applied sciences Review β-Caryophyllene: A Sesquiterpene with Countless Biological Properties 1, 1, 1 1, 1 Fabrizio Francomano y, Anna Caruso y, Alexia Barbarossa , Alessia Fazio *, Chiara La Torre , Jessica Ceramella 1, Rosanna Mallamaci 2 , Carmela Saturnino 3, Domenico Iacopetta 1 and Maria Stefania Sinicropi 1 1 Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende, Italy; [email protected] (F.F.); [email protected] (A.C.); [email protected] (A.B.); [email protected] (C.L.T.); [email protected] (J.C.); [email protected] (D.I.); [email protected] (M.S.S.) 2 Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Via Orabona 4, 70124 Bari, Italy; [email protected] 3 Department of Science, University of Basilicata, 85100 Potenza, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-0984-493013 The authors have contributed equally to the manuscript. y Received: 18 November 2019; Accepted: 9 December 2019; Published: 11 December 2019 Abstract: β-Caryophyllene (BCP), a natural bicyclic sesquiterpene, is a selective phytocannabinoid agonist of type 2 receptors (CB2-R). It isn’t psychogenic due to the absence of an affinity to cannabinoid receptor type 1 (CB1). Among the various biological activities, BCP exerts anti-inflammatory action via inhibiting the main inflammatory mediators, such as inducible nitric oxide synthase (iNOS), Interleukin 1 beta (IL-1β), Interleukin-6 (IL-6), tumor necrosis factor-alfa (TNF-α), nuclear factor kapp a-light-chain-enhancer of activated B cells (NF-κB), cyclooxygenase 1 (COX-1), cyclooxygenase 2 (COX-2). Peroxisome proliferator-activated receptors alpha (PPAR-α) effects are also mediated by the activation of PPAR-α and PPAR-γ receptors. In detail, many studies, in vitro and in vivo, suggest that the treatment with β-caryophyllene improves the phenotype of animals used to model various inflammatory pathologies, such as nervous system diseases (Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, stroke), atherosclerosis, and tumours (colon, breast, pancreas, lymphoma, melanoma and glioma cancer). Furthermore, pre-clinical data have highlighted that BCP is potentially useful in Streptococcus infections, osteoporosis, steatohepatitis, and exerts anticonvulsant, analgesic, myorelaxing, sedative, and antidepressive effects. BCP is non-toxic in rodents, with a Lethal dose, 50% (LD50) greater than 5000 mg/kg. Nevertheless, it inhibits various cytochrome P450 isoforms (above all, CYP3A4), which metabolise xenobiotics, leading to adverse effects, due to drug levels over therapeutic window. All the reported data have highlighted that both pharmacological and toxicological aspects need to be further investigated with clinical trials. Keywords: sesquiterpene; inflammatory pathologies; nutraceuticals 1. Introduction Sesquiterpenoids are an extremely wide group of secondary metabolites found in the plant kingdom [1,2]. Their main carbon backbone consists of 15 atoms and several synthases action leads to a great variety of chemical structures. In particular, bicyclic sesquiterpenoids have raised attention in the bio-pharmacological field, even as essential oils. Among them, β-caryophyllene is one of the major component of essential oils extracted from spice and food plants [3–7], such as black pepper (Piper nigrum L.), rosemary (Rosmarinus officinalis), cinnamon (Cinnamomum spp.) Appl. Sci. 2019, 9, 5420; doi:10.3390/app9245420 www.mdpi.com/journal/applsci Appl. Sci. 2019, 9, 5420 2 of 19 oregano (Origanum vulgare L.) basil (Ocimum spp.), thyme (Thymus vulgaris), sage (Salvia officinalis), mintAppl. Sci.(Mentha 2019, 9, x piperita FOR PEER), gingerREVIEW (Zingiber officinale), chinotto (Citrus Myrtfolia Raf) [8], and cloves2 of 19 (Syzygium aromaticum)[9,10]. It was also found in citronella, (Cymbopogon), pine tree (Pinus), Chenopodiumginger (Zingiber ambrosioides officinale),, Cannabischinotto ( sativaCitrus, inMyrtfolia plants ofRaf) the [8 genus], and Copaiferacloves (Syzygium, Artemisia aromaticum, Murraya,) Cordia[9,10]., SpiranthesIt was also, Ocimumfound in, Croton citronella,[9,10 (],Cymbopogon and in the), leaves pine oftreeAnnona (Pinus Cherimola), Chenopodium[11]. Thisambrosioides plant compound, Cannabis wassativa approved, in plants byof the Food genus and Copaifera Drug Administration, Artemisia, Murraya (FDA), Cordia and,European Spiranthes, Food Ocimum Safety, Croton Authority [9,10], (EFSA)and in the and leaves it is used of Annona as flavour Cherimola enhancer [11]. [This9] and plant in cosmeticscompound [12 was]. In approved nature, BCPby Food mainly and occurs Drug asAdtransministration-caryophyllene (FDA) and ((E)-BCP) European (1) Food mixed Safety with Authority small