Non-psychotropic plant cannabinoids:new therapeutic opportunities from anancient herb
Angelo A. Izzo
, Raffaele Capasso
, Vincenzo Di Marzo
Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy
Institute of Biomolecular Chemistry, National Research Council, Pozzuoli (NA), Italy
Department of Medicinal Chemistry and Natural Products, Hebrew University Medical Faculty, Jerusalem, Israel
Endocannabinoid Research Group, Italy
-tetrahydrocannabinol binds cannabinoid (CB
)receptors,whichareactivatedbyendogenouscom-pounds (endocannabinoids) and are involved in a widerange of physiopathological processes (e.g. modulationof neurotransmitter release, regulation of pain percep-tion, and of cardiovascular, gastrointestinal and liverfunctions). The well-known psychotropic effects of
-tetrahydrocannabinol, which are mediated by activationof brain CB
receptors, have greatly limited its clinicaluse. However, the plant
contains many can-nabinoids with weak or no psychoactivity that, thera-peutically, might be more promising than
-tetrahydrocannabinol. Here, we provide an overviewof the recent pharmacological advances, novel mechan-isms of action, and potential therapeutic applications ofsuch non-psychotropic plant-derived cannabinoids.Special emphasis is given to cannabidiol, the possibleapplications of which have recently emerged in inﬂam-mation, diabetes, cancer, affective and neurodegenera-tive diseases, and to
-tetrahydrocannabivarin, a novelCB
antagonistwhichexertspotentiallyusefulactionsinthe treatment of epilepsy and obesity.Introduction
produces over 421 chemicalcompounds, includingabout80terpeno-phenol compoundsnamed phytocannabinoids that have not been detected inany other plant[1
4]. For obvious reasons, most attentionhasbeenpaidto
-THC),whichis the most psychotropic component and binds speciﬁc G-protein-coupled receptors named cannabinoid (CB
) receptors[5,6]. The discovery of a speciﬁc cell mem-brane receptor for
-THC was followed by isolation andidentiﬁcationofendogenous(animal)ligandstermedendo-cannabinoids. The two main endocannabinoids are ana-ndamide (which is metabolized mostly by fatty acid amidehydrolase (FAAH)) and 2-arachidonoylglycerol (which ismostly degraded by monoglyceride lipase (MAGL))[5,6].Cannabinoid receptors, endogenous ligands that activatethem, and the mechanisms for endocannabinoid biosyn-thesis and inactivation constitute the ‘‘endocannabinoidsystem’’. With its ability to modulate several physiologicaland pathophysiological processes (e.g. neurotransmitter
Transient receptor potential (TRP)
: Transient receptor potential (TRP) is asuperfamily of non-selective, ligand-gated cation channels. They can besubdivided in six main subfamilies: the TRPC (‘Canonical’), TRPV (’Vanilloid’),TRPM (‘Melastatin’), TRPP (‘Polycystin’), TRPML (‘Mucolipin’) and the TRPA(‘Ankyrin’) group. At least six TRPs (TRPV1, TRPV2, TRPV3, TRPV4, TRPM8 andTRPA1) have been shown to be expressed in primary afferent nociceptors,where they act as transducers for thermal, chemical and mechanical stimuli.Many TRPs are activated by natural compounds, such as capsaicin (TRPV1),cannabidiol (TRPV2), incensole acetate (TRPV3), menthol (TRPM8) andmustard oil isothiocyanates (TRPA1)
: Uptake of adenosine is a primary mechanism of terminat-ing adenosine signalling. Adenosine is a multifunctional, ubiquitous moleculethat activate four known adenosine receptors (A
receptor is an important regulator of inflammation.
: GPR55 is an orphan G-protein-coupled receptor originally identified insilico from the expressed sequence tags database. GPR55 may be activated byplant and synthetic endocannabinoids as well as by anandamide-relatedacylethanolamides and may be antagonized by cannabidiol. Possible role inantinociception.
Peroxisome proliferator-activated receptors (PPARs)
: Peroxisome prolifera-tors-activated receptors (PPARs) belong to a family of nuclear receptorscomprising three isoforms:
. Among these, PPAR
is involved in theregulation of cellular glucose uptake, protection against atherosclerosis andcontrol of immune reactions. Activation of PPAR
attenuates neurodegenera-tive and inflammatory processes.
: Lipoxygenases are non-heme iron-containing enzymesthat catalyze the dioxygenation of polyunsaturated fatty acids, such asarachidonic acid and linolenic acids. Three major LOX isoforms have beendiscovered (i.e., 5-, 12-, and 15-LOX). 5-LOX is responsible for the production of leukotrienes-inflammatory lipid mediator. 15-LOX oxygenates not only freefatty acids but also complex substrates such as phospholipids, cholesterolester, and the cholesterol ester in the low density lipoprotein particle, with arole in atherosclerosis and inflammation
: Glycine receptors, which belong to the superfamily of transmitter-gated ion channels - are pentamers formed either from
subunitsalone, or from both
subunits. They are activated by glycine, one of themajor inhibitory neurotransmitters in posterior areas of the vertebrate centralnervous system. Glycine receptors are also involved in inflammation, immuneresponse and cytoprotection.
: The abnormal-cannabidiol receptor is aputative receptor expressed in the endothelium of rat mesenteric bed, whichcan be activated by abnormal-cannabidiol (abn-cbd), a synthetic analogue of cannabidiol. This endothelial receptor, distinct from the currently knowncannabinoid receptors, has also been suggested to mediate anandamide-induced relaxation in the whole mesenteric bed of the rat.
: The 5-HT
receptor is one of the best-characterized 5-HTreceptors. This G protein-coupled receptor is involved a number of physiolo-gical or pathophysiological processes, including anxiety, mood, depression,vasoreactive headache, food intake, immune regulation, and cardiovascularregulation.
TIPS-730; No of Pages 13
see front matter