Cannabidiol modulation of oxidative stress and signalling, Sonia R. Pereira et al., 2021

Cannabidiol modulation of oxidative stress and signalling

Sonia R. Pereira, Becky Hackett, David N. O’Driscoll, Melody Cui Sun and Eric J. Downer

Neuronal Signaling, 2021, 5,  NS20200080

doi : 10.1042/NS20200080


Cannabidiol (CBD), one of the primary non-euphoric components in the Cannabis sativa L. plant, has undergone clinical development over the last number of years as a therapeutic for patients with Lennox-Gastaut syndrome and Dravet syndromes. This phytocannabinoid demonstrates functional and pharmacological diversity, and research data indicate that CBD is a comparable antioxidant to common antioxidants. This review gathers the latest knowledge regarding the impact of CBD on oxidative signalling, with focus on the proclivity of CBD to regulate antioxidants and control the production of reactive oxygen species. CBD is considered an attractive therapeutic agent for neuroimmune disorders, and a body of literature indicates that CBD can regulate redox function at multiple levels, with a range of downstream effects on cells and tissues. However, pro-oxidant capacity of CBD has also been reported, and hence caution must be applied when considering CBD from a therapeutic standpoint. Such pro- and antioxidant functions of CBD may be cell- and model-dependent and may also be influenced by CBD dose, the duration of CBD treatment and the underlying pathology.



Production of reactive oxygen species (ROS) is commonly associated with oxidative stress and its
pathological role in inflammatory diseases such as multiple sclerosis (MS), rheumatoid arthritis (RA), atherosclerosis and inflammatory bowel disease (IBD) [1–5]. During infection, immune cells produce
ROS via the NADPH oxidase 2 (NOX2) complex as a mechanism to eradicate pathogens [6]. When NOX2-generated ROS production is dysregulated due to mutations in NOX2 complex proteins, this can result in defective phagocyte function characterized by severe and recurrent infections defined as chronic granulomatous disease (CGD) [7].Moreover, ROS produced in the phagosome to activate proteolytic enzymes can escape the immune cell, thus damaging the surrounding tissue [8]. Despite this, it is clear that a deficiency in ROS production has the proclivity to aggravate disease processes [9]. In addition, leukocytes isolated from individuals with chronic MS produce less superoxide than those with a milder disease [10], and a similar scenario has been identified in Guillain–Barr´e syndrome (a subtype of acute inflammatory demyelinating polyneuropathy), where evidence suggests that leukocytes produce lower levels of oxygen radicals in the most severe cases of disease [11]. Taken together, these findings support a complex role of ROS in regulating inflammation in disease.

In recent years, cannabinoid molecules, such as cannabidiol (CBD) and 9-tetrahydrocannabinol (9- THC), have drawn attention due to their anti-inflammatory, antioxidant and neuroprotective properties [12,13]. The most well-described targets for cannabinoids are their specific receptors, the cannabinoid receptors CB1 and CB2 [14,15], but their pharmacological actions are not solely limited to these receptors. Indeed, cannabinoids are lipophilic and certain cannabinoids have also been shown to target a wide range of receptors, including the peroxisome proliferator-activated receptors (PPARs), the transient receptor potential cation channel subfamily V member 1 (TRPV1), G-protein-coupled receptor 55 (GPR55), the 5-hydroxytryptamine receptor subtype 1A (5-HT1A), glycine α1 and α1β receptors, in addition to ion channels (Ca2+) and enzymes such as the adenosine membrane transporter phospholipase A2, lipoxygenase (LO) and cyclooxygenase-2 (COX-2) [16–22]. Depending both on the cannabinoid structure and cell/tissue targeted, the pharmacological effects of cannabinoids may vary. Overall, cannabinoids have been shown to possess therapeutic efficacy in several inflammatory and neuronal diseases [23]. Given that the production of ROS is an intrinsic feature of neuroinflammation and peripheral immune responses, this review aims to gather the latest knowledge on the action of cannabinoids on oxidative signalling, with focus on the phytocannabinoid CBD. CBD is selected for review given recent advances in its therapeutic development [24–26].

Oxidative signalling and stress

The production and maintenance of controlled levels of intracellular ROS has a key role in several physiological functions, including the maintainance of redox homeostasis, cell cycle signalling and hormone production [27,28].When present, ROS can regulate several signalling pathways by reacting with transcription factors and genes, modifying their structure and thus their function. Hence, ROS can modulate gene expression patterns and signalling proteins related to the stress response and cell survival mechanisms [29]. It is when this homeostasis is impaired, by either an overproduction of ROS or inefficient ROS scavenging mechanisms, that oxidative stress ensues, promoting cellular damage, lipid peroxidation, DNAmodifications and enzyme inactivation, and when persistent, can ultimately lead to cell death and tissue destruction [30–32]. This rationale has been the basis for the development of several anticancer drugs [33–35].