Harnessing the Endocannabinoid 2-Arachidonoylglycerol to Lower Intraocular Pressure in a Murine Model.
Harnessing the Endocannabinoid 2-Arachidonoylglycerol to Lower Intraocular Pressure in a Murine Model