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

doi:10.1111/j.1476-5381.2011.01410.x

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

Medical Sciences

Research output: Contribution to journal › Article › peer-review

46 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 language	English
Pages (from-to)	2450-2461
Number of pages	12
Journal	British Journal of Pharmacology
Volume	165
Issue number	8
Early online date	23 Mar 2012
DOIs	https://doi.org/10.1111/j.1476-5381.2011.01410.x
Publication status	Published - Apr 2012

Bibliographical 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 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.

Funding

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 Horvath 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.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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

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Cite this

Batkai, S., Mukhopadhyay, P., Horvath, B., Rajesh, M., Gao, R. Y., Mahadevan, A., Amere, M., Battista, N., Lichtman, A. H., Gauson, L. A., Maccarrone, M., Pertwee, R. G., & 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, 165(8), 2450-2461. https://doi.org/10.1111/j.1476-5381.2011.01410.x

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

Research output: Contribution to journal › Article › peer-review

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

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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.",

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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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doi = "10.1111/j.1476-5381.2011.01410.x",

language = "English",

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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

SN - 0007-1188

VL - 165

SP - 2450

EP - 2461

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

IS - 8

ER -

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

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

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