β-Caryophyllene ameliorates cisplatin-induced nephrotoxicity in a cannabinoid 2 receptor-dependent manner

Abstract

(E)-β-caryophyllene (BCP) is a natural sequiterpene found in many essential oils of spice (best known for contributing to the spiciness of black pepper) and food plants with recognized anti-inflammatory properties. Recently it was shown that BCP is a natural agonist of endogenous cannabinoid 2 (CB2) receptors, which are expressed in immune cells and mediate anti-inflammatory effects. In this study we aimed to test the effects of BCP in a clinically relevant murine model of nephropathy (induced by the widely used antineoplastic drug cisplatin) in which the tubular injury is largely dependent on inflammation and oxidative/nitrative stress. β-caryophyllene dose-dependently ameliorated cisplatin-induced kidney dysfunction, morphological damage, and renal inflammatory response (chemokines MCP-1 and MIP-2, cytokines TNF-α and IL-1β, adhesion molecule ICAM-1, and neutrophil and macrophage infiltration). It also markedly mitigated oxidative/nitrative stress (NOX-2, NOX-4 expression, 4-HNE and 3-NT content) and cell death. The protective effects of BCP against biochemical and histological markers of nephropathy were absent in CB2 knockout mice. Thus, BCP may be an excellent therapeutic agent to prevent cisplatin-induced nephrotoxicity through a CB2 receptor dependent pathway. Given the excellent safety profile of BCP in humans it has tremendous therapeutic potential in multitude of diseases associated with inflammation and oxidative stress.

β-Caryophyllene Ameliorates the Alzheimer-Like Phenotype in APP/PS1 Mice through CB2 Receptor Activation and the PPARγ Pathway

“…β-Caryophyllene has previously been shown to be a selective agonist of CB2 receptor [44,56]. We investigated whether a CB2-selective antagonist could prevent the protective effects of β-caryophyllene.…”

β‐Caryophyllene protects against alcoholic steatohepatitis by attenuating inflammation and metabolic dysregulation in mice

“…This makes BCP a promising food-derived agent that may be exploited therapeutically to treat various inflammatory diseases (Gertsch et al, 2008). BCP has been reported to exert protective effects in experimental animal models of inflammatory pain (Gertsch et al, 2008), kidney injury (Horvath et al, 2012b), ischaemic stroke (Choi et al, 2013), Parkinson's disease (Ojha et al, 2016), toxic hepatitis (D-galactosamine-and endotoxin-induced) (Cho et al, 2015), experimental liver fibrosis (Mahmoud et al, 2014) and colitis (Bento et al, 2011). BCP has been also proposed recently, to have anti-addictive potential (Al Mansouri et al, 2014).…”

Cannabinoid Receptor 2 Expression in Human Proximal Tubule Cells is Regulated by Albumin Independent of ERK1/2 Signaling

“…In diabetic STZ animals, hallmark indicators of renal damage are elevated such as TGF-β and fibronectin, in addition to the development of albuminuria [1]. Significantly, there is also an infiltration of macrophages, which abundantly express CB2 [29]. Thus, it is likely that the CB2 receptor expression in whole kidney samples is influenced by infiltrating macrophages offsetting the downregulation of CB2 in podocytes and proximal tubule cells.…”