Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy.

Abstract

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.

• Authors: Mohanraj Rajesh, Partha Mukhopadhyay, Sándor Bátkai, Vivek Patel, Keita Saito, Shingo Matsumoto, Yoshihiro Kashiwaya, Béla Horváth, Bani Mukhopadhyay, Lauren Becker, György Haskó, Lucas Liaudet, David A Wink, Aristidis Veves, Raphael Mechoulam, Pál Pacher
• Journal: Journal of the American College of Cardiology (J Am Coll Cardiol) Vol. 56 Issue 25 Pg. 2115-25 (Dec 14 2010) ISSN: 1558-3597 [Electronic] United States
• PMID: 21144973 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Chemical References

• Blood Glucose
• Insulin
• NF-kappa B
• Reactive Oxygen Species
• Cannabidiol
• Glucose

Topics

• Animals
• Apoptosis (drug effects)
• Blood Glucose (drug effects)
• Body Weight (drug effects)
• Cannabidiol (pharmacology, therapeutic use)
• Cells, Cultured
• Diabetic Cardiomyopathies (drug therapy, metabolism, pathology)
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Fibrosis
• Glucose
• Hemodynamics (drug effects)
• Humans
• Insulin (metabolism)
• MAP Kinase Signaling System (drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• Myocardium (pathology)
• Myocytes, Cardiac (drug effects)
• NF-kappa B (metabolism)
• Oxidative Stress (drug effects)
• Pancreas (drug effects, metabolism)
• Reactive Oxygen Species (metabolism)