Omega-3 Endocannabinoid-Epoxides Are Novel Anti-inflammatory and Anti-Pain Lipid Metabolites (FS15-01-19).
Omega-3 Endocannabinoid-Epoxides Are Novel Anti-inflammatory and Anti-Pain Lipid Metabolites (FS15-01-19).
复制标题
Omega-3 内源性大麻素环氧化物是新型抗炎和止痛脂质代谢物 (FS15-01-19)。
DOI：
--
复制
发表时间：
2019
影响因子：
4.8
通讯作者：
William R Arnold
中科院分区：
文献类型：
--
作者：
A. Das;Josephine E Watson;Lauren N Carnevale;William R Arnold
目标
Omega-3 脂肪酸衍生的内源性大麻素通过细胞色素 P450 代谢，形成具有抗炎作用的生物活性内源性大麻素环氧化物。
方法
脂质组学、LC-MS/MS、小胶质细胞培养、脂质合成、提取、酶学。
结果
大麻素存在于大麻中，也由 ω-3 和 ω-6 脂肪酸在体内自然产生。众所周知，大麻中的外源性大麻素具有一定的欣快作用，但它们也具有抗炎作用。我们的研究揭示了一系列酶促反应，将 ω-3 脂肪酸转化为抗炎内源性大麻素环氧化物，其通过体内与大麻相同的受体发挥作用（PNAS 2017）。内源性大麻素是大麻素受体 1 和 2（CB1 和 CB2）的配体。 CB1 受体激动剂具有精神作用，而 CB2 受体激动剂具有抗炎作用。因此，人们对发现 CB2 选择性激动剂来减轻炎症病理产生了浓厚的兴趣。该工作详细介绍了天然存在的 ω-3 衍生的内源性大麻素环氧化物的发现和表征，这些环氧化物是通过细胞色素 P450 环氧化酶对 ω-3 内源性大麻素进行酶促氧化而形成的。这些双功能 ω-3 内源性大麻素环氧化物表现出优先与 CB2 受体结合的特性，具有抗炎和血管舒张作用，并可相互调节血小板聚集。 ω-3 内源性大麻素环氧化物的其他一些区域异构体是 CB1 的部分激动剂，可阻止肿瘤细胞转移 (J. Med. Chem 2018)。由于其生理特性，它们有望在神经炎症和疼痛中发挥重要作用。
结论
这一发现证明了 omega-3 脂肪酸如何产生一些与大麻相同的药用品质，但没有精神作用。总之，ω-3内源性大麻素环氧化物的浓度与其他内源性大麻素相当，预计在体内炎症过程中发挥关键作用。
资金来源
美国心脏协会科学家发展奖、美国国立卫生研究院 (NIH) R01、NIH R03、美国农业部、国家多发性硬化症协会。
Objectives
Omega-3 fatty acid derived endocannabinoids are metabolized by cytochrome P450s to form bioactive endocannabinoid epoxides that are anti-inflammatory.
Methods
Lipidomics, LC-MS/MS, microglial cells culture, lipid synthesis, extractions, enzymology.
Results
Cannabinoids are found in marijuana and also are produced naturally in the body from ω-3 and ω-6 fatty acids. Exocannabinoids in marijuana, are known to be responsible for some of its euphoric effects, but they also exhibit anti-inflammatory benefits. Our study revealed a cascade of enzymatic reactions that convert ω-3 fatty acids into anti-inflammatory endocannabinoid epoxides that act through the same receptors in the body as marijuana (PNAS 2017). Endocannabinoids are ligands for cannabinoid receptor 1 and 2 (CB1 and CB2). CB1 receptor agonists exhibit psychotropic properties while CB2 receptor agonists have anti-inflammatory effects. Consequently, there is a strong interest in the discovery of CB2 selective agonists to mitigate inflammatory pathologies. The work details the discovery and characterization of naturally occurring ω-3-derived endocannabinoid epoxides that are formed via enzymatic oxidation of ω-3 endocannabinoids by cytochrome P450 epoxygenases. These dual functional ω-3 endocannabinoid epoxides exhibit preference towards binding to CB2 receptor and are anti-inflammatory and vasodilatory and reciprocally modulate platelet aggregation. Some of the other regioisomers of ω-3 endocannabinoid epoxides are partial agonists of CB1 and stop tumor cell metastasis (J. Med. Chem 2018). By virtue of their physiological properties, they are expected to play important roles in neuroinflammation and pain.
Conclusions
This finding demonstrates how omega-3 fatty acids can produce some of the same medicinal qualities as marijuana, but without a psychotropic effect. In summary, the ω-3 endocannabinoid epoxides are found at concentrations comparable to those of other endocannabinoids and are expected to play critical roles during inflammation in vivo.
Funding Sources
American Heart Association Scientist Development award, National Institute of Health (NIH) R01, NIH R03, USDA, National Multiple Sclerosis Society.