Cannabidiol Treatment Ameliorates Acetaminophen-Induced Hepatotoxicity in Mice
The possible therapeutic effect of cannabidiol, the major non-psychotropic Cannabis constituent, was investigated against acute hepatotoxicity induced by a single oral dose of acetaminophen (500mg/kg) in mice. Cannabidiol (two intraperitoneal injections, 5mg/kg, each) was given 1 hour and 12 hours following acetaminophen administration. Acetaminophen administration caused significant elevations of serum alanine aminotransferase, and hepatic malondialdehyde, and nitric oxide levels, and a significant decrease in hepatic reduced glutathione. Cannabidiol significantly attenuated the deterioration in the measured biochemical parameters resulted from acetaminophen administration. Also, histopathological examination showed that cannabidiol markedly attenuated ameliorated acetaminophen-induced liver tissue damage. These results emphasize that cannabidiol represents a potential therapeutic option to protect against acetaminophen hepartotoxicity which is a common clinical problem.
Digital Object Identifier (DOI): doi.org/10.5281/zenodo.1076052Procedia APA BibTeX Chicago EndNote Harvard JSON MLA RIS XML ISO 690 PDF Downloads 2598
 W.C. Maddrey, "Drug induced hepatotoxicity," J. Clin. Gastroenterol., vol. 39, pp. 883-889, 2005.
 L.P. James, P.R. Mayeux, J.A. Hinson, "Acetaminophen-induced hepatotoxicity," Drug Metab. Dispos., vol. 31, pp. 1499-1506, 2003.
 H. Jaeschke, M.R. McGill, C.D. Williams, A. Ramachandran, "Currentissues with acetaminophenhepatotoxicity—a clinically relevant model to test the efficacy of natural products," LifeSci., vol. 88, pp. 737-745, 2011.
 P. Mukhopadhyay, M. Rajesh, B. Horvath, S. Batkai, 0. Park, G. Tanashian, R.Y. Gao, V. Patel, D.A. Wink, L. Liaudet, G. Hasko, R. Mechoulam, P. Pacher, "Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death," Free Radic. Biol. Med., vol. 50, pp. 1368-1381, 2011.
 M.R. Pazos, V. Cinquina, A. Gomez, R. Layunta, M. Santos, J. Fernandez-Ruiz, J. Martinez-Orgado, "Cannabidiol administration after hypoxia-ischemia to newborn rats reduces long-term brain injury and restores neurobehavioral function," Neuropharmacology, vol. 63, pp. 776-783, 2012.
 T. Iuvone, G. Esposito, D. De Filippis, C. Scuderi, L. Steardo, "Cannabidiol: a promising drug for neurodegenerative disorders?," CNS Neurosci. Ther., vol. 15, pp. 65-75, 2009.
 D.R. Blake, P. Robson, M. Ho, R.W. Jubb, C.S. McCabe, "Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis," Rheumatology (Oxford), vol. 45, pp. 50-52, 2006.
 M. Rajesh, P. Mukhopadhyay, S. Batkai, V. Patel, K. Saito, S. Matsumoto, Y. Kashiwaya, B. Horvath, B. Mukhopadhyay, L. Becker, G. Hasko, L. Liaudet, D.A. Wink, A. Veves, R. Mechoulam, P. Pacher, "Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy," J. Am. Coll. Cardiol., vol. 56, pp. 2115-2125, 2010.
 R. Durst, H. Danenberg, R. Gallily, R. Mechoulam, K. Meir, E. Grad, R. Beeri, T. Pugatsch, E. Tarsish, C. Lotan, "Cannabidiol, a non-psychoactive Cannabis constituent, protects against myocardial ischemic reperfusion injury,” Am. J. Physiol. Heart Circ. Physiol., vol. 293, pp. H3602-H3607, 2007.
 C. Girish, B.C. Koner, S. Jayanthi, K. Ramachandra Rao, B. Rajesh, S.C. Pradhan, “Hepatoprotective activity of picroliv, curcumin and ellagic acid com- pared to silymarin on paracetamol induced liver toxicity in mice,” Fundam. Clin. Pharmacol., vol. 23, pp. 735-745, 2009.
