Author + information
- Received May 15, 2010
- Revision received July 5, 2010
- Accepted July 6, 2010
- Published online December 14, 2010.
- Mohanraj Rajesh, PhD⁎,
- Partha Mukhopadhyay, PhD⁎,
- Sándor Bátkai, MD, PhD⁎,
- Vivek Patel⁎,
- Keita Saito, PhD‡,
- Shingo Matsumoto, PhD‡,
- Yoshihiro Kashiwaya, MD, PhD†,
- Béla Horváth, MD, PhD⁎,
- Bani Mukhopadhyay, PhD⁎,
- Lauren Becker⁎,
- György Haskó, MD, PhD§,
- Lucas Liaudet, MD∥,
- David A. Wink, PhD‡,
- Aristidis Veves, MD¶,
- Raphael Mechoulam, PhD# and
- Pál Pacher, MD, PhD⁎,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Pál Pacher, Section on Oxidative Stress Tissue Injury, Laboratory of Physiological Studies, National Institutes of Health/NIAAA, 5625 Fishers Lane, MSC-9413, Bethesda, Maryland 20892-9413
Objectives In this study, we have investigated the effects of cannabidiol (CBD) on myocardial dysfunction, inflammation, oxidative/nitrative stress, cell death, and interrelated signaling pathways, using a mouse model of type I diabetic cardiomyopathy and primary human cardiomyocytes exposed to high glucose.
Background Cannabidiol, the most abundant nonpsychoactive constituent of Cannabis sativa (marijuana) plant, exerts anti-inflammatory effects in various disease models and alleviates pain and spasticity associated with multiple sclerosis in humans.
Methods Left ventricular function was measured by the pressure-volume system. Oxidative stress, cell death, and fibrosis markers were evaluated by molecular biology/biochemical techniques, electron spin resonance spectroscopy, and flow cytometry.
Results Diabetic cardiomyopathy was characterized by declined diastolic and systolic myocardial performance associated with increased oxidative-nitrative stress, nuclear factor-κB and mitogen-activated protein kinase (c-Jun N-terminal kinase, p-38, p38α) activation, enhanced expression of adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1), tumor necrosis factor-α, markers of fibrosis (transforming growth factor-β, connective tissue growth factor, fibronectin, collagen-1, matrix metalloproteinase-2 and -9), enhanced cell death (caspase 3/7 and poly[adenosine diphosphate-ribose] polymerase activity, chromatin fragmentation, and terminal deoxynucleotidyl transferase dUTP nick end labeling), and diminished Akt phosphorylation. Remarkably, CBD attenuated myocardial dysfunction, cardiac fibrosis, oxidative/nitrative stress, inflammation, cell death, and interrelated signaling pathways. Furthermore, CBD also attenuated the high glucose-induced increased reactive oxygen species generation, nuclear factor-κB activation, and cell death in primary human cardiomyocytes.
Conclusions Collectively, these results coupled with the excellent safety and tolerability profile of CBD in humans, strongly suggest that it may have great therapeutic potential in the treatment of diabetic complications, and perhaps other cardiovascular disorders, by attenuating oxidative/nitrative stress, inflammation, cell death and fibrosis.
Drs. Rajesh and Partha Mukhopadhyay contributed equally to this article. This study was supported by the Intramural Research Program of the NIH/NIAAA (to Dr. Pacher) and NIDA Grant DA9789 (to Dr. Mechoulam). Dr. Horváth is a recipient of a Hungarian Research Council Scientific Research Fund Fellowship (NKTH-OTKA-EU, MB08-80238). Dr. Veves receives funding from Novartis for an investigator-initiated research grant, unrelated to this study. Dr. Mechoulam is a consultant for GW Pharmaceuticals, United Kingdom, which is not involved in this publication and is unaware of it. All other authors have reported that they have no relationships to disclose.
- Received May 15, 2010.
- Revision received July 5, 2010.
- Accepted July 6, 2010.
- American College of Cardiology Foundation