Abstract
Agomelatine, an agonist of melatonergic MT1 and MT2 receptors and a selective 5-hydroxytryptamine 2C receptor antagonist, is widely applied in treating depression and insomnia symptoms in several neurogenerative diseases. However, the neuroprotective effect of agomelatine in Alzheimer’s disease (AD) is less known. In this study, a total of 30 mice were randomly divided into three groups, namely, wild type (WT), APP/PS1, and agomelatine (50 mg/kg). After 30 days, the Morris water maze was performed to test the cognitive ability of mice. Then, all mice were sacrificed, and the hippocampus tissues were collected for ELISA, Western blot, and immunofluorescence analysis. In this study, we found that agomelatine attenuated spatial memory deficit, amyloid-β (Aβ) deposition, tau phosphorylation, and neuroinflammation in the hippocampus of APP/PS1 mice. Further study demonstrated that agomelatine treatment upregulated the protein expression of DHCR24 and downregulated P-Akt, P-mTOR, p-p70s6k, Hes1, and Notch1 expression. In summary, our results identified that agomelatine could improve cognitive impairment and ameliorate AD-like pathology in APP/PS1 mice via activating DHCR24 signaling and inhibiting Akt/mTOR and Hes1/Notch1 signaling pathway. Agomelatine may become a promising drug candidate in the therapy of AD.
Highlights
As the most common progressive neurogenerative disease, the etiology of Alzheimer’s disease (AD) is not clear
We identified that antidepressant agomelatine improved cognitive deficits and ameliorated AD-like pathologies, including Aβ deposition, tau protein hyperphosphorylation, and neuroinflammation in amyloid precursor protein (APP)/PS1 mice, via activating DHCR24 signaling and inhibiting Akt/mammalian target of rapamycin (mTOR) and Hes1/Notch1 signaling pathway
The above parameters could be partly reversed by agomelatine intervention (AGO: 31.71 ± 8.97 s, P = 0.0003; agomelatine treatment (AGO): 25 ± 7.07%, P = 0.0213; AGO: 24 ± 6.99%, P = 0.0126)
Summary
As the most common progressive neurogenerative disease, the etiology of Alzheimer’s disease (AD) is not clear. Tau protein hyperphosphorylation could induce tau aggregation and the formation of NFT, aggravate synaptic impairment, and promote neurodegeneration (Ahmed et al, 2014; Gao et al, 2018). With the progression of AD, aberrant and excessive inflammatory response, accompanied by the change of microglial polarization, provides a toxic effect, resulting in neuronal injury, Aβ deposition (Krabbe et al, 2013), tau Agmelatine Ameliorates AD-Associated Cognitive Impairment hyperphosphorylation (Bhaskar et al, 2010), and synaptic loss (Hansen et al, 2018). Modulating cerebral neuroinflammation and promoting microglial polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotype could suppress the pathological damage of AD in vitro and in vivo (Yao and Zu, 2020). Exploring novel and practical therapeutic approaches targeting Aβ, NFTs, and neuroinflammation may become a good orientation in the AD field
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