amount (EFSA) of and the isomersit is used (Z)- as flavourβ-caryophyllene enhancer ((Z)-BCP)[9] and in (cosmetics2) and α-humulene [12]. In n (αature,-caryophyllene) BCP mainly (3 )[occurs12], and as trans its oxidation-caryophyllene derivative, ((E)-βBCP)-caryophyllene (1) mixed oxidewith (BCPO)small amount (4) (Figure of1 ).the isomers (Z)-β-caryophyllene ((Z)-BCP) (2) and α-humulene (α- caryophyllene) (3) [12], and its oxidation derivative, β-caryophyllene oxide (BCPO) (4) (Figure 1). O H H H H H H 3 1 2 4 Figure 1. Structures of sesquiterpenes (1–4). Figure 1: Structures of sesquiterpenes (1–4). BCP belongs to cannabinoid family, which are ligands of the cannabinoid receptors present in the organism.BCP belongs Cannabinoid to cannabinoid receptors CB1-Rfamily, and which CB2-R are areligands metabotropic of the cannabinoid receptors are receptors G protein present (protein in bindingthe organism. GTP)-coupled Cannabinoid receptors, receptors involved CB1-R in and the CB2 regulation-R are metabotropic of neurotransmitters receptors responsible are G protein for maintaining(protein binding an energetic GTP)-coupled balance, receptors, in the metabolism, involved in and the in regulation the immune of neurotransmitters response. The aforementioned responsible receptorsfor maintaining are bound an energetic and activated balance, by endogenous in the metabolism cannabinoids,, and derivativesin the immune of arachidonic response. acid,The includingaforementioned 2-arachidonoylglycerol receptors are bound and andN-arachidonoylethanolamine, activated by endogenous bettercannabinoids, known as derivatives anandamide. of Botharachidonic receptors acid, are including bound by 2-arachidonoylglycerol a lot of proteins in various and N- pathways,arachidonoylethanolamine, acting as mediators better of cellularknown responsesas anandamide. to biological Both molecules.receptors are bound by a lot of proteins in various pathways, acting as mediatorsUnlike of cellular the main responses traditional to biological cannabinoids, molecules. such as D8-tetrahydrocannabinol (5), D9- 8 9 tetrahydrocannabinolUnlike the main (6 )traditional and cannabinol cannabinoids, (7) (Figure 2such), able as to Δ activate-tetrahydrocannabinol both receptors, BCP(5), hasΔ - atetrahydrocannabinol very different chemical (6) structureand cannabinol and it is (7 a) selective(Figure 2), agonist able to of activate CB2-R. both Furthermore, receptors, BCP BCP has has no a very side edifferentffects, not chemical activating structure CB1-Rs and (mainly it is expresseda selective inagonist the central of CB2 nervous-R. Furthermore, system, but BCP also has in theno liver,side lungs,effects, heart, not activating blood vessels CB1- andRs (mainly digestive expressed tract). CB2-Rs in the arecentral mainly nervous found system, in peripheral but also tissues in the and liver, in immunelungs, heart, system blood cells vessels (B and and NK digestive lymphocytes, tract). macrophages, CB2-Rs are mainly mast cells)found and, in peripheral to a lesser tissues extent, and in the in centralimmune nervous system system cells (B (brain, and NK neurons, lymphocytes, microglia) macrophages, [13]. The expression mast cells) of CB2-Rsand, to ina lesser the central extent, nervous in the systemcentral isnervous increased system in neurodegenerative (brain, neurons, pathologies, microglia) such[13]. asThe Parkinson’s expression disease, of CB2 Alzheimer’s-Rs in the disease,central amyotrophicnervous system lateral is sclerosisincreased (ALS) in andneurodegenerative in some tumours pathologies, like gliomas such [14]. as Parkinson’s disease, Alzheimer’sThe binding disease, of BCP amyotrophic to CB2-Rs lateral is responsible sclerosis for (ALS) many and cellular in some events: tumours like gliomas [14]. The activation of G α-subunit inhibits the activity of adenylate cyclase, the enzyme which • i/o converts ATP in cAMP (cyclic AMP) and activates phospholipase C (PLC), determining calcium release from IP3 (inositol trisphosphate)-sensitive calcium channels, increasing the intracellular level of calcium; The activation of the complex formed by G β- and γ-subunits, which modulate various pathways • i/o modifying the expression and the activity of many target proteins [15]. Appl. Sci. 2019, 9, x FOR PEER REVIEW 2 of 19 ginger (Zingiber officinale), chinotto (Citrus Myrtfolia Raf) [8], and cloves (Syzygium aromaticum) [9,10]. It was also found in citronella, (Cymbopogon), pine tree (Pinus), Chenopodium ambrosioides, Cannabis sativa, in plants of the genus Copaifera, Artemisia, Murraya, Cordia, Spiranthes, Ocimum, Croton [9,10], and in the leaves of Annona Cherimola [11].