Delta(8)-Tetrahydrocannabivarin prevents hepatic ischaemia/reperfusion injury by decreasing oxidative stress and inflammatory responses through cannabinoid CB2 receptors

Sandor Batkai, Partha Mukhopadhyay, Bela Horvath, Mohanraj Rajesh, Rachel Y. Gao, Anu Mahadevan, Mukkanti Amere, Natalia Battista, Aron H. Lichtman, Lisa A. Gauson, Mauro Maccarrone, Roger G. Pertwee, Pal Pacher*

*Corresponding author for this work

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

BACKGROUND AND PURPOSE

Activation of cannabinoid CB2 receptors protects against various forms of ischaemia-reperfusion (I/R) injury. Delta(8)-Tetrahydrocannabivarin (Delta(8)-THCV) is a synthetic analogue of the plant cannabinoid Delta(9)-tetrahydrocannabivarin, which exhibits anti-inflammatory effects in rodents involving activation of CB2 receptors. Here, we assessed effects of Delta(8)-THCV and its metabolite 11-OH-Delta(8)-THCV on CB2 receptors and against hepatic I/R injury.

EXPERIMENTAL APPROACH

Effects in vitro were measured with human CB2 receptors expressed in CHO cells. Hepatic I/R injury was assessed in mice with 1h ischaemia and 2, 6 or 24h reperfusion in vivo.

KEY RESULTS

Displacement of [H-3]CP55940 by Delta(8)-THCV or 11-OH-Delta(8)-THCV from specific binding sites in CHO cell membranes transfected with human CB2 receptors (hCB(2)) yielded K-i values of 68.4 and 59.95 nM respectively. Delta(8)-THCV or 11-OH-Delta(8)-THCV inhibited forskolin-stimulated cAMP production by hCB(2) CHO cells (EC50 = 12.95 and 14.3 nM respectively). Delta(8)-THCV, given before induction of I/R, attenuated hepatic injury (measured by serum alanine aminotransferase and aspartate aminotransferase levels), decreased tissue protein carbonyl adducts, 4-hydroxy-2-nonenal, the chemokines CCL3 and CXCL2, TNF-alpha, intercellular adhesion molecule 1 (CD54) mRNA levels, tissue neutrophil infiltration, caspase 3/7 activity and DNA fragmentation. Protective effects of Delta(8)-THCV against liver damage were still present when the compound was given at the beginning of reperfusion. Pretreatment with a CB2 receptor antagonist attenuated the protective effects of Delta(8)-THCV, while a CB1 antagonist tended to enhance it.

CONCLUSIONS AND IMPLICATIONS

Delta(8)-THCV activated CB2 receptors in vitro, and decreased tissue injury and inflammation in vivo, associated with I/R partly via CB2 receptor activation.

Original languageEnglish
Pages (from-to)2450-2461
Number of pages12
JournalBritish Journal of Pharmacology
Volume165
Issue number8
Early online date23 Mar 2012
DOIs
Publication statusPublished - Apr 2012

Keywords

  • cannabinoids
  • oxidative stress
  • inflammation
  • ischaemia-reperfusion
  • ISCHEMIA-REPERFUSION INJURY
  • NITRIC-OXIDE
  • CELL-DEATH
  • IN-VIVO
  • ISCHEMIA/REPERFUSION INJURY
  • DIABETIC CARDIOMYOPATHY
  • DELTA(9)-TETRAHYDROCANNABIVARIN
  • PEROXYNITRITE
  • DYSFUNCTION
  • PROTECTS

Cite this

Delta(8)-Tetrahydrocannabivarin prevents hepatic ischaemia/reperfusion injury by decreasing oxidative stress and inflammatory responses through cannabinoid CB2 receptors. / Batkai, Sandor; Mukhopadhyay, Partha; Horvath, Bela; Rajesh, Mohanraj; Gao, Rachel Y.; Mahadevan, Anu; Amere, Mukkanti; Battista, Natalia; Lichtman, Aron H.; Gauson, Lisa A.; Maccarrone, Mauro; Pertwee, Roger G.; Pacher, Pal.

In: British Journal of Pharmacology, Vol. 165, No. 8, 04.2012, p. 2450-2461.

