Cannabinoid antagonist AM 281 reduces mortality rate and neurologic dysfunction after cecal ligation and puncture in rats

Kikuchi, Yuji; Hara, Hiroshi; Kunimoto, Fumio; Saito, Shigeru; Goto, Fumio

doi:10.1097/01.ccm.0000187010.14426.cc

Cited by 22 publications

(8 citation statements)

References 22 publications

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“…It has been reported that the cannabinoid antagonist AM281 reduced the mortality rate and neurologic dysfunction after CLP in rats (19). This antagonist has a much higher affinity for CB1R as compared with CB2R.…”

Section: Discussionmentioning

confidence: 99%

“…In vivo pharmacology studies with this compound have been shown to reduce mortality in rats following cecal ligation and puncture (CLP) (19). Additionally, AM281 treatment during the rat peritonitis model prevented neurological dysfunction as well as changes in systemic hemodynamics (19, 20). Finally, AM281 administration attenuated serum TNF-α and IL-1β levels up to 3 h following an LPS injection (21).…”

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confidence: 99%

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The Cannabinoid Receptor 2 Is Critical for the Host Response to Sepsis

Tschöp

Kasten

Nogueiras

et al. 2009

The Journal of Immunology

110

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Leukocyte function can be modulated through the cannabinoid receptor 2 (CB2R). Using a cecal ligation and puncture (CLP) model of sepsis, we examined the role of the CB2R during the immune response to an overwhelming infection. CB2R-knock out (KO) mice showed decreased survival as compared with wild-type mice. CB2R-KO mice also had increased serum IL-6 and bacteremia. Twenty-four hours after CLP, the CB2R-deficient mice had increased lung injury. Additionally, CB2R-deficiency led to increased neutrophil recruitment, decreased neutrophil activation, and decreased p38 activity at the site of infection. Consistent with a novel role for CB2R in sepsis, CB2R-agonist treatment in wild-type mice increased the mean survival time in response to CLP. Treatment with CB2R-agonist also decreased serum IL-6 levels, bacteremia, and damage to the lungs compared with vehicle-treated mice. Finally, the CB2R agonist decreased neutrophil recruitment, while increasing neutrophil activation and p38 activity at the site of infection compared with vehicle-treated mice. These data suggest that CB2R is a critical regulator of the immune response to sepsis and may be a novel therapeutic target.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The Cannabinoid Receptor 2 Is Critical for the Host Response to Sepsis

Tschöp

Kasten

Nogueiras

et al. 2009

The Journal of Immunology

110

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“…In addition to their well‐known immunological and neurobehavioral actions, CBs and their endogenous and synthetic analogues exert complex cardiodepressive and vasodilatory effects, which have been implicated in the mechanism of hypotension associated with haemorrhagic ( Wagner et al , 1997 ; Cainazzo et al , 2002 ), endotoxic ( Varga et al , 1998 ; Liu et al , 2003 , 2006 ; Batkai et al , 2004a ; Kadoi and Goto, 2006 ), septic ( Kadoi et al , 2005 ), and cardiogenic shock ( Wagner et al , 2001 , 2003 ), advanced liver cirrhosis ( Batkai et al , 2001 ; Ros et al , 2002 ), cirrhotic cardiomyopathy ( Gaskari et al , 2005 ; Pacher et al , 2005c ; Moezi et al , 2006 ; Yang et al , 2007 ; Batkai et al , 2007a ), doxorubicin‐induced heart failure ( Mukhopadhyay et al , 2007 ) and the shock associated with necrotizing pancreatitis ( Matsuda et al , 2005 ). Importantly, these cardiovascular depressive effects could be prevented or reversed by pretreatment with CB 1 antagonists, and are subjects of numerous comprehensive recent overviews ( Randall et al , 2002 ; Hiley and Ford, 2004 ; Lamontagne et al , 2006 ; Lepicier et al , 2006 ; Mallat et al , 2007 ; Mendizabal and Adler‐Graschinsky, 2007 ; Pacher et al , 2005a , 2005b , 2006a ).…”

Section: Circulatory Shock (Full Organ/body Ischaemia And/or I/r)mentioning

confidence: 99%

Endocannabinoids and cannabinoid receptors in ischaemia–reperfusion injury and preconditioning

