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Monoacylglycerol Lipase Regulates Fever Response.

Sanchez-Alavez M, Nguyen W, Mori S, Moroncini G, Viader A, Nomura DK, Cravatt BF, Conti B - PLoS ONE (2015)

Bottom Line: Cyclooxygenase inhibitors such as ibuprofen have been used for decades to control fever through reducing the levels of the pyrogenic lipid transmitter prostaglandin E2 (PGE2).We also show that a cannabinoid CB1 receptor antagonist does not attenuate these anti-pyrogenic effects of MAGL inhibitors.Thus, much like traditional nonsteroidal anti-inflammatory drugs, MAGL inhibitors can control fever, but appear to do so through restricted control over prostaglandin production in the nervous system.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA, 92037, United States of America.

ABSTRACT
Cyclooxygenase inhibitors such as ibuprofen have been used for decades to control fever through reducing the levels of the pyrogenic lipid transmitter prostaglandin E2 (PGE2). Historically, phospholipases have been considered to be the primary generator of the arachidonic acid (AA) precursor pool for generating PGE2 and other eicosanoids. However, recent studies have demonstrated that monoacyglycerol lipase (MAGL), through hydrolysis of the endocannabinoid 2-arachidonoylglycerol, provides a major source of AA for PGE2 synthesis in the mammalian brain under basal and neuroinflammatory states. We show here that either genetic or pharmacological ablation of MAGL leads to significantly reduced fever responses in both centrally or peripherally-administered lipopolysaccharide or interleukin-1β-induced fever models in mice. We also show that a cannabinoid CB1 receptor antagonist does not attenuate these anti-pyrogenic effects of MAGL inhibitors. Thus, much like traditional nonsteroidal anti-inflammatory drugs, MAGL inhibitors can control fever, but appear to do so through restricted control over prostaglandin production in the nervous system.

No MeSH data available.


Related in: MedlinePlus

Genetic or pharmacological ablation of MAGL reduces fever response in peripheral LPS-induced fever model.(A) CBT profile following i.p. injection of LPS (100 μg/kg) or vehicle (Saline) of Mgll+/+ mice treated i.p. with JZL184 (40 mg/kg). *p<0.05, Mgll+/++ Veh vs. Mgll+/+ + LPS; #p<0.05, Mgll+/++ LPS vs. Mgll-/- + LPS; &p<0.05, Mgll+/+ + Veh vs. Mgll-/- + LPS. (B) CBT profile of Mgll-/- and Mgll+/+ mice following i.p. injection of LPS (100 μg/kg) or vehicle (Saline) as indicated. Injection was performed at time 0. Data are shown as mean ± sem, n = 6 mice per group, *p<0.05, Mgll+/++ Veh + Veh vs. Mgll+/+ + Veh + LPS; # p<0.05, Mgll+/++ Veh+ LPS vs. Mgll+/++ JZL184 + LPS.
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pone.0134437.g002: Genetic or pharmacological ablation of MAGL reduces fever response in peripheral LPS-induced fever model.(A) CBT profile following i.p. injection of LPS (100 μg/kg) or vehicle (Saline) of Mgll+/+ mice treated i.p. with JZL184 (40 mg/kg). *p<0.05, Mgll+/++ Veh vs. Mgll+/+ + LPS; #p<0.05, Mgll+/++ LPS vs. Mgll-/- + LPS; &p<0.05, Mgll+/+ + Veh vs. Mgll-/- + LPS. (B) CBT profile of Mgll-/- and Mgll+/+ mice following i.p. injection of LPS (100 μg/kg) or vehicle (Saline) as indicated. Injection was performed at time 0. Data are shown as mean ± sem, n = 6 mice per group, *p<0.05, Mgll+/++ Veh + Veh vs. Mgll+/+ + Veh + LPS; # p<0.05, Mgll+/++ Veh+ LPS vs. Mgll+/++ JZL184 + LPS.

Mentions: We next tested whether a peripherally induced fever response could be mitigated upon ablation of MAGL. We induced a fever response in mice by i.p. injection of the exogenous pyrogen lipopolysaccharide (LPS) (100 μg/kg), leading to prolonged and elevated CBT. Mgll-/- mice showed significantly attenuated fever responses compared to LPS-treated Mgll+/+ mice (Fig 2A). We next used the MAGL inhibitor JZL184 [34] to test whether pharmacological blockade of MAGL also affected fever responses. We treated mice with a dose JZL184 (40 mg/kg. i.p., 1 hr before LPS injection) that we have previously shown to produce complete inhibition of MAGL in vivo, leading to profound elevations in brain 2-AG and suppression of brain AA and prostaglandins [21]. We found that JZL184 significantly reduced CBT and fever response elicited by LPS, compared to vehicle-treated LPS-administered controls (Fig 2B).


