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: 5.71). 02/2011; 50(10):1368-81. DOI: 10.1016/j.freeradbiomed.2011.02.021
Source: PubMed

ABSTRACT 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: Paclitaxel (PAC) is associated with a chemotherapy-induced neuropathic pain (CIPN) state that can lead to the cessation of treatment in late stage breast cancer patients, even in the absence of alternate therapies. Indeed, to date no one drug or drug class is considered to be effective for reversal of CIPN. We have recently reported that chronic administration of the non-psychoactive and non-toxic cannabinoid, cannabidiol (CBD) prevents the onset of PAC-induced mechanical and thermal sensitivity in a mouse model of CIPN. In this investigation, we sought to discover pathways through which CBD inhibits CIPN and to determine whether the cannabinoid had any unforeseen deleterious effects on nervous system function or chemotherapy efficacy. The ability of acute CBD pretreatment to prevent PAC-induced mechanical sensitivity was assessed using Von Frey filament testing. The effect of CBD on place conditioning and on autoshaping, a conditioned learning and memory task, were determined to determine whether the cannabinoid produced any negative CNS effects. The potential positive or negative interaction of CBD and PAC on breast cancer cell viability was determined using the MTT assay and the combination index (CI). Treatment with PAC (4.0 and 8.0 mg/kg X 4 inj) produced significant mechanical sensitivity in female C57Bl/6 mice that was prevented by administration of CBD (2.5 - 10 mg/kg). The protective effect of CBD was reversed by co-administration of the 5-HT1A antagonist WAY 100635, but not the CB1 antagonist SR141716 or the CB2 antagonist SR144528. CBD produced no conditioned rewarding effects in comparison to morphine which served as a positive control. CBD also did not affect acquisition or retention in the autoshaping procedure. At optimal concentrations, CBD+PAC combinations produce additive to synergistic inhibition of breast cancer cell viability. Our data suggest that CBD is protective against PAC-induced neurotoxicity and that this effect is in part mediated by the 5-TH1A receptor system. Furthermore, CBD treatment was devoid of other nervous system effects such as conditioned reward or cognitive impairment. CBD also did not attenuate the efficacy of PAC in inhibiting breast cancer cell viability. Taken together, adjunct treatment with CBD during PAC chemotherapy treatment may be safe and effective in the prevention or attenuation of CIPN.
    British Journal of Pharmacology 10/2013; 171. DOI:10.1111/bph.12439 · 4.99 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.
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    ABSTRACT: The therapeutic potential of cannabidiol, the major non-psychotropic Cannabis constituent, was investigated in rats exposed to ischemia/reperfusion liver injury. Ischemia was induced by clamping the pedicle of the left hepatic lobe for 30 min, and cannabidiol (5mg/kg, i.v.) was given 1h following the procedure and every 24h thereafter for 2 days. Ischemia/reperfusion caused significant elevations of serum alanine aminotransferase and hepatic malondialdehyde, tumor necrosis factor-α and nitric oxide levels, associated with significant decrease in hepatic reduced glutathione. Cannabidiol significantly attenuated the deterioration in the measured biochemical parameters mediated by ischemia/reperfusion. Histopathological examination showed that cannabidiol ameliorated ischemia/reperfusion-induced liver damage. Immunohistochemical analysis revealed that cannabidiol significantly reduced the expression of inducible nitric oxide synthase, cyclooxygenase-2, nuclear factor-κB, Fas ligand and caspase-3, and increased the expression of survivin protein in ischemic/reperfused liver tissue. These results emphasize that cannabidiol represents a potential therapeutic option to protect the liver against hypoxia-reoxygenation injury.
    European journal of pharmacology 09/2011; 670(1):216-23. DOI:10.1016/j.ejphar.2011.08.048 · 2.68 Impact Factor
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