Pacher

Haskó

2008

British J Pharmacology

199

195

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Ischaemia-reperfusion (I/R) is a pivotal mechanism of organ injury during stroke, myocardial infarction, organ transplantation and vascular surgeries. Ischaemic preconditioning (IPC) is a potent endogenous form of tissue protection against I/R injury. On the one hand, endocannabinoids have been implicated in the protective effects of IPC through cannabinoid CB 1 /CB 2 receptordependent and -independent mechanisms. However, there is evidence suggesting that endocannabinoids are overproduced during various forms of I/R, such as myocardial infarction or whole body I/R associated with circulatory shock, and may contribute to the cardiovascular depressive state associated with these pathologies. Previous studies using synthetic CB 1 receptor agonists or knockout mice demonstrated CB 1 receptor-dependent protection against cerebral I/R injury in various animal models. In contrast, several follow-up reports have shown protection afforded by CB 1 receptor antagonists, but not agonists. Excitedly, emerging studies using potent CB 2 receptor agonists and/or knockout mice have provided compelling evidence that CB 2 receptor activation is protective against myocardial, cerebral and hepatic I/R injuries by decreasing the endothelial cell activation/inflammatory response (for example, expression of adhesion molecules, secretion of chemokines, and so on), and by attenuating the leukocyte chemotaxis, rolling, adhesion to endothelium, activation and transendothelial migration, and interrelated oxidative/nitrosative damage. This review is aimed to discuss the role of endocannabinoids and CB receptors in various forms of I/R injury (myocardial, cerebral, hepatic and circulatory shock) and preconditioning, and to delineate the evidence supporting the therapeutic utility of selective CB 2 receptor agonists, which are devoid of psychoactive effects, as a promising new approach to limit I/R-induced tissue damage.

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“…While in another study, CB2R seems like a strong destroyer in the same sepsis model [15]. Cannabinoid antagonist AM 281 was reported to reduce mortality rate after CLP in rats [16], while very recently, Lehmann and his colleagues found that CB2R activation reduced intestinal leukocyte recruitment and inflammation in rat acute sepsis models [17]. These controversial results leave this issue ambiguous.…”

Section: Introductionmentioning

confidence: 99%

Cannabinoid Receptor 2 Protects against Acute Experimental Sepsis in Mice

Gui

Sun

Luo

et al. 2013

Mediators of Inflammation

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The systemic inflammatory response syndrome can be self-limited or can progress to severe sepsis and septic shock. Despite significant advances in the understanding of the molecular and cellular mechanisms of septic shock, it is still one of the most frequent and serious problems confronting clinicians in the treatments. And the effects of cannabinoid receptor 2 (CB2R) on the sepsis still remain undefined. The present study was aimed to explore the role and mechanism of CB2R in acute sepsis model of mice. Here, we found that mice were more vulnerable for lipopolysaccharide- (LPS-) induced death and inflammation after CB2R deletion (CB2R−/−). CB2R agonist, GW405833, could significantly extend the survival rate and decrease serum proinflammatory cytokines in LPS-treated mice. GW405833 dose-dependently inhibits proinflammatory cytokines release in splenocytes and peritoneal macrophages as well as splenocytes proliferation, and these effects were partly abolished in CB2R−/− splenocytes but completely abolished in CB2R−/− peritoneal macrophages. Further studies showed that GW405833 inhibits LPS-induced phosphorylation of ERK1/2 and STAT3 and blocks IκBα degradation and NF-κB p65 nuclear translocation in macrophages. All data together showed that CB2R provides a protection and is a potential therapeutic target for the sepsis.

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Cannabinoid antagonist AM 281 reduces mortality rate and neurologic dysfunction after cecal ligation and puncture in rats

Cited by 22 publications

References 22 publications

The Cannabinoid Receptor 2 Is Critical for the Host Response to Sepsis

The Cannabinoid Receptor 2 Is Critical for the Host Response to Sepsis

Endocannabinoids and cannabinoid receptors in ischaemia–reperfusion injury and preconditioning

Cannabinoid Receptor 2 Protects against Acute Experimental Sepsis in Mice

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