Monoacylglycerol Lipase Regulates Fever Response.

Sanchez-Alavez M, Nguyen W, Mori S, Moroncini G, Viader A, Nomura DK, Cravatt BF, Conti B - PLoS ONE (2015)

Genetic or pharmacological ablation of MAGL reduces fever response in peripheral LPS-induced fever model.(A) CBT profile following i.p. injection of LPS (100 μg/kg) or vehicle (Saline) of Mgll+/+ mice treated i.p. with JZL184 (40 mg/kg). *p<0.05, Mgll+/++ Veh vs. Mgll+/+ + LPS; #p<0.05, Mgll+/++ LPS vs. Mgll-/- + LPS; &p<0.05, Mgll+/+ + Veh vs. Mgll-/- + LPS. (B) CBT profile of Mgll-/- and Mgll+/+ mice following i.p. injection of LPS (100 μg/kg) or vehicle (Saline) as indicated. Injection was performed at time 0. Data are shown as mean ± sem, n = 6 mice per group, *p<0.05, Mgll+/++ Veh + Veh vs. Mgll+/+ + Veh + LPS; # p<0.05, Mgll+/++ Veh+ LPS vs. Mgll+/++ JZL184 + LPS.
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pone.0134437.g002: Genetic or pharmacological ablation of MAGL reduces fever response in peripheral LPS-induced fever model.(A) CBT profile following i.p. injection of LPS (100 μg/kg) or vehicle (Saline) of Mgll+/+ mice treated i.p. with JZL184 (40 mg/kg). *p<0.05, Mgll+/++ Veh vs. Mgll+/+ + LPS; #p<0.05, Mgll+/++ LPS vs. Mgll-/- + LPS; &p<0.05, Mgll+/+ + Veh vs. Mgll-/- + LPS. (B) CBT profile of Mgll-/- and Mgll+/+ mice following i.p. injection of LPS (100 μg/kg) or vehicle (Saline) as indicated. Injection was performed at time 0. Data are shown as mean ± sem, n = 6 mice per group, *p<0.05, Mgll+/++ Veh + Veh vs. Mgll+/+ + Veh + LPS; # p<0.05, Mgll+/++ Veh+ LPS vs. Mgll+/++ JZL184 + LPS.
Mentions: We next tested whether a peripherally induced fever response could be mitigated upon ablation of MAGL. We induced a fever response in mice by i.p. injection of the exogenous pyrogen lipopolysaccharide (LPS) (100 μg/kg), leading to prolonged and elevated CBT. Mgll-/- mice showed significantly attenuated fever responses compared to LPS-treated Mgll+/+ mice (Fig 2A). We next used the MAGL inhibitor JZL184 [34] to test whether pharmacological blockade of MAGL also affected fever responses. We treated mice with a dose JZL184 (40 mg/kg. i.p., 1 hr before LPS injection) that we have previously shown to produce complete inhibition of MAGL in vivo, leading to profound elevations in brain 2-AG and suppression of brain AA and prostaglandins [21]. We found that JZL184 significantly reduced CBT and fever response elicited by LPS, compared to vehicle-treated LPS-administered controls (Fig 2B).

Bottom Line: Cyclooxygenase inhibitors such as ibuprofen have been used for decades to control fever through reducing the levels of the pyrogenic lipid transmitter prostaglandin E2 (PGE2).We also show that a cannabinoid CB1 receptor antagonist does not attenuate these anti-pyrogenic effects of MAGL inhibitors.Thus, much like traditional nonsteroidal anti-inflammatory drugs, MAGL inhibitors can control fever, but appear to do so through restricted control over prostaglandin production in the nervous system.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA, 92037, United States of America.

ABSTRACT
Cyclooxygenase inhibitors such as ibuprofen have been used for decades to control fever through reducing the levels of the pyrogenic lipid transmitter prostaglandin E2 (PGE2). Historically, phospholipases have been considered to be the primary generator of the arachidonic acid (AA) precursor pool for generating PGE2 and other eicosanoids. However, recent studies have demonstrated that monoacyglycerol lipase (MAGL), through hydrolysis of the endocannabinoid 2-arachidonoylglycerol, provides a major source of AA for PGE2 synthesis in the mammalian brain under basal and neuroinflammatory states. We show here that either genetic or pharmacological ablation of MAGL leads to significantly reduced fever responses in both centrally or peripherally-administered lipopolysaccharide or interleukin-1β-induced fever models in mice. We also show that a cannabinoid CB1 receptor antagonist does not attenuate these anti-pyrogenic effects of MAGL inhibitors. Thus, much like traditional nonsteroidal anti-inflammatory drugs, MAGL inhibitors can control fever, but appear to do so through restricted control over prostaglandin production in the nervous system.

No MeSH data available.


Related in: MedlinePlus