 M.N. Nagi, H.A. Almakki, M.M. Sayed-Ahmed, A.M. Al-Bekairi, “Thymoquinone supplementation reverses acetaminophen-induced oxidative stress, nitric oxide production and energy decline in mice liver,” Food Chem. Toxicol., vol. 48, pp. 2361-2365, 2010.
 H.S. Oz, T.S. Chen, “Green-tea polyphenols downregulate cyclooxygenase and Bcl-2 activity in acetaminophen-induced hepatotoxicity,” Dig. Dis. Sci., vol. 53, pp. 2980-2988, 2008.
 S.L. Yan, S.T. Wu, M.C. Yin, H.T. Chen, H.C. Chen, “Protective effects from carnosine and histidine on acetaminophen-induced liver injury,” J. Food Sci., vol. 74, pp. H259-H265, 2009.
 G. Kuvandik, M. Duru, A. Nacar, Z. Yonden, R. Helvaci, A. Koc, T. Kozlu, H. Kaya, S. Sogüt, “Effects of erdosteine on acetaminopheninduced hepatotoxicity in rats,” Toxicol. Pathol., vol. 36, pp. 714-719, 2008.
 R.M. Clancy, S.B. Abramson, “Nitric oxide: a novel mediator of inflammation,” Proc. Soc. Exp. Biol. Med., vol. 210, pp. 93-101, 1995.
 H. Pan, P. Mukhopadhyay, M. Rajesh, V. Patel, B. Mukhopadhyay, B. Gao, G. Hasko, P. Pacher, “Cannabidiol attenuates cisplatin-induced nephrotoxicity by decreasing oxidative/nitrosative stress, inflammation, and cell death,” J. Pharmacol. Exp. Ther., vol. 328, pp. 708-714, 2009.
 I.H. Shaik, R. Mehvar, “Cytochrome P450 induction by Phenobarbital exacerbates warm hepatic ischemia-reperfusion injury in rat livers,” Free Radic. Res., vol. 44, pp. 441-453, 2010.
 F. Borrelli, G. Aviello, B. Romano, P. Orlando, R. Capasso, F. Maiello, F. Guadagno, S. Petrosino, F. Capasso, V. Di Marzo, A.A. Izzo, “Cannabidiol, a safe and non-psychotropic ingredient of the marijuana plant Cannabis sativa, is protective in a murine model of colitis,” J. Mol. Med., vol. 87, pp. 1111-1121, 2009.
 L. Ruiz-Valdepeñas, J.A. Martínez-Orgado, C. Benito, A. Millán, R.M. Tolón, J. Romero, “Cannabidiol reduces lipopolysaccharide-induced vascular changes and inflammation in the mouse brain: an intravital microscopy study,” J. Neuroinflammation, vol. 8, p. 5, 2001.
 B. Costa, M. Colleoni, S. Conti, D. Parolaro, C. Franke, A.E. Trovato, G. Giagnoni, “Oral anti-inflammatory activity of cannabidiol, a nonpsychoactive constituent of cannabis, in acute carrageenan-induced inflammation in the rat paw,” Naun Schm. Arch. Pharmacol., vol. 369, pp. 294-299, 2004.
 M. Begg, P. Pacher, S. Batkai, D. Osei-Hyiaman, L. Offertaler, F.M. Mo, J. Liu, G. Kunos, “Evidence for novel cannabinoid receptors,” Pharmacol. Ther., vol. 106, pp. 133-145, 2005.
 T. Bisogno, L. Hanus, L. De Petrocellis, S. Tchilibon, D.E. Ponde, I. Brandi, A.S. Moriello, J.B. Davis, R. Mechoulam, V. Di Marzo, « Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide,” Br. J. Pharmacol., vol. 134, pp. 845-852, 2001.
 E.J. Carrier, J.A. Auchampach, C.J. Hillard, “Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression,” Proc. Natl. Acad. Sci. USA, vol. 103, pp. 7895-7900, 2006.