CB2 and GPR55 Receptors as Therapeutic Targets for Systemic Immune Dysregulation

Burkovskiy, Ian; Yang, Hye-Won; Sardinha, Joel; Lehmann, Christian

doi:10.3389/fphar.2016.00264

Cited by 30 publications

(27 citation statements)

References 84 publications

(112 reference statements)

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“…GPR55, which is strongly expressed in the nervous and immune systems as well as in other tissues, is a G-protein coupled receptor [93]. Activation of GPR55 increases the intracellular level of calcium ions [94].…”

Section: Gpr Receptorsmentioning

confidence: 99%

Antioxidative and Anti-Inflammatory Properties of Cannabidiol

2019

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Cannabidiol (CBD) is one of the main pharmacologically active phytocannabinoids of Cannabis sativa L. CBD is non-psychoactive but exerts a number of beneficial pharmacological effects, including anti-inflammatory and antioxidant properties. The chemistry and pharmacology of CBD, as well as various molecular targets, including cannabinoid receptors and other components of the endocannabinoid system with which it interacts, have been extensively studied. In addition, preclinical and clinical studies have contributed to our understanding of the therapeutic potential of CBD for many diseases, including diseases associated with oxidative stress. Here, we review the main biological effects of CBD, and its synthetic derivatives, focusing on the cellular, antioxidant, and anti-inflammatory properties of CBD.Antioxidants 2020, 9, 21 2 of 20 Moreover, this phytocannabinoid accelerated wound healing in a diabetic rat model by protecting the endothelial growth factor (VEGF) [11]. In addition, by preventing the formation of oxidative stress in the retina neurons of diabetic animals, CBD counteracted tyrosine nitration, which can lead to glutamate accumulation and neuronal cell death [12].This review summarizes the chemical and biological effects of CBD and its natural and synthetic derivatives. Particular attention was paid to the antioxidant and anti-inflammatory effects of CBD and its derivatives, bearing in mind the possibilities of using this phytocannabinoid to protect against oxidative stress and the consequences associated with oxidative modifications of proteins and lipids. Although CBD demonstrates safety and a good side effect profile in many clinical trials [4], all of the therapeutic options for CBD discussed in this review are limited in a concentration-dependent manner. Molecular Structure of CBDCBD is a terpenophenol compound containing twenty-one carbon atoms, with the formula C 21 H 30 O 2 and a molecular weight of 314.464 g/mol (Figure 1). The chemical structure of cannabidiol, 2-[1R-3-methyl-6R-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1, 3-benzenediol, was determined in 1963 [13]. The current IUPAC preferred terminology is 2-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol. Naturally occurring CBD has a (−)-CBD structure [14]. The CBD molecule contains a cyclohexene ring (A), a phenolic ring (B) and a pentyl side chain. In addition, the terpenic ring (A) and the aromatic ring (B) are located in planes that are almost perpendicular to each other [15]. There are four known CBD side chain homologs, which are methyl, n-propyl, n-butyl, and n-pentyl [16]. All known CBD forms (Table 1) have absolute trans configuration in positions 1R and 6R [16].

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Section: Gpr Receptorsmentioning

confidence: 99%

Antioxidative and Anti-Inflammatory Properties of Cannabidiol

2019

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“…Administration of the CB1 receptor antagonist SR141716A in CB1 receptor-KO mice reduced anxiety-like behavior (Haller et al, 2002) while the CB1 receptor inverse agonist AM251 did not induce any significant alterations in anxiety-like behavior in CB1 receptor-KO mice (Thiemann et al, 2009). Our present findings that show an increase TH and decrease in α2-AR and β1-AR expression levels in CB1 receptor-KO mice may suggest involvement of a non-CB1 receptor and adrenergic receptors including vanilloid type 1 receptors (TRPV1) and GPR55 (Hong et al, 2009; Laricchiuta et al, 2013; Biernacki and Skrzydlewska, 2016;Marichal-Cancino et al, 2016; Zhou et al, 2016). It has been shown that eCBS can act to TRPV1 and GPR55 (Chavez et al, 2010; Hong et al, 2009; Laricchiuta et al, 2013; Biernacki and Skrzydlewska, 2016;Marichal-Cancino et al, 2016; Zhou et al, 2016).…”

Section: Discussionmentioning

confidence: 50%

“…Our present findings that show an increase TH and decrease in α2-AR and β1-AR expression levels in CB1 receptor-KO mice may suggest involvement of a non-CB1 receptor and adrenergic receptors including vanilloid type 1 receptors (TRPV1) and GPR55 (Hong et al, 2009; Laricchiuta et al, 2013; Biernacki and Skrzydlewska, 2016;Marichal-Cancino et al, 2016; Zhou et al, 2016). It has been shown that eCBS can act to TRPV1 and GPR55 (Chavez et al, 2010; Hong et al, 2009; Laricchiuta et al, 2013; Biernacki and Skrzydlewska, 2016;Marichal-Cancino et al, 2016; Zhou et al, 2016). Our electrophysiology data in WT mice confirmed findings from earlier studies in rats indicating that stimulation of α2-adrenoceptors enhances the excitability of mPFC pyramidal neurons coupled with an increase in cellular input resistance (Andrews and Lavin, 2006; Carr et al, 2007; Reyes et al, 2012; Cathel et al, 2014).…”

