Melatonin receptor stimulation by agomelatine prevents Aβ-induced tau phosphorylation and oxidative damage in PC12 cells

Abstract

Purpose

As a novel antidepressant drug, agomelatine has good therapeutic effect on the mood disorder and insomnia in Alzheimer’s disease (AD). Recent studies have shown the neuroprotective function of agomelatine, including anti-oxidative and anti-apoptosis effect. However, it remains unclear whether agomelatine exerts neuroprotection in AD. Thus, the neuroprotective effect of agomelatine against amyloid beta _25–35 (Aβ_25–35)-induced toxicity in PC12 cells was evaluated in this study.

Methods

The concentration of malondialdehyde (MDA), LDH, and ROS was investigated to evaluate oxidative damage. The expression of P-tau, tau, PTEN, P-Akt, Akt, P-GSK3β, and GSK3β proteins was assessed by Western blotting. Our results demonstrated that Aβ_25–35 significantly increased the content of MDA, LDH, and ROS. Meanwhile, Aβ_25–35 upregulated the expression of P-tau and PTEN as well as downregulated P-Akt and P-GSK3β expression. These effects could be blocked by agomelatine pretreatment. Furthermore, luzindole, the melatonin receptor (MT) antagonist, could reverse the neuroprotective effect of agomelatine.

Conclusion

The results demonstrated that antidepressant agomelatine might prevent the tau protein phosphorylation and oxidative damage induced by Aβ_25–35 in PC12 cells by activating MT-PTEN/Akt/GSK3β signaling. This study provided a novel therapeutic target for AD in the future.

Keywords:

• agomelatine
• Alzheimer’s disease
• oxidative stress
• tau hyperphosphorylation

Acknowledgments

The authors thank Heng-bing Zu (Department of Neurology, Jinshan Hospital Affiliated to Fudan University, Shanghai, China) for excellent technical assistance in this study. The study was supported by research grants from Research Project of Jinshan District Health and Family Planning Commission (No JSKJ-KTMS-2018-19), Qi Hang project of Jinshan Hospital (No 2018-JSYYQH-06).

Disclosure

The authors report no conflicts of interest in this work.