N-linoleyltyrosine protects PC12 cells against oxidative damage via autophagy: Possible involvement of CB1 receptor regulation

Oxidative stress is one of the main pathogenic factors of neurodegenerative diseases. As the ligand of cannabinoid type 1 (CB1) and 2 (CB2) receptors, anandamide (AEA) exerts benign antioxidant activities. However, the instability of AEA results in low levels in vivo, which limit its further application. Based on the structure of AEA, N-linoleyltyrosine (NITyr) was synthesized in our laboratory and was hypothesized to possess a similar function to that of AEA. To the best of our knowledge, the present study demonstrates for the first time, the activities and mechanisms of NITyr. NITyr treatment attenuated hydrogen peroxide (H(2)O(2))-induced cytotoxicity, with the most promiment effect observed at 1 µmol/l. Treatment with NITyr also suppressed the H(2)O(2)-induced elevation of reactive oxygen species (ROS) and enhanced the expression of the autophagy-related proteins, LC3-II, beclin-1, ATG 5 and ATG13. The autophagic inhibitor, 3-methyladenine, reversed the effects of NITyr on ROS levels and cellular viability. Furthermore, AM251, a CB1 receptor antagonist, but not AM630 (a CB2 receptor antagonist), diminished the effects of NITyr on cell viability, ROS generation and autophagy-related protein expression. However, NITyr increased the protein expression of both the CB1 and CB2 receptors. Therefore, NITyr was concluded to protect PC12 cells against H(2)O(2)-induced oxidative injury by inducing autophagy, a process which may involve the CB1 receptor.