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DM Kerr B Harhen BN Okine LJ Egan DP Finn M Roche 《British journal of pharmacology》2013,169(4):808-819
Background and purpose
JZL184 is a selective inhibitor of monoacylglycerol lipase (MAGL), the enzyme that preferentially catabolizes the endocannabinoid 2-arachidonoyl glycerol (2-AG). Here, we have studied the effects of JZL184 on inflammatory cytokines in the brain and plasma following an acute immune challenge and the underlying receptor and molecular mechanisms involved.Experimental approach
JZL184 and/or the CB1 receptor antagonist, AM251 or the CB2receptor antagonist, AM630 were administered to rats 30 min before lipopolysaccharide (LPS). 2 h later cytokine expression and levels, MAGL activity, 2-AG, arachidonic acid and prostaglandin levels were measured in the frontal cortex, plasma and spleen.Key results
JZL184 attenuated LPS-induced increases in IL-1β, IL-6, TNF-α and IL-10 but not the expression of the inhibitor of NFkB (IκBα) in rat frontal cortex. AM251 attenuated JZL184-induced decreases in frontal cortical IL-1β expression. Although arachidonic acid levels in the frontal cortex were reduced in JZL184-treated rats, MAGL activity, 2-AG, PGE2 and PGD2 were unchanged. In comparison, MAGL activity was inhibited and 2-AG levels enhanced in the spleen following JZL184. In plasma, LPS-induced increases in TNF-α and IL-10 levels were attenuated by JZL184, an effect partially blocked by AM251. In addition, AM630 blocked LPS-induced increases in plasma IL-1β in the presence, but not absence, of JZL184.Conclusion and implications
Inhibition of peripheral MAGL in rats by JZL184 suppressed LPS-induced circulating cytokines that in turn may modulate central cytokine expression. The data provide further evidence for the endocannabinoid system as a therapeutic target in treatment of central and peripheral inflammatory disorders.Linked Articles
This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-4 & http://dx.doi.org/10.1111/bph.2012.167.issue-8 相似文献949.
SK Kaushal M. Ch. KS Dagar M. Ch. R Vyas M. Ch. A Singh MD PU Iyer MD S Radhakrishnan DM S Shrivastava DM KS Iyer M. Ch. 《Indian Journal of Thoracic and Cardiovascular Surgery》2000,16(1):11-14
Background Ebstein’s anomaly of the tricuspid valve is a complex malformation. Historically, because valve replacement yielded poor results, surgical treatment has focused on valvuloplasties with or without associated procedures. An individualised combination of surgical procedures was practised over three years and forms the subject of this presentation. Method Between November 1995 and September 1999, 7 patients with Ebstein’s anomaly underwent surgical repair (age 3.5 to 40 years). Cyanosis with severe tricuspid regurgitation was present in all. Surgical repair, individualised according to the morphology of the tricuspid valve and right ventricle to provide maximum possible symptom free survival, included, (1) Tricuspid valve: Replacement (n=1); Repair (Carpentier type n=1, Unicuspid repair n=5), (2) Atrial septal defect: left open (n=1), closed partially (n=1), closed compeletely (n=5), and (3) Bidirectional Cavopulmonary Shunt (BCPS)-4 Results There was no hospital death. Intraoperative transoesophageal echocardiography showed only mild tricuspid regurgitation in all, following repair. There were no late deaths at a mean follow up of 29 months. All but one patient were in functional Class 1 New York Heart Association(NYHA). Complications included a thrombus in the right ventricular cavity six months postoperatively in one patient. Conclusion Individualisation of surgical management in Ebstein’s anomaly provides optimal results. 相似文献
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Acute epiphyseal osteomyelitis in children 总被引:1,自引:0,他引:1
Nine children over 20 months of age had acute osteomyelitis of the epiphysis of a long bone. The clinical features varied, but all of the patients had pain at the infected site and an elevated erythrocyte sedimentation rate. The distal femur was involved in seven cases, the proximal tibia in two, and the proximal humerus in one. In two patients there was a contiguous metaphyseal lesion, while the other seven patients (eight sites) had lesions limited to the epiphysis. Bone scintigraphy clearly identified the infected sites in all seven patients in whom it was performed, and allowed an early diagnosis in four cases. Radiographs showed a lytic lesion of the epiphysis that corresponded to the scintigraphic findings in all cases. The vascular supply to the epiphysis and the microscopic structure of the epiphyseal venous sinusoids provide locations that favor lodgement of blood-borne organisms. The epiphysis of the child should be recognized as another site of hematogenous osteomyelitis. 相似文献