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BACKGROUND AND PURPOSE: Activation of cannabinoid 2 (CB(2) ) receptors is protective against various forms of reperfusion injury. Δ(8) -tetrahydrocannabivarin (Δ(8) -THCV) is a synthetic analog of the plant cannabinoid Δ(9) -tetrahydrocannabivarin, which has been reported to exert anti-inflammatory effects in rodents involving activation of CB(2) receptors. EXPERIMENTAL APPROACH: In this study we have explored if Δ(8) -THCV or its metabolite 11-OH-Δ(8) -THCV activates CB(2) receptors in vitro, and if Δ(8) -THCV protects against hepatic ischemia/reperfusion (I/R) injury in vivo. KEY
RESULTS: Displacement of [(3) H]CP55940 by Δ(8) -THCV or 11-OH-Δ(8) -THCV from specific binding sites in Chinese hamster ovary (CHO) cell membranes transfected with human CB(2) receptors (hCB(2) ) yielded K(i) values of 68.4 and 59.95 nM, respectively. Δ(8) -THCV or 11-OH-Δ(8) -THCV inhibited the forskolin-stimulated cyclic AMP production by hCB(2) CHO cells (EC(50) = 12.95 and 14.3 nM, respectively). Δ(8) -THCV, given prior to the induction of I/R, significantly attenuated the extent of liver damage (measured by serum alanine aminotransferase and aspartate aminotransferase levels), decreased tissue protein carbonyl adducts, 4-hydroxy-2-nonenal (HNE), macrophage inflammatory protein-1alpha and 2 (MIP-1α/CCL3, MIP-2/CXCL2), tumor necrosis factor-alpha (TNF-α), inter-cellular adhesion molecule 1 (ICAM-1/CD54) mRNA levels, tissue neutrophil infiltration, caspase3/7 activity and DNA fragmentation. The protective effect of Δ(8) -THCV against liver damage was also preserved when given at the beginning of reperfusion. CB(2) receptor antagonist pretreatment attenuated the protective effect of Δ(8) -THCV, while CB(1) antagonist rather tended to enhance it.
CONCLUSIONS AND
IMPLICATIONS: Δ(8) -THCV can activate CB(2) receptors in vitro and decrease tissue injury and inflammation associated with I/R partly via CB(2) receptor activation.
Source: Unboundmedicine.com
RESULTS: Displacement of [(3) H]CP55940 by Δ(8) -THCV or 11-OH-Δ(8) -THCV from specific binding sites in Chinese hamster ovary (CHO) cell membranes transfected with human CB(2) receptors (hCB(2) ) yielded K(i) values of 68.4 and 59.95 nM, respectively. Δ(8) -THCV or 11-OH-Δ(8) -THCV inhibited the forskolin-stimulated cyclic AMP production by hCB(2) CHO cells (EC(50) = 12.95 and 14.3 nM, respectively). Δ(8) -THCV, given prior to the induction of I/R, significantly attenuated the extent of liver damage (measured by serum alanine aminotransferase and aspartate aminotransferase levels), decreased tissue protein carbonyl adducts, 4-hydroxy-2-nonenal (HNE), macrophage inflammatory protein-1alpha and 2 (MIP-1α/CCL3, MIP-2/CXCL2), tumor necrosis factor-alpha (TNF-α), inter-cellular adhesion molecule 1 (ICAM-1/CD54) mRNA levels, tissue neutrophil infiltration, caspase3/7 activity and DNA fragmentation. The protective effect of Δ(8) -THCV against liver damage was also preserved when given at the beginning of reperfusion. CB(2) receptor antagonist pretreatment attenuated the protective effect of Δ(8) -THCV, while CB(1) antagonist rather tended to enhance it.
CONCLUSIONS AND
IMPLICATIONS: Δ(8) -THCV can activate CB(2) receptors in vitro and decrease tissue injury and inflammation associated with I/R partly via CB(2) receptor activation.
Source: Unboundmedicine.com