Research output: Contribution to journalArticle

Batkai, S, Mukhopadhyay, P, Horvath, B, Rajesh, M, Gao, RY, Mahadevan, A, Amere, M, Battista, N, Lichtman, AH, Gauson, LA, Maccarrone, M, Pertwee, RG & Pacher, P 2012, 'Delta(8)-Tetrahydrocannabivarin prevents hepatic ischaemia/reperfusion injury by decreasing oxidative stress and inflammatory responses through cannabinoid CB2 receptors', British Journal of Pharmacology, vol. 165, no. 8, pp. 2450-2461. https://doi.org/10.1111/j.1476-5381.2011.01410.x
Batkai, Sandor ; Mukhopadhyay, Partha ; Horvath, Bela ; Rajesh, Mohanraj ; Gao, Rachel Y. ; Mahadevan, Anu ; Amere, Mukkanti ; Battista, Natalia ; Lichtman, Aron H. ; Gauson, Lisa A. ; Maccarrone, Mauro ; Pertwee, Roger G. ; Pacher, Pal. / Delta(8)-Tetrahydrocannabivarin prevents hepatic ischaemia/reperfusion injury by decreasing oxidative stress and inflammatory responses through cannabinoid CB2 receptors. In: British Journal of Pharmacology. 2012 ; Vol. 165, No. 8. pp. 2450-2461.
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abstract = "BACKGROUND AND PURPOSEActivation of cannabinoid CB2 receptors protects against various forms of ischaemia-reperfusion (I/R) injury. Delta(8)-Tetrahydrocannabivarin (Delta(8)-THCV) is a synthetic analogue of the plant cannabinoid Delta(9)-tetrahydrocannabivarin, which exhibits anti-inflammatory effects in rodents involving activation of CB2 receptors. Here, we assessed effects of Delta(8)-THCV and its metabolite 11-OH-Delta(8)-THCV on CB2 receptors and against hepatic I/R injury.EXPERIMENTAL APPROACHEffects in vitro were measured with human CB2 receptors expressed in CHO cells. Hepatic I/R injury was assessed in mice with 1h ischaemia and 2, 6 or 24h reperfusion in vivo.KEY RESULTSDisplacement of [H-3]CP55940 by Delta(8)-THCV or 11-OH-Delta(8)-THCV from specific binding sites in CHO cell membranes transfected with human CB2 receptors (hCB(2)) yielded K-i values of 68.4 and 59.95 nM respectively. Delta(8)-THCV or 11-OH-Delta(8)-THCV inhibited forskolin-stimulated cAMP production by hCB(2) CHO cells (EC50 = 12.95 and 14.3 nM respectively). Delta(8)-THCV, given before induction of I/R, attenuated hepatic injury (measured by serum alanine aminotransferase and aspartate aminotransferase levels), decreased tissue protein carbonyl adducts, 4-hydroxy-2-nonenal, the chemokines CCL3 and CXCL2, TNF-alpha, intercellular adhesion molecule 1 (CD54) mRNA levels, tissue neutrophil infiltration, caspase 3/7 activity and DNA fragmentation. Protective effects of Delta(8)-THCV against liver damage were still present when the compound was given at the beginning of reperfusion. Pretreatment with a CB2 receptor antagonist attenuated the protective effects of Delta(8)-THCV, while a CB1 antagonist tended to enhance it.CONCLUSIONS AND IMPLICATIONSDelta(8)-THCV activated CB2 receptors in vitro, and decreased tissue injury and inflammation in vivo, associated with I/R partly via CB2 receptor activation.",
keywords = "cannabinoids, oxidative stress, inflammation, ischaemia-reperfusion, ISCHEMIA-REPERFUSION INJURY, NITRIC-OXIDE, CELL-DEATH, IN-VIVO, ISCHEMIA/REPERFUSION INJURY, DIABETIC CARDIOMYOPATHY, DELTA(9)-TETRAHYDROCANNABIVARIN, PEROXYNITRITE, DYSFUNCTION, PROTECTS",
author = "Sandor Batkai and Partha Mukhopadhyay and Bela Horvath and Mohanraj Rajesh and Gao, {Rachel Y.} and Anu Mahadevan and Mukkanti Amere and Natalia Battista and Lichtman, {Aron H.} and Gauson, {Lisa A.} and Mauro Maccarrone and Pertwee, {Roger G.} and Pal Pacher",
note = "Acknowledgements This study was supported by the National Institutes of Health(DA-03672, DA-005488 and DA-009789) and Intramural Research Program of NIH/NIAAA. Dr Horv{\'a}th is a recipient of a Hungarian Research Council Scientific Research Fund Fellowship (NKTH-OTKA-EU, MB08-80238). The authors are indebted to Dr George Kunos for providing key resources and support.",
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month = "4",
doi = "10.1111/j.1476-5381.2011.01410.x",
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TY - JOUR

T1 - Delta(8)-Tetrahydrocannabivarin prevents hepatic ischaemia/reperfusion injury by decreasing oxidative stress and inflammatory responses through cannabinoid CB2 receptors

AU - Batkai, Sandor

AU - Mukhopadhyay, Partha

AU - Horvath, Bela

AU - Rajesh, Mohanraj

AU - Gao, Rachel Y.

AU - Mahadevan, Anu

AU - Amere, Mukkanti

AU - Battista, Natalia

AU - Lichtman, Aron H.

AU - Gauson, Lisa A.

AU - Maccarrone, Mauro

AU - Pertwee, Roger G.

AU - Pacher, Pal

N1 - Acknowledgements This study was supported by the National Institutes of Health(DA-03672, DA-005488 and DA-009789) and Intramural Research Program of NIH/NIAAA. Dr Horváth is a recipient of a Hungarian Research Council Scientific Research Fund Fellowship (NKTH-OTKA-EU, MB08-80238). The authors are indebted to Dr George Kunos for providing key resources and support.

