A saturated N-acylethanolamine other than N-palmitoyl ethanolamine with anti-inflammatory properties:: A neglected story...
A saturated N-acylethanolamine other than N-palmitoyl ethanolamine with anti-inflammatory properties:: A neglected story...
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DOI：
10.1111/j.1365-2826.2008.01689.x
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发表时间：
2008-05-01
影响因子：
3.2
通讯作者：
Leon, A.
中科院分区：
文献类型：
--
作者：
Carbonare, M. Dalle;Del Giudice, E.;Leon, A.
n -酰基乙醇胺，包括内源性大麻素anandamide和大麻素受体无活性饱和化合物n -棕榈酰乙醇胺和n -硬脂酰乙醇胺，是由脂肪酸酰胺水解酶（FAAH）降解的长链脂肪酸的乙醇胺，已知在退化的组织和细胞中积累。虽然很多证据支持anandamide和n -棕榈酰乙醇胺的保护性抗炎作用，但关于n -硬脂酰乙醇胺的生物活性的信息很少。采用被动ige诱导皮肤过敏反应的小鼠模型，我们发现n -硬脂酰乙醇胺在体内具有显著的抗炎特性，支持了内源性n -硬脂酰乙醇胺与n -棕榈酰乙醇胺类似，是一种能够下调皮肤过敏性炎症的生物活性信号脂质的假设。这种作用，虽然被合成的非选择性CB1/CB2受体激动剂（如WIN55, 212-2）模拟，但对CB1或CB2受体拮抗剂不敏感，而是被capsazepine完全逆转，capsazepine是TRPV1受体的竞争性拮抗剂。此外，CB1受体拮抗剂虽然能有效拮抗WIN55,212-2诱导的低温，但并没有降低WIN55,212-2的抗炎作用，而CB2受体拮抗剂本身无活性，却增强了WIN55,212-2的作用，这表明非CB1/CB2受体参与了WIN55,212-2的抗炎作用。所有这些，再加上FAAH是体内饱和n -硬脂酰乙醇胺浓度的主要调节因子，以及n -棕榈酰乙醇胺，提出了一种猜测，即使用饱和n -酰基乙醇胺（如n -硬脂酰乙醇胺）或能够增加其局部浓度的FAAH抑制剂（而不是选择性CB受体激动剂）进行药物治疗，可能对减轻皮肤过敏性炎症有很好的治疗效果。
N-acylethanolamines, which include the endocannabinoid anandamide and the cannabinoid receptor-inactive saturated compounds N-palmitoyl ethanolamine and N-stearoyl ethanolamine, are ethanolamines of long-chain fatty acids degraded by fatty acid amide hydrolase (FAAH) known to accumulate in degenerating tissues and cells. Whilst much evidence supports a protective anti-inflammatory role of both anandamide and N-palmitoyl ethanolamine, very little information is available with regard to the bioactivity of N-stearoyl ethanolamine. Employing a murine model of passive IgE-induced cutaneous anaphylaxis, we have found that N-stearoyl ethanolamine is endowed with marked anti-inflammatory properties in vivo, supporting the hypothesis that endogenous N-stearoyl ethanolamine is, in analogy to N-palmitoyl ethanolamine, a bioactive signalling lipid capable of downregulating allergic inflammation in the skin. This effect, although mimicked by synthetic, non-selective, CB1/CB2 receptor agonists, such as WIN55, 212-2, was not sensitive to CB1 or CB2 receptor antagonists, but rather was fully reversed by capsazepine, a competitive antagonist of the TRPV1 receptor. Moreover, CB1 receptor antagonists, although effective in antagonising the WIN55,212-2-induced hypothermia, did not reduce the anti-inflammatory effect of WIN55,212-2, whilst CB2 receptor antagonists, per se inactive, potentiated the WIN55,212-2 effect, suggesting an involvement of non-CB1/CB2 receptors in the anti-inflammatory action of WIN55,212-2. All this, together with demonstration of FAAH as a major regulator of the in vivo concentrations of saturated N-stearoyl ethanolamine, in addition to N-palmitoyl ethanolamine, raise the speculation that pharmacological treatments with saturated N-acylethanolamines such as N-stearoyl ethanolamine, or alternatively FAAH inhibitors able to increase their local concentration, rather than selective CB receptor agonists, might be of promising therapeutic benefit in reducing allergic inflammation in the skin.