A new cannabinoid CB 2receptor agonist HU-910 attenuates oxidative stress, inflammation and cell death associated with hepatic ischaemia/reperfusion injury

Bela Horváth, Lital Magid, Partha Mukhopadhyay, Sándor Bátkai, Mohanraj Rajesh, Ogyi Park, Galin Tanchian, Rachel Y. Gao, Catherine E. Goodfellow, Michelle Glass, Raphael Mechoulam, Pál Pacher

Research output: Contribution to journalArticle

Abstract

BACKGROUND AND PURPOSE: Cannabinoid CB 2 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 [ 3H]CP55940 by HU-910 from specific binding sites in CHO cell membranes transfected with human CB 2or CB 1 receptors (hCB 1/2) yielded K i values of 6 nM and 1.4 μM respectively. HU-910 inhibited forskolin-stimulated cyclic AMP production by hCB 2 CHO cells (EC 50 = 162 nM) and yielded EC 50 of 26.4 nM in [ 35S]GTPγS binding assays using hCB 2expressing CHO membranes. HU-910 given before ischaemia significantly attenuated levels of I/R-induced hepatic proinflammatory chemokines (CCL3 and CXCL2), TNF-α, 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-α production in isolated Kupffer cells and expression of adhesion molecules in primary human liver sinusoidal endothelial cells stimulated with TNF-α. Pretreatment with a CB 2 receptor antagonist attenuated the protective effects of HU-910, while pretreatment with a CB 1 antagonist tended to enhance them. CONCLUSION AND IMPLICATIONS: HU-910 is a potent CB 2 receptor agonist which may exert protective effects in various diseases associated with inflammation and tissue injury. LINKED ARTICLES: This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.

Original languageEnglish (US)
Pages (from-to)2462-2478
Number of pages17
JournalBritish Journal of Pharmacology
Volume165
Issue number8
DOIs
StatePublished - Apr 2012
Externally publishedYes

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Cannabinoids
Reperfusion Injury
Oxidative Stress
Cell Death
Inflammation
Liver
Reperfusion
Ischemia
CHO Cells
Medicine
Cannabinoid Receptor CB2
Chemokine CXCL2
Chemokine CCL3
HU-910
Kupffer Cells
Neutrophil Infiltration
Wounds and Injuries
Cell Adhesion Molecules
Colforsin
Brain Ischemia

Keywords

  • Cannabinoids
  • Inflammation
  • Ischaemia-reperfusion
  • Oxidative stress

ASJC Scopus subject areas

  • Pharmacology

Cite this

A new cannabinoid CB 2receptor agonist HU-910 attenuates oxidative stress, inflammation and cell death associated with hepatic ischaemia/reperfusion injury. / Horváth, Bela; Magid, Lital; Mukhopadhyay, Partha; Bátkai, Sándor; Rajesh, Mohanraj; Park, Ogyi; Tanchian, Galin; Gao, Rachel Y.; Goodfellow, Catherine E.; Glass, Michelle; Mechoulam, Raphael; Pacher, Pál.

In: British Journal of Pharmacology, Vol. 165, No. 8, 04.2012, p. 2462-2478.

Research output: Contribution to journalArticle

Horváth, B, Magid, L, Mukhopadhyay, P, Bátkai, S, Rajesh, M, Park, O, Tanchian, G, Gao, RY, Goodfellow, CE, Glass, M, Mechoulam, R & Pacher, P 2012, 'A new cannabinoid CB 2receptor agonist HU-910 attenuates oxidative stress, inflammation and cell death associated with hepatic ischaemia/reperfusion injury', British Journal of Pharmacology, vol. 165, no. 8, pp. 2462-2478. https://doi.org/10.1111/j.1476-5381.2011.01381.x
Horváth, Bela ; Magid, Lital ; Mukhopadhyay, Partha ; Bátkai, Sándor ; Rajesh, Mohanraj ; Park, Ogyi ; Tanchian, Galin ; Gao, Rachel Y. ; Goodfellow, Catherine E. ; Glass, Michelle ; Mechoulam, Raphael ; Pacher, Pál. / A new cannabinoid CB 2receptor agonist HU-910 attenuates oxidative stress, inflammation and cell death associated with hepatic ischaemia/reperfusion injury. In: British Journal of Pharmacology. 2012 ; Vol. 165, No. 8. pp. 2462-2478.
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AU - Horváth, Bela

AU - Magid, Lital

AU - Mukhopadhyay, Partha

AU - Bátkai, Sándor

AU - Rajesh, Mohanraj

AU - Park, Ogyi

AU - Tanchian, Galin

AU - Gao, Rachel Y.

AU - Goodfellow, Catherine E.

AU - Glass, Michelle

AU - Mechoulam, Raphael

AU - Pacher, Pál

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N2 - BACKGROUND AND PURPOSE: Cannabinoid CB 2 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 [ 3H]CP55940 by HU-910 from specific binding sites in CHO cell membranes transfected with human CB 2or CB 1 receptors (hCB 1/2) yielded K i values of 6 nM and 1.4 μM respectively. HU-910 inhibited forskolin-stimulated cyclic AMP production by hCB 2 CHO cells (EC 50 = 162 nM) and yielded EC 50 of 26.4 nM in [ 35S]GTPγS binding assays using hCB 2expressing CHO membranes. HU-910 given before ischaemia significantly attenuated levels of I/R-induced hepatic proinflammatory chemokines (CCL3 and CXCL2), TNF-α, 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-α production in isolated Kupffer cells and expression of adhesion molecules in primary human liver sinusoidal endothelial cells stimulated with TNF-α. Pretreatment with a CB 2 receptor antagonist attenuated the protective effects of HU-910, while pretreatment with a CB 1 antagonist tended to enhance them. CONCLUSION AND IMPLICATIONS: HU-910 is a potent CB 2 receptor agonist which may exert protective effects in various diseases associated with inflammation and tissue injury. LINKED ARTICLES: This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.

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