PY - 2012/4

Y1 - 2012/4

N2 - BACKGROUND AND PURPOSEActivation of cannabinoid CB2 receptors protects against various forms of ischaemia-reperfusion (I/R) injury. Delta(8)-Tetrahydrocannabivarin (Delta(8)-THCV) is a synthetic analogue of the plant cannabinoid Delta(9)-tetrahydrocannabivarin, which exhibits anti-inflammatory effects in rodents involving activation of CB2 receptors. Here, we assessed effects of Delta(8)-THCV and its metabolite 11-OH-Delta(8)-THCV on CB2 receptors and against hepatic I/R injury.EXPERIMENTAL APPROACHEffects in vitro were measured with human CB2 receptors expressed in CHO cells. Hepatic I/R injury was assessed in mice with 1h ischaemia and 2, 6 or 24h reperfusion in vivo.KEY RESULTSDisplacement of [H-3]CP55940 by Delta(8)-THCV or 11-OH-Delta(8)-THCV from specific binding sites in CHO cell membranes transfected with human CB2 receptors (hCB(2)) yielded K-i values of 68.4 and 59.95 nM respectively. Delta(8)-THCV or 11-OH-Delta(8)-THCV inhibited forskolin-stimulated cAMP production by hCB(2) CHO cells (EC50 = 12.95 and 14.3 nM respectively). Delta(8)-THCV, given before induction of I/R, attenuated hepatic injury (measured by serum alanine aminotransferase and aspartate aminotransferase levels), decreased tissue protein carbonyl adducts, 4-hydroxy-2-nonenal, the chemokines CCL3 and CXCL2, TNF-alpha, intercellular adhesion molecule 1 (CD54) mRNA levels, tissue neutrophil infiltration, caspase 3/7 activity and DNA fragmentation. Protective effects of Delta(8)-THCV against liver damage were still present when the compound was given at the beginning of reperfusion. Pretreatment with a CB2 receptor antagonist attenuated the protective effects of Delta(8)-THCV, while a CB1 antagonist tended to enhance it.CONCLUSIONS AND IMPLICATIONSDelta(8)-THCV activated CB2 receptors in vitro, and decreased tissue injury and inflammation in vivo, associated with I/R partly via CB2 receptor activation.

AB - BACKGROUND AND PURPOSEActivation of cannabinoid CB2 receptors protects against various forms of ischaemia-reperfusion (I/R) injury. Delta(8)-Tetrahydrocannabivarin (Delta(8)-THCV) is a synthetic analogue of the plant cannabinoid Delta(9)-tetrahydrocannabivarin, which exhibits anti-inflammatory effects in rodents involving activation of CB2 receptors. Here, we assessed effects of Delta(8)-THCV and its metabolite 11-OH-Delta(8)-THCV on CB2 receptors and against hepatic I/R injury.EXPERIMENTAL APPROACHEffects in vitro were measured with human CB2 receptors expressed in CHO cells. Hepatic I/R injury was assessed in mice with 1h ischaemia and 2, 6 or 24h reperfusion in vivo.KEY RESULTSDisplacement of [H-3]CP55940 by Delta(8)-THCV or 11-OH-Delta(8)-THCV from specific binding sites in CHO cell membranes transfected with human CB2 receptors (hCB(2)) yielded K-i values of 68.4 and 59.95 nM respectively. Delta(8)-THCV or 11-OH-Delta(8)-THCV inhibited forskolin-stimulated cAMP production by hCB(2) CHO cells (EC50 = 12.95 and 14.3 nM respectively). Delta(8)-THCV, given before induction of I/R, attenuated hepatic injury (measured by serum alanine aminotransferase and aspartate aminotransferase levels), decreased tissue protein carbonyl adducts, 4-hydroxy-2-nonenal, the chemokines CCL3 and CXCL2, TNF-alpha, intercellular adhesion molecule 1 (CD54) mRNA levels, tissue neutrophil infiltration, caspase 3/7 activity and DNA fragmentation. Protective effects of Delta(8)-THCV against liver damage were still present when the compound was given at the beginning of reperfusion. Pretreatment with a CB2 receptor antagonist attenuated the protective effects of Delta(8)-THCV, while a CB1 antagonist tended to enhance it.CONCLUSIONS AND IMPLICATIONSDelta(8)-THCV activated CB2 receptors in vitro, and decreased tissue injury and inflammation in vivo, associated with I/R partly via CB2 receptor activation.

KW - cannabinoids

KW - oxidative stress

KW - inflammation

KW - ischaemia-reperfusion

KW - ISCHEMIA-REPERFUSION INJURY

KW - NITRIC-OXIDE

KW - CELL-DEATH

KW - IN-VIVO

KW - ISCHEMIA/REPERFUSION INJURY

KW - DIABETIC CARDIOMYOPATHY

KW - DELTA(9)-TETRAHYDROCANNABIVARIN

KW - PEROXYNITRITE

KW - DYSFUNCTION

KW - PROTECTS

U2 - 10.1111/j.1476-5381.2011.01410.x

DO - 10.1111/j.1476-5381.2011.01410.x

M3 - Article

VL - 165

SP - 2450

EP - 2461

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 8

ER -