Section: Discussionmentioning

confidence: 50%

Cortical adrenoceptor expression, function and adaptation under conditions of cannabinoid receptor deletion

Reyes

Carvalho

Szot

et al. 2017

Experimental Neurology

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A neurochemical target at which cannabinoids interact to have global effects on behavior is brain noradrenergic circuitry. Acute and repeated administration of a cannabinoid receptor synthetic agonist is capable of increasing multiple indices of noradrenergic activity. This includes cannabinoid-induced 1) increases in norepinephrine (NE) release in the medial prefrontal cortex (mPFC); 2) desensitization of cortical α2-adrenoceptor-mediated effects; 3) activation of c-Fos in brainstem locus coeruleus (LC) noradrenergic neurons; and 4) increases in anxiety-like behaviors. In the present study, we sought to examine adaptations in adrenoceptor expression and function under conditions of cannabinoid receptor type 1 (CB1r) deletion using knockout (KO) mice and compare these to wild type (WT) controls. Electrophysiological analysis of α2-adrenoceptor-mediated responses in mPFC slices in WT mice showed a clonidine-induced α2-adrenoceptor-mediated increase in mPFC cell excitability coupled with an increase in input resistance. In contrast, CB1r KO mice showed an α2-adrenoceptor-mediated decrease in mPFC cell excitability. We then examined protein expression levels of α2- and β1-adrenoceptor subtypes in the mPFC as well as TH expression in the locus coeruleus (LC) of mice deficient in CB1r. Both α2- and β1-adrenoceptors exhibited a significant decrease in expression levels in CB1r KO mice when compared to WT in the mPFC, while a significant increase in TH was observed in the LC. To better define whether the same cortical neurons express α2A-adrenoceptor and CB1r in mPFC, we utilized highresolution immunoelectron microscopy. We localized α2A-adrenoceptors in a knock-in mouse that expressed a hemoagglutinin (HA) tag downstream of the α2A-adrenoceptor promoter. Although the α2A-adrenoceptor was often identified pre-synaptically, we observed colocalization of CB1r with α2-adrenoceptors post-synaptically in the same mPFC neurons. Finally, using receptor binding, we confirmed prior results showing that α2A-adrenoceptor is unchanged in mPFC following acute or chronic exposure to the synthetic cannabinoid receptor agonist, WIN 55,212-2, but is increased, following chronic treatment followed by a period of abstinence. Taken together, these data provide convergent lines of evidence indicating cannabinoid regulation of the cortical adrenergic system.

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“…Cannabinoids have emerged as prominent modulators of diverse physiological and pathological processes. As such, efforts are underway to examine the efficacy of cannabinoid agonist and antagonists as therapeutic agents (McPartland et al, 2014 ; Russo, 2016 ; Toguri et al, 2016 ; Zhou et al, 2016 ). Cannabinoids primarily exert their effects through the cannabinoid receptors (CB1 and CB2); however, other receptors and molecular targets are now known to be important for their activity.…”

Section: Discussionmentioning

confidence: 99%

Cannabinoids Modulate Neuronal Activity and Cancer by CB1 and CB2 Receptor-Independent Mechanisms

2017

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Cannabinoids include the active constituents of Cannabis or are molecules that mimic the structure and/or function of these Cannabis-derived molecules. Cannabinoids produce many of their cellular and organ system effects by interacting with the well-characterized CB1 and CB2 receptors. However, it has become clear that not all effects of cannabinoid drugs are attributable to their interaction with CB1 and CB2 receptors. Evidence now demonstrates that cannabinoid agents produce effects by modulating activity of the entire array of cellular macromolecules targeted by other drug classes, including: other receptor types; ion channels; transporters; enzymes, and protein- and non-protein cellular structures. This review summarizes evidence for these interactions in the CNS and in cancer, and is organized according to the cellular targets involved. The CNS represents a well-studied area and cancer is emerging in terms of understanding mechanisms by which cannabinoids modulate their activity. Considering the CNS and cancer together allow identification of non-cannabinoid receptor targets that are shared and divergent in both systems. This comparative approach allows the identified targets to be compared and contrasted, suggesting potential new areas of investigation. It also provides insight into the diverse sources of efficacy employed by this interesting class of drugs. Obtaining a comprehensive understanding of the diverse mechanisms of cannabinoid action may lead to the design and development of therapeutic agents with greater efficacy and specificity for their cellular targets.

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CB2 and GPR55 Receptors as Therapeutic Targets for Systemic Immune Dysregulation

Cited by 30 publications

References 84 publications

Antioxidative and Anti-Inflammatory Properties of Cannabidiol

Antioxidative and Anti-Inflammatory Properties of Cannabidiol

Cortical adrenoceptor expression, function and adaptation under conditions of cannabinoid receptor deletion

Cannabinoids Modulate Neuronal Activity and Cancer by CB1 and CB2 Receptor-Independent Mechanisms

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