Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death

Laboratory of Physiologic Studies, National Institutes of Health, Bethesda, MD 20892, USA.
Free Radical Biology and Medicine (Impact Factor: 5.74). 02/2011; 50(10):1368-81. DOI: 10.1016/j.freeradbiomed.2011.02.021
Source: PubMed


Ischemia/reperfusion (I/R) is a pivotal mechanism of liver damage after liver transplantation or hepatic surgery. We have investigated the effects of cannabidiol (CBD), the nonpsychotropic constituent of marijuana, in a mouse model of hepatic I/R injury. I/R triggered time-dependent increases/changes in markers of liver injury (serum transaminases), hepatic oxidative/nitrative stress (4-hydroxy-2-nonenal, nitrotyrosine content/staining, and gp91phox and inducible nitric oxide synthase mRNA), mitochondrial dysfunction (decreased complex I activity), inflammation (tumor necrosis factor α (TNF-α), cyclooxygenase 2, macrophage inflammatory protein-1α/2, intercellular adhesion molecule 1 mRNA levels; tissue neutrophil infiltration; nuclear factor κB (NF-κB) activation), stress signaling (p38MAPK and JNK), and cell death (DNA fragmentation, PARP activity, and TUNEL). CBD significantly reduced the extent of liver inflammation, oxidative/nitrative stress, and cell death and also attenuated the bacterial endotoxin-triggered NF-κB activation and TNF-α production in isolated Kupffer cells, likewise the adhesion molecule expression in primary human liver sinusoidal endothelial cells stimulated with TNF-α and attachment of human neutrophils to the activated endothelium. These protective effects were preserved in CB2 knockout mice and were not prevented by CB1/2 antagonists in vitro. Thus, CBD may represent a novel, protective strategy against I/R injury by attenuating key inflammatory pathways and oxidative/nitrative tissue injury, independent of classical CB1/2 receptors.

