Activation of cannabinoid 2 receptors protects against cerebral ischemia by inhibiting neutrophil recruitment
Activation of cannabinoid 2 receptors protects against cerebral ischemia by inhibiting neutrophil recruitment
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DOI：
10.1096/fj.09-141275
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发表时间：
2010-03-01
期刊：
影响因子：
4.8
通讯作者：
Schwaninger, Markus
中科院分区：
文献类型：
--
作者：
Murikinati, Sasidhar;Juettler, Eric;Schwaninger, Markus
大麻素2受体（CB2）的激活减少了几个器官的缺血性损伤。然而，这种保护作用的机制尚不清楚。在缺血性脑卒中小鼠模型中，我们发现CB2激动剂JWH-133 (1 mg。公斤(1)。D(-1))减少缺血后3天测量的梗死面积。在cb2缺失小鼠中，JWH-133的神经保护作用消失，证实了JWH-133的特异性。对骨髓嵌合小鼠的分析表明，骨髓源性细胞介导CB2对缺血性脑损伤的影响。通过FACS分析和测量中性粒细胞标记酶髓过氧化物酶的水平显示，CB2激活减少了缺血脑中中性粒细胞的数量。事实上，我们在体外发现CB2的激活抑制了中性粒细胞对脑内皮细胞的粘附。JWH-133 （1 μ M）还通过激活MAP激酶p38，干扰内源性趋化因子CXCL2 （30 ng/ml）诱导的中性粒细胞迁移。这种对中性粒细胞的影响可能是JWH-133介导的神经保护作用的原因，因为当中性粒细胞耗尽时，JWH-133不再具有保护作用。总之，我们的数据表明，通过激活中性粒细胞中的p38， CB2激动剂可以抑制中性粒细胞向大脑的募集，并保护大脑免受缺血性损伤。-Murikinati， S., Juttler， E., Keinert， T., Ridder， D. A., Muhammad， S., Waibler， Z., Ledent， C., Zimmer， A., Kalinke， U., Schwaninger， M.大麻素2受体的激活通过抑制中性粒细胞募集来保护脑缺血。中国生物医学工程学报，2009,33(2):444 - 444。www.fasebj.org
Activation of the cannabinoid 2 receptor (CB2) reduces ischemic injury in several organs. However, the mechanisms underlying this protective action are unclear. In a mouse model of ischemic stroke, we show that the CB2 agonist JWH-133 (1 mg . kg(-1) . d(-1)) decreases the infarct size measured 3 d after onset of ischemia. The neuroprotective effect of JWH-133 was lost in CB2-deficient mice, confirming the specificity of JWH-133. Analysis of bone marrow chimeric mice revealed that bone marrow-derived cells mediate the CB2 effect on ischemic brain injury. CB2 activation reduced the number of neutrophils in the ischemic brain as shown by FACS analysis and by measuring the levels of the neutrophil marker enzyme myeloperoxidase. Indeed, we found in vitro that CB2 activation inhibits adherence of neutrophils to brain endothelial cells. JWH-133 (1 mu M) also interfered with the migration of neutrophils induced by the endogenous chemokine CXCL2 (30 ng/ml) through activation of the MAP kinase p38. This effect on neutrophils is likely responsible for the neuroprotection mediated by JWH-133 because JWH-133 was no longer protective when neutrophils were depleted. In conclusion, our data demonstrate that by activating p38 in neutrophils, CB2 agonists inhibit neutrophil recruitment to the brain and protect against ischemic brain injury.-Murikinati, S., Juttler, E., Keinert, T., Ridder, D. A., Muhammad, S., Waibler, Z., Ledent, C., Zimmer, A., Kalinke, U., Schwaninger, M. Activation of cannabinoid 2 receptors protects against cerebral ischemia by inhibiting neutrophil recruitment. FASEB J. 24, 788-798 (2010). www.fasebj.org