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