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    • "However, such investigations into prevention of PAC-induced CIPN in rodents are few. Interestingly, CBD has also recently been reported to protect against the onset of type I diabetic peripheral neuropathic pain (Toth et al., 2010), hepatic ischaemia/ reperfusion injury (Mukhopadhyay et al., 2011), and retinal inflammation and degeneration (El-Remessy et al., 2008) in rodent models. While clinical trials are ongoing investigating the anti-inflammatory effects of CBD as a monotherapy in disease states such as inflammatory bowel disease and graft versus host disease, its efficacy at preventing the onset of neuropathic pain in humans remains to be determined. "
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    ABSTRACT: Background and purpose: Paclitaxel (PAC) is associated with chemotherapy-induced neuropathic pain (CIPN) that can lead to the cessation of treatment in cancer patients even in the absence of alternate therapies. We previously reported that chronic administration of the non-psychoactive cannabinoid cannabidiol (CBD) prevents PAC-induced mechanical and thermal sensitivity in mice. Hence, we sought to determine receptor mechanisms by which CBD inhibits CIPN and whether CBD negatively effects nervous system function or chemotherapy efficacy. Experimental approach: The ability of acute CBD pretreatment to prevent PAC-induced mechanical sensitivity was assessed, as was the effect of CBD on place conditioning and on an operant-conditioned learning and memory task. The potential interaction of CBD and PAC on breast cancer cell viability was determined using the MTT assay. Key results: PAC-induced mechanical sensitivity was prevented by administration of CBD (2.5 - 10 mg·kg⁻¹) in female C57Bl/6 mice. This effect was reversed by co-administration of the 5-HT(1A) antagonist WAY 100635, but not the CB₁ antagonist SR141716 or the CB₂ antagonist SR144528. CBD produced no conditioned rewarding effects and did not affect conditioned learning and memory. Also, CBD + PAC combinations produce additive to synergistic inhibition of breast cancer cell viability. Conclusions and implications: Our data suggest that CBD is protective against PAC-induced neurotoxicity mediated in part by the 5-HT(1A) receptor system. Furthermore, CBD treatment was devoid of conditioned rewarding effects or cognitive impairment and did not attenuate PAC-induced inhibition of breast cancer cell viability. Hence, adjunct treatment with CBD during PAC chemotherapy may be safe and effective in the prevention or attenuation of CIPN.
    British Journal of Pharmacology 10/2013; 171(3). DOI:10.1111/bph.12439 · 4.84 Impact Factor
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    • "The liver, which plays a crucial role in metabolism and homeostasis, is one of the organs that is most susceptible to injury arising from hemorrhagic shock, the outcome of which is often fatal [1]. Several studies on ischemic-reperfusion injury of the liver have suggested that p38 MAPK plays a pivotal role in the progression of hemorrhage-induced damage [2], [3], [4], [5], [6]. p38 MAPK has been postulated to be one of the key factors promoting the expression of pro-inflammatory cytokines such as TNF-α and IL-1β [7]. "
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    ABSTRACT: Hemorrhagic shock is a frequent cause of liver failure and often leads to a fatal outcome. Several studies have revealed that p38 MAPK is a key mediator in hemorrhagic damage of the primary organs through the activation of proinflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β. However, the precise role of these factors in liver damage following hemorrhagic shock is unclear. In this study, we used FR167653, a specific inhibitor of p38 MAPK phosphorylation, to examine the role of p38 MAPK in liver damage occurring up to 5 hours after a hemorrhagic episode in a rat model. Activation of p38 MAPK in the liver as well as an increase in hepatic mRNA expression and serum concentrations of TNF-α and IL-1β occurred during the early phase after hemorrhage. Increased serum levels of hepatic enzymes, as well as histological damage and activated neutrophil accumulation in the liver, were observed in the late phase following hemorrhagic shock. FR167653 inhibited the inflammation-related hepatic injury following hemorrhagic shock. Bacterial lipopolysaccharide (LPS) derived from the gut appeared to have little effects on the hepatic damage. These results demonstrate that p38 MAPK activation is induced by hepatic ischemia during hemorrhagic shock and plays an important role both in the hepatic expression of proinflammatory cytokines and in the development of inflammation-related liver damage.
    PLoS ONE 01/2012; 7(1):e30124. DOI:10.1371/journal.pone.0030124 · 3.23 Impact Factor
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    • " , inflammatory cells can transmigrate to the parenchyma and attach to and damage hepatocytes by releasing proteolytic enzymes and oxidants , ultimately leading to cell death ( both apoptotic and necrotic ) and organ failure ( Jaeschke , 2006 ; Pacher and Hasko , 2008 ) . Consistent with earlier reports ( Moon et al . , 2008 ; Abe et al . , 2009 ; Mukhopadhyay et al . , 2011b ) , we found that the acute inflammatory response in our hepatic I / R model peaked between 2 and 6 h of reperfusion , with marked increases ( up Figure 11 HU - 910 treatment ( administered after ischaemia ) attenuates oxida - tive stress and cell death at 24 h following ischaemia . Ischaemia / reperfusion ( I / R ) induced significant "
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    ABSTRACT: BACKGROUND AND PURPOSE Cannabinoid CB2 receptor activation has been reported to attenuate myocardial, cerebral and hepatic ischaemia-reperfusion (I/R) injury. EXPERIMENTAL APPROACH We have investigated the effects of a novel CB2 receptor agonist ((1S,4R)-2-(2,6-dimethoxy-4-(2-methyloctan-2-yl)phenyl)-7,7-dimethylbicyclo[2.2.1]hept-2-en-1-yl) methanol (HU-910) on liver injury induced by 1 h of ischaemia followed by 2, 6 or 24 h of reperfusion, using a well-established mouse model of segmental hepatic I/R. KEY RESULTS Displacement of [H-3]CP55940 by HU-910 from specific binding sites in CHO cell membranes transfected with human CB2 or CB1 receptors (hCB(1/2)) yielded K-i values of 6 nM and 1.4 mM respectively. HU-910 inhibited forskolin-stimulated cyclic AMP production by hCB(2) CHO cells (EC50 = 162 nM) and yielded EC50 of 26.4 nM in [S-35]GTP gamma S binding assays using hCB(2) expressing CHO membranes. HU-910 given before ischaemia significantly attenuated levels of I/R-induced hepatic proinflammatory chemokines (CCL3 and CXCL2), TNF-alpha, inter-cellular adhesion molecule-1, neutrophil infiltration, oxidative stress and cell death. Some of the beneficial effect of HU-910 also persisted when given at the beginning of the reperfusion or 1 h after the ischaemic episode. Furthermore, HU-910 attenuated the bacterial endotoxin-triggered TNF-alpha production in isolated Kupffer cells and expression of adhesion molecules in primary human liver sinusoidal endothelial cells stimulated with TNF-alpha. Pretreatment with a CB2 receptor antagonist attenuated the protective effects of HU-910, while pretreatment with a CB1 antagonist tended to enhance them. CONCLUSION AND IMPLICATIONS HU-910 is a potent CB2 receptor agonist which may exert protective effects in various diseases associated with inflammation and tissue injury.
    British Journal of Pharmacology 03/2011; 165(8):2462-78. DOI:10.1111/j.1476-5381.2011.01381.x · 4.84 Impact Factor
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