β-Caryophyllene Mitigates Collagen Antibody Induced Arthritis (CAIA) in Mice Through a Cross-Talk between CB2 and PPAR-γ Receptors

Abstract

β-caryophyllene (BCP) is a cannabinoid receptor 2 (CB2) agonist that tempers inflammation. An interaction between the CB2 receptor and peroxisome proliferator-activated receptor gamma (PPAR-γ) has been suggested and PPAR-γ activation exerts anti-arthritic effects. The aim of this study was to characterize the therapeutic activity of BCP and to investigate PPAR-γ involvement in a collagen antibody induced arthritis (CAIA) experimental model. CAIA was induced through intraperitoneal injection of a monoclonal antibody cocktail and lipopolysaccharide (LPS; 50 μg/100 μL/ip). CAIA animals were then randomized to orally receive either BCP (10 mg/kg/100 μL) or its vehicle (100 μL of corn oil). BCP significantly hampered the severity of the disease, reduced relevant pro-inflammatory cytokines, and increased the anti-inflammatory cytokine IL-13. BCP also decreased joint expression of matrix metalloproteinases 3 and 9. Arthritic joints showed increased COX2 and NF-ĸB mRNA expression and reduced expression of the PPARγ coactivator-1 alpha, PGC-1α, and PPAR-γ. These conditions were reverted following BCP treatment. Finally, BCP reduced NF-ĸB activation and increased PGC-1α and PPAR-γ expression in human articular chondrocytes stimulated with LPS. These effects were reverted by AM630, a CB2 receptor antagonist. These results suggest that BCP ameliorates arthritis through a cross-talk between CB2 and PPAR-γ.

β-Caryophyllene Inhibits Cell Proliferation through a Direct Modulation of CB2 Receptors in Glioblastoma Cells

“…In this experimental approach, U373 cells highly expressed NF-κB, whereas BCP treatment significantly reduced its expression. In addition, previous studies have indicated a possible crosstalk between the CB2 receptor and PPAR-γ [12,20]. The PPAR-γ receptor activation reduces pro-inflammatory cytokine release, thus exerting an anti-inflammatory effect [21].…”

Chemopreventive Potential of Caryophyllane Sesquiterpenes: An Overview of Preliminary Evidence

“…Indeed, it has been characterized by a plethora of biological activities, among which analgesic, anti-inflammatory, antioxidant, neuroprotective, and antiproliferative were the most investigated; moreover, it has been reported to affect phospholipid cooperativity and membrane permeability ( Table 3 ). These properties have provided benefits in several experimental models of disease, such as neurodegeneration, inflammation, pain, anxiety, depression, autoimmune diseases, metabolic ailments, osteoarthritis and some cancer models [ 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 ,…”

“…Such benefits have been usually ascribed to the ability of β-caryophyllene to selectively activate the cannabinoid CB2 receptors (CB2Rs) [ 123 , 124 , 128 , 139 , 149 , 153 , 213 ], and to modulate further targets in the endocannabinoidome (i.e., the endogenous lipid signaling system including several fatty acid-derived mediators and their receptors, and their metabolic enzymes), such as the peroxisome proliferator-activated receptors (PPARs) and the fatty acid amide hydrolase (FAAH), which is a degrading enzyme of the endocannabinoid neurotransmitters [ 123 , 124 , 128 , 214 ]. Interestingly, a peripheral release of endogenous opioids seems to mediate the antinociceptive effects of β-caryophyllene, although nonpsychoactive responses have been also described [ 124 ].…”

“…The antiproliferative activity of caryophyllane sesquiterpenes has been often associated with the activation of pro-apoptotic signalings. Particularly, α-humulene induced apoptosis in liver cancer cells [ 210 ], while β-caryophyllene in different in vitro cancer models, including neuroblastoma, lymphoma, glioblastoma, osteosarcoma, and oral cancer cells [ 128 , 154 , 155 , 156 , 158 ]. The apoptotic cell death induced by the sesquiterpene in oral KB cancer cells was associated with morphological changes, lowered cell growth, and reduced metastasizing abilities, which was likely due to the activation of a mitochondrial-mediated apoptotic pathway [ 155 ].…”

Therapeutic Potential of β-Caryophyllene: A Dietary Cannabinoid in Diabetes and Associated Complications

“…Cannabinoids are known to interact or crosstalk with a family of peroxisome proliferated activator receptors (PPARs) including three distinct subtypes namely PPAR-α, PPAR-β/δ, and PPAR-γ that are encoded by distinct genes and are regulated by steroids and lipid metabolites and control lipid and glucose homeostasis and inflammatory responses [ 40 , 65 , 67 , 68 ]. The activation of CB2R on the surface of the cells triggers the intracellular signaling cascade that leads to the activation of PPARs [ 69 ]. The PPARs belongs to the members of nuclear receptor superfamily that functions as ligand-activated transcription factors and plays significantly in cellular proliferation, differentiation, organogenesis, inflammation, as well as the expression of hepatic enzymes regulating glucose homeostasis, insulin sensitivity, and lipid metabolism [ 70 ].…”