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, 82 (6), 1382-9

Cannabinoid-2 Receptor Agonist HU-308 Protects Against Hepatic Ischemia/Reperfusion Injury by Attenuating Oxidative Stress, Inflammatory Response, and Apoptosis

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Cannabinoid-2 Receptor Agonist HU-308 Protects Against Hepatic Ischemia/Reperfusion Injury by Attenuating Oxidative Stress, Inflammatory Response, and Apoptosis

Mohanraj Rajesh et al. J Leukoc Biol.

Abstract

In this study, we have investigated the role of the cannabinoid CB(2) (CB(2)) receptor in an in vivo mouse model of hepatic ischemia/reperfusion (I/R) injury. In addition, we have assessed the role of the CB(2) receptor in TNF-alpha-induced ICAM-1 and VCAM-1 expression in human liver sinusoidal endothelial cells (HLSECs) and in the adhesion of human neutrophils to HLSECs in vitro. The potent CB(2) receptor agonist HU-308, given prior to the induction of I/R, significantly attenuated the extent of liver damage (measured by serum alanine aminotransferase and lactate dehydrogenase) and decreased serum and tissue TNF-alpha, MIP-1alpha, and MIP-2 levels, tissue lipid peroxidation, neutrophil infiltration, DNA fragmentation, and caspase 3 activity. The protective effect of HU-308 against liver damage was also preserved when given right after the ischemic episode. HU-308 also attenuated the TNF-alpha-induced ICAM-1 and VCAM-1 expression in HLSECs, which expressed CB(2) receptors, and the adhesion of human neutrophils to HLSECs in vitro. These findings suggest that selective CB(2) receptor agonists may represent a novel, protective strategy against I/R injury by attenuating oxidative stress, inflammatory response, and apoptosis.

Figures

Fig. 1
Fig. 1
CB2 agonist limits liver I/R-induced damage, lipid peroxidation, and neutrophil infiltration. (A) Serum transaminase ALT and (B) LDH levels; (C) liver MDA level and (D) MPO activity in sham or in mice exposed to 60/120 min I/R, pretreated with vehicle, HU-308 (10 mg/kg), AM251 (1 mg/kg) + HU-308, or AM630 (1 mg/kg) + HU-308 (n=7–12/each group; *, P<0.05, vs. I/R; #, P<0.05, versus I/R+HU-308).
Fig. 2
Fig. 2
CB2 receptor agonist decreases proinflammatory markers in serum and liver. (A and B) TNF-α, MIP-2, and MIP-1α and levels in serum and liver tissue, measured by ELISA in sham or in mice exposed to 60/120 min I/R, pretreated with vehicle, HU-308 (10 mg/kg), or AM630 (1 mg/kg) + HU-308 (n=6–12/each group; *, P<0.05, vs. I/R; #, P<0.05, vs. I/R+HU-308).
Fig. 3
Fig. 3
CB2 receptor agonist decreases I/R-induced apoptosis. (A) Caspase 3 activity and (B) DNA fragmentation in sham or in mice exposed to 60/120 min I/R, pretreated with vehicle, HU-308 (10 mg/kg), or AM630 (1 mg/kg) + HU-308 (n=6–8/each group; *, P<0.05, vs. I/R; #, P<0.05, vs. I/R+HU-308).
Fig. 4
Fig. 4
CB2 receptor agonist decreases histological damage and neutrophil infiltration 24 h following ischemia. Representative liver sections of sham mice, of mice exposed to 1 h/24 h I/R with vehicle, or HU-308 pretreatment. (A) H&E staining. (B) MPO staining (brown) contrastained with nuclear fast red. A similar histological profile was seen in three to four livers/group. The original scale bars indicate 50 μm.
Fig. 5
Fig. 5
CB2 receptor agonist decreases TNF-α-induced overexpression of ICAM-1 and VCAM-1 in HLSECs. (A) CB2 receptor expression in HLSECs (RT-PCR). (B and C) ICAM-1 expression; (D and E) VCAM-1 expression (*, P<0.05, vs. TNF-α; #, P<0.05, vs. TNF-α+HU-308; n=9).
Fig. 6
Fig. 6
CB2 antagonist attenuates TNF-α-induced neutrophil adhesion to HLSECs. Representative images and quantification of human neutrophil adhesion to human liver endothelial cells. (*, P<0.05, vs. TNF-α; #, P<0.05, vs. TNF-α + HU-308; n=4).

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