in MWM of APP/PS1 mice (n=10). (C) The representive locus plot after SIN treatment in the probe trial. (D) SIN treatment prolonged the time spent in target quadrant. (E) SIN treatment increased the frequencies of passing through the goal. ^**P<0.01, compared with normal group; ^##P<0.01, compared with APP/PS1 group.

Figure 3

SIN treatment ameliorated the overexpression of Aβ_(1–42) in the hippocampus and cortex of APP/PS1 mice by immunohistochemistry (n=5). ^**P<0.01 vs WT group. ^##P<0.01 vs APP/PS1 group.

Figure 4

Typical chromatograms of the signals of NTs and their metabolites, together with DHBA in mice brain samples. Representative MRM chromatograms of GABA, Glu, NE, ACh, DA, 5-HT, HVA, 5-HIAA, DOPAC, and DHBA (IS).

Figure 5

Levels of 9 NTs in mice brain normal group, AD model group, SIN-treated group. Results are expressed as mean±SEM (n=10 in each group). ^*P<0.05 vs the normal group. ^#P<0.05 vs the AD model group.