Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress

doi:10.1016/j.freeradbiomed.2011.01.007

Free Radical Biology and Medicine

Volume 51, Issue 5, 1 September 2011, Pages 1054-1061

https://doi.org/10.1016/j.freeradbiomed.2011.01.007 Get rights and content

Abstract

Oxidative stress with reactive oxygen species generation is a key weapon in the arsenal of the immune system for fighting invading pathogens and initiating tissue repair. If excessive or unresolved, however, immune-related oxidative stress can initiate further increasing levels of oxidative stress that cause organ damage and dysfunction. Targeting oxidative stress in various diseases therapeutically has proven more problematic than first anticipated given the complexities and perversity of both the underlying disease and the immune response. However, growing evidence suggests that the endocannabinoid system, which includes the CB₁ and CB₂ G-protein-coupled receptors and their endogenous lipid ligands, may be an area that is ripe for therapeutic exploitation. In this context, the related nonpsychotropic cannabinoid cannabidiol, which may interact with the endocannabinoid system but has actions that are distinct, offers promise as a prototype for anti-inflammatory drug development. This review discusses recent studies suggesting that cannabidiol may have utility in treating a number of human diseases and disorders now known to involve activation of the immune system and associated oxidative stress, as a contributor to their etiology and progression. These include rheumatoid arthritis, types 1 and 2 diabetes, atherosclerosis, Alzheimer disease, hypertension, the metabolic syndrome, ischemia–reperfusion injury, depression, and neuropathic pain.

Introduction

(−)-Cannabidiol (CBD) is the major nonpsychotropic cannabinoid compound derived from the plant Cannabis sativa, commonly known as marijuana. CBD was first isolated in 1940 and its structure and stereochemistry were determined in 1963 [1], [2]. Interest in exploiting CBD therapeutically was initially focused on its interactions with the primary psychotropic ingredient of Cannabis, Δ⁹-THC, and its sedative and antiepileptic effects and later its antipsychotic and anxiolytic actions and utility in treating movement disorders [3]. As chronicled elsewhere [3], the past several years have seen a renewed interest in CBD because of the discovery of its antioxidative, anti-inflammatory, and neuroprotective effects, actions that occur for the most part independent of the canonical cannabinoid CB₁ and CB₂ receptors [1], [4]. CBD may prove to have therapeutic utility in a number of conditions involving both inflammation and oxidative stress, including Parkinson disease, diabetes, rheumatoid arthritis, Alzheimer disease, and ischemia–reperfusion injury.

The contribution of the endocannabinoid system to inflammation and regulation of the immune system is an area of intense study that is beyond the scope of this article, and the reader is referred to several recent excellent reviews [5], [6], [7], [8]. However, a brief overview of the system is helpful in discussing CBD. The endocannabinoid system comprises the following: (1) the G-protein-coupled cannabinoid receptors CB₁ and CB₂, which are located in both the central nervous system and the periphery; (2) their arachidonate-based lipid ligands, e.g., 2-arachidonoylglycerol and anandamide (N-arachidonoylethanolamine); and (3) the enzymes that synthesize and degrade these ligands. The endocannabinoid system plays a role in a variety of physiological processes including appetite, pain sensation, and mood. Evidence indicates that both CB₁ and CB₂ are expressed by cells of the immune system and are upregulated in the activation state. Levels of CB₂ appear to be higher than those of CB₁, with decreasing amounts of CB₂ in human B cells, natural killer (NK) cells, monocytes, polymorphonuclear neutrophils, and T cells [6]. Macrophages and related cells, microglia and osteoclasts, express both cannabinoid receptors. CB₂ activation of immune cells is associated with changes in cytokine release and migration [6].

