The Mechanism of Cannabidiol-Mediated Oxidative Stress and Apoptosis in Human Monocytes The Mechanism of Cannabidiol-Mediated Oxidative Stress and Apoptosis in Human Monocytes The Mechanism of Cannabidiol-Mediated Oxidative Stress and Apoptosis in Human Monocytes
Date Issued
2012
Date
2012
Author(s)
Lin, Yi-Hsuan
Abstract
Cannabidiol (CBD), the major non-psychotropic cannabinoid contained in the plant Cannabis sativa, possesses a number of promising pharmacological activities, such as anti-inflammation and immunomodulation. CBD is known to induce apoptosis in both transformed and primary immune cells, including lymphocytes, thymocytes and monocytes, through oxidative stress-related mechanisms. The objective of this study was to investigate the underlying mechanisms for CBD-induced oxidative stress and apoptosis in monocytes. Consistent with previous results, 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 exposure. By comparison, CBD rapidly elicited the depolarization of mitochondrial membrane potential within 5 min, and the oxidation of cardiolipin, a major lipid component of the mitochondrial inner membrane, within 15 min of exposure. CBD also induced the release of cytochrome c from mitochondria to the cytosol, confirming that mitochondria are targeted by CBD. Furthermore, results from confocal microscopy demonstrated that the intracellular ROS measured by 2’,7’-dichlorofluorescein co-localized with the mitochondrial probe MitoTracker in CBD-treated monocytes. Flow cytometric analyses revealed that CBD induced the mitochondrial permeability transition (MPT) as evidenced by a marked decrease in the mitochondrial fluorescence of calcein. CBD-mediated apoptosis and mitochondrial depolarization were significantly attenuated in the presence of the mitochondrial permeability transition pore (MPTP pore) inhibitor cyclosporin A, but not affected by the calcineurin inhibitor FK506. Cyclosporin A also prevented cardiolipin oxidation and MPT induced by CBD. Taken together, the present study suggests that CBD may act at the level of mitochondria to initiate oxidative stress and apoptosis via MPTP-dependent mechanisms in human peripheral monocytes.
Subjects
apoptosis
cannabidiol
mitochondrial permeability transition
monocyte
reactive oxygen species
Type
thesis
File(s)![Thumbnail Image]()
Loading...
Name
ntu-101-R99629009-1.pdf
Size
23.32 KB
Format
Adobe PDF
Checksum
(MD5):0ca5d4c95068d58bb4b0e999d5847a74