Cannabidiol induced apoptosis in human monocytes through mitochondrial permeability transition pore-mediated ROS production

• Published in: Free radical biology & medicine 2018-08, Vol.124, p.311-318
• Main Authors: Wu, Hsin-Ying, Huang, Chung-Hsiung, Lin, Yi-Hsuan, Wang, Chia-Chi, Jan, Tong-Rong
• Format: Article
• Language: English
• Subjects: Apoptosis; Cannabidiol; Mitochondrial; Monocyte; Oxidative stress
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2018.06.023

Cannabidiol (CBD) has been reported to induce apoptosis in immune cells through oxidative stress-related mechanisms. The objective of the present study was to investigate the cellular mechanisms for CBD-induced apoptosis and oxidative stress in human monocytes. Exposure of freshly isolated human monocytes to CBD induced apoptosis in a time- and concentration-dependent manner. Time-course analyses revealed the induction of intracellular reactive oxygen species (ROS) at 1–2 h post CBD (16 μM) exposure. By comparison, the CBD treatment rapidly elicited the depolarization of mitochondrial membrane potential (MMP) within 5 min, and the oxidation of cardiolipin, a major lipid component of the mitochondrial inner membrane, within 15 min. Moreover, CBD induced the release of cytochrome c (Cyt c) from mitochondria. Mechanistic studies revealed that CBD-induced ROS production and apoptosis were not associated with the alteration of mitochondrial superoxide dismutase activity, the electron leakage through mitochondrial respiratory chain, and Fe2+- and Ca2+-mediated mechanisms. In contrast, CBD-induced apoptosis and MMP depolarization were markedly attenuated by the mitochondrial permeability transition pore (MPTP) inhibitor cyclosporin A (CsA), but not the calcineurin inhibitor FK506. Furthermore, CsA prevented cardiolipin oxidation and the MPTP opening induced by CBD. The present study suggests that CBD acts on the mitochondria to elicit ROS generation and apoptosis through MPTP opening and provides critical insights into the cellular mechanisms for CBD-induced oxidative stress in apoptotic monocytes. [Display omitted] •Mechanisms for CBD-induced apoptosis and oxidative stress in monocytes are studied.•CBD elicited MMP depolarization and cardiolipin oxidation before ROS production.•CBD induced Cyt c release from mitochondria.•Cyclosporin A, but not FK506, prevented CBD-induced apoptosis and MMP depolarization.•CBD-induced ROS generation and apoptosis is mediated by opening MPTP.