Abstract:
BACKGROUND: Agomelatine is a clinically proven treatment for neuropsychiatric symptoms, such as anxiety and depression. Furthermore, our previous study has demonstrated that agomelatine ameliorates cognitive behaviors, hippocampal synaptic plasticity, and brain pathology in a mouse model of Alzheimer’s disease. However, it remains unclear whether agomelatine can improve anxiety and depression-like behaviors in Alzheimer’s disease model mice. 
OBJECTIVE: To investigate the improving effects of agomelatine on anxiety- and depression-like behaviors in APP/PS1 transgenic mice and its underlying molecular mechanisms. 
METHODS: (1) Eighteen APP/PS1 transgenic mice were randomly divided into model control group (n=9) and model intervention group (n=9). Another wild-type mice were randomized into control group (n=9) and intervention group (n=9). Model intervention group and intervention group were intraperitoneally injected with 10 mg/kg agomelatine per day for 31 continuous days. Behavioral experiments, including the elevated cross maze and forced swimming tests, and mRNA sequencing of the hippocampus were then performed. (2) Mouse hippocampal neuronal cell lines (HT22) and brain microvascular endothelial cell lines (bEnd.3) were cultured and divided into four groups: blank group without any drug, drug group with 20 µmol/L agomelatine, model group with 10 µmol/L β-amyloid 1-42, and experimental group with 10 µmol/L β-amyloid 1-42+20 µmol /L agomelatine. After 24 hours of incubation, protein expression of S416p-tau and S9p-GSK3β in HT22 cells was detected by immunoblotting, and protein expression of low-density lipoprotein receptor-related protein 1 and glycosylation end-product receptor in bEnd.3 cells was detected by immunoblotting.
RESULTS AND CONCLUSION: In the elevated plus maze test, the time spent in the open arms (P < 0.01) and the entries into open arms (P < 0.05) in the mice of model control group were evidently lower than those in the control group, whereas those were obviously increased in the model intervention group compared with the model control group (P < 0.05). Forced swimming test results showed that the immobile time exhibited a marked increase in the model control group compared with the control group (P < 0.05), but it was significantly decreased in the model intervention group compared with the model control group (P < 0.05). Hippocampal tissue mRNA sequencing showed that agomelatine enhanced the expression of low-density lipoprotein receptor-related protein 1 in the hippocampus of APP/PS1 mice. Western blot analysis revealed that the level of S416p-tau in HT22 cells was higher in the model group than the blank group (P < 0.05), while it was markedly decreased in the experimental group compared with the model group (P < 0.05); the level of S9p-GSK3β in HT22 cells was higher in the drug group than the blank group (P < 0.05) as well as higher in the experimental group than the model group (P < 0.05). Moreover, the expression of low-density lipoprotein receptor-related protein 1 in bEnd.3 cells was higher in the experimental group than the model group (P < 0.05). To conclude, agomelatine can alleviate anxiety- and depression-like behaviors in Alzheimer’s disease mice by promoting the clearance of β-amyloid and phosphorylated tau.

Key words: Alzheimer’s disease, agomelatine, APP/PS1 transgenic mice, anxiety, depression