Cannabinoid activation of PPARα;: a novel neuroprotective mechanism
Cannabinoid activation of PPARα;: a novel neuroprotective mechanism
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DOI：
10.1038/sj.bjp.0707478
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发表时间：
2007-11-01
影响因子：
7.3
通讯作者：
Bennett, A. J.
中科院分区：
文献类型：
--
作者：
Sun, Y.;Alexander, S. P. H.;Bennett, A. J.
背景和目的：虽然CB1受体的激活能引起大麻素对神经的保护作用，但一些大麻素被报道为过氧化物酶体增殖物激活受体（PPAR）配体，提供了一种替代的保护机制。因此，我们研究了一系列大麻素激活PPAR α和n -油基乙醇胺（OEA）的能力，n -油基乙醇胺是一种内源性大麻素样化合物（ECL），可以唤起神经保护。实验方法：分别在无细胞和转染的HeLa细胞制剂中测定PPAR α的占用率和基因转激活电位。在小鼠体内通过脂肪动员和基因转录估计PPAR α激活。研究了野生型和PPAR α基因破坏小鼠的神经保护作用。关键结果：发现ecl OEA、anandamide、noladin醚和virodamine与纯化的PPAR α配体结合域结合，并增加PPAR α驱动的转录活性。高亲和力合成CB1/2大麻素激动剂WIN 55212-2与PPAR α激动剂非诺贝特等同结合，刺激PPAR α介导的基因转录。植物大麻素d9四氢大麻酚无效果。OEA和WIN 55212-2在体内诱导脂肪溶解，而OEA预处理减少了野生型小鼠大脑中动脉闭塞的梗死体积，但在PPAR α缺失小鼠中没有。OEA处理还导致小鼠大脑皮层中NF κ B抑制蛋白I κ B的表达增加，而NF κ B调节蛋白COX-2的表达受到抑制。结论和意义：这些数据表明，一系列不同结构的大麻素化合物具有激活PPAR α的潜力，并表明这些药物至少有一些神经保护特性可能是由核受体激活介导的。
Background and purpose: Although CB1 receptor activation evokes neuroprotection in response to cannabinoids, some cannabinoids have been reported to be peroxisome proliferator activated receptor (PPAR) ligands, offering an alternative protective mechanism. We have, therefore, investigated the ability of a range of cannabinoids to activate PPAR alpha and for N-oleoylethanolamine (OEA), an endogenous cannabinoid-like compound (ECL), to evoke neuroprotection.Experimental approach: Assays of PPAR alpha occupancy and gene transactivation potential were conducted in cell-free and transfected HeLa cell preparations, respectively. In vivo estimates of PPAR alpha activation through fat mobilization and gene transcription were conducted in mice. Neuroprotection in vivo was investigated in wild-type and PPAR alpha gene-disrupted mice.Key results: The ECLs OEA, anandamide, noladin ether and virodhamine were found to bind to the purified PPAR alpha ligand binding domain and to increase PPAR alpha-driven transcriptional activity. The high affinity synthetic CB1/2 cannabinoid agonist WIN 55212-2 bound to PPAR alpha equipotently with the PPAR alpha agonist fenofibrate, and stimulated PPAR alpha-mediated gene transcription. The phytocannabinoid D 9 tetrahydrocannabinol was without effect. OEA and WIN 55212-2 induced lipolysis in vivo, while OEA pre-treatment reduced infarct volume from middle cerebral artery occlusion in wild-type, but not in PPAR alpha-null mice. OEA treatment also led to increased expression of the NF kappa B-inhibitory protein, I kappa B, in mouse cerebral cortex, while expression of the NF kappa B-regulated protein COX-2 was inhibited.Conclusions and implications: These data demonstrate the potential for a range of cannabinoid compounds, of diverse structures, to activate PPAR alpha and suggest that at least some of the neuroprotective properties of these agents could be mediated by nuclear receptor activation.