Section snippets

Biochemistry of cannabidiol

CBD (Fig. 1) is a resorcinol-based compound that was shown to have direct, potent antioxidant properties by cyclic voltammetry and a spectrophotometric assay of oxidation in a Fenton reaction [9]. In an in vitro glutamate neuronal toxicity model, CBD was shown to be more protective than either α-tocopherol or vitamin C and comparable to butylated hydroxytoluene (BHT); although as noted by the authors, CBD, unlike BHT, does not seem to promote tumors [9]. CBD was also reported to act as an

Mechanisms of action

Several interactions with relevance to the immune system and oxidative stress are discussed here. First, despite having low affinity for CB₁ and CB₂ receptors, CBD has been shown to antagonize the actions of cannabinoid CB₁/CB₂ receptor agonists in the low-nanomolar range, consistent with noncompetitive inhibition [13]. At 1–10 μM, CBD appears to function as an inverse agonist at both CB₁ and CB₂ receptors [13]. Second, CBD acts as an inhibitor (IC₅₀ 28 μM) of fatty acid amide hydrolase (FAAH),

Actions on immune cells

CBD has been shown to modulate the function of the immune system. Overall these actions may be nuanced and concentration-dependent, but in general include suppression of both cell-mediated and humoral immunity and involve inhibition of proliferation, maturation, and migration of immune cells, antigen presentation, and humoral response [1], [13]. Key aspects are discussed here. In most in vivo models of inflammation, CBD attenuates inflammatory cell migration/infiltration (e.g., neutrophils) [22]

Pain

Neuropathic pain is associated with microglia activation in the spinal cord and brain and their subsequent release of proinflammatory cytokines, such as interleukin-6 (IL-6), IL-1β, and TNFα [33]. The etiology of neuropathic pain, which is common in cancer, diabetes, multiple sclerosis, and peripheral nerve injury, is poorly understood, but recent evidence indicates that increased ROS generation by microglial cells is the critical initiating factor [34]. The drug Sativex, which consists of Δ⁹

Diabetes and diabetic complications

CBD was shown to reduce either the initiation of diabetes or the development of overt or latent diabetes in NOD mice by reducing insulitis [39], [40]. This action was accompanied by a shift in the immune response from a dominant Th1 pattern with proinflammatory cytokines to a Th2 pattern with increased levels of the anti-inflammatory cytokine IL-10. Major effectors of β-cell death in type 1 diabetes are various free radicals and oxidant species, including nitric oxide (NO), and infiltrating

Hypertension

Although CBD has not been considered for treating hypertension, a parallel between the role of microglia in diabetes and hypertension deserves mention. Activation of microglia within the paraventricular nucleus (PVN) was recently shown to contribute to neurogenic hypertension resulting from chronic angiotensin II infusion in the rat [46]. Microglia activation was associated with enhanced expression of proinflammatory cytokines, the acute administration of which into the left ventricle or PVN

Ischemia–reperfusion injury

Redox stress and ROS produced by ischemia–reperfusion of organs activates the immune system, which aids in repair by removing debris and stimulating remodeling. An excessive or prolonged inflammatory response, however, may prove detrimental to organ function by exacerbating ROS production and causing death of the parenchyma. Several hours after ischemia–reperfusion in the heart, a model of myocardial infarction, neutrophils accumulate in the myocardium [51]. Several lines of evidence suggest

Depression

CBD is reported to have antidepressive actions, the basis for which is not established although activation of 5-HT_1A receptors may be involved at least at higher concentrations [13], [57], [58]. Growing evidence in recent years has implicated proinflammatory cytokines, free radical species, and oxidants in the etiology of depression [59], [60]. One explanation is that the resultant oxidative stress adversely affects glial cell function and leads to neuron damage in the brain.

Neurodegenerative diseases

Microglial hyperactivation is a common feature of a number of neurodegenerative diseases, including Parkinson, Alzheimer, Huntington, amyotrophic lateral sclerosis, and multiple sclerosis [61], [62]. Activated microglia produce a number of pro- and anti-inflammatory cytokines, chemokines, glutamate, neurotrophic factors, and prostanoids and a variety of free radicals that together create a state of oxidative stress. Alzheimer disease, which is the most common form of dementia, is characterized

Obesity and the metabolic syndrome

Metabolic syndrome is a combination of medical disturbances including central obesity, glucose intolerance, hypertension, and dyslipidemia that increases the risk for developing cardiovascular diseases and type 2 diabetes. Adipocyte dysfunction leading to a low-grade chronic inflammatory state is thought to underpin the etiology of the metabolic syndrome [76]. Metabolic overload of adipocytes causes production of ROS, proinflammatory cytokines, and adipokines that activate inflammatory genes

Atherosclerosis

Atherosclerosis is an inflammatory disease in which monocytes/macrophages play a critical role in the initiation and progression, as well as rupture, of the atherosclerotic plaque [88]. Plaques form in the arterial wall at areas of disturbed flow and endothelial dysfunction (Fig. 2). The initiating event is the transcytosis of low-density lipoprotein (LDL) into the subendothelial space where it is trapped by binding to proteoglycans of the extracellular matrix [88], [89]. LDL is oxidized by

Conclusions

Inflammation and oxidative stress are intimately involved in the genesis of many human diseases. Unraveling that relationship therapeutically has proven challenging, in part because inflammation and oxidative stress “feed off” each other. However, CBD would seem to be a promising starting point for further drug development given its antioxidant (although relatively modest) and anti-inflammatory actions on immune cells, such as macrophages and microglia. CBD also has the advantage of not having

Acknowledgments

This work was supported by grants from the National Heart, Lung, and Blood Institute (R01HL088101-04 and R01HL088101-02S1).

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Review ArticleCannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress

Abstract

Introduction

Section snippets

Biochemistry of cannabidiol

Mechanisms of action

Actions on immune cells

Pain

Diabetes and diabetic complications

Hypertension

Ischemia–reperfusion injury

Depression

Neurodegenerative diseases

Obesity and the metabolic syndrome

Atherosclerosis

Conclusions

Acknowledgments

Trends Pharmacol. Sci.

Immunobiology

Pharmacol. Res.

Brain Res.

Trends Immunol.

J. Neuroimmunol.

J. Biol. Chem.

Toxicol. Appl. Pharmacol.

Int. Immunopharmacol.

Toxicol. Lett.

Lancet Neurol.

Neurotherapeutics

Neuropharmacology

Am. J. Pathol.

Exp. Eye Res.

J. Am. Coll. Cardiol.

Curr. Opin. Pharmacol.

Int. Immunopharmacol.

Pharmacol. Biochem. Behav.

Prog. Neuropsychopharmacol. Biol. Psychiatry

Prog. Neuropsychopharmacol. Biol. Psychiatry

Brain Res. Rev.

Free Radic. Biol. Med.

Int. J. Dev. Neurosci.

Neurosci. Lett.

Trends Endocrinol. Metab.

Immunobiology

Eur. J. Pharmacol.

Pharmacol. Biochem. Behav.

Curr. Opin. Pharmacol.

J. Lipid Res.

J. Mol. Cell. Cardiol.

Free Radic. Biol. Med.

Cannabidiol—recent advances

Chem. Biodivers.

Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action

Rev. Bras. Psiquiatr.

Non-CB1, non-CB2 receptors for endocannabinoids, plant cannabinoids, and synthetic cannabimimetics: focus on G-protein-coupled receptors and transient receptor potential channels

J. Neuroimmune Pharmacol.

Cannabinoid receptors: a brief history and "what's hot"

Front. Biosci.

The emerging role of the endocannabinoid system in cardiovascular disease

Semin. Immunopathol.

Neuroprotective antioxidants from marijuana

Ann. NY Acad. Sci.

Cannabinoids protect cells from oxidative cell death: a receptor-independent mechanism

J. Pharmacol. Exp. Ther.

Comparison of cannabidiol, antioxidants, and diuretics in reversing binge ethanol-induced neurotoxicity

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The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin

Br. J. Pharmacol.

Cannabidiol, extracted from Cannabis sativa, selectively inhibits inflammatory hypermotility in mice

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Mediation of cannabidiol anti-inflammation in the retina by equilibrative nucleoside transporter and A2A adenosine receptor

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Review Article
Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress

Non-CB₁, non-CB₂ receptors for endocannabinoids, plant cannabinoids, and synthetic cannabimimetics: focus on G-protein-coupled receptors and transient receptor potential channels

The diverse CB₁ and CB₂ receptor pharmacology of three plant cannabinoids: Δ⁹-tetrahydrocannabinol, cannabidiol and Δ⁹-tetrahydrocannabivarin

Mediation of cannabidiol anti-inflammation in the retina by equilibrative nucleoside transporter and A_2A adenosine receptor

Inhibition of human neutrophil chemotaxis by endogenous cannabinoids and phytocannabinoids: evidence for a site distinct from CB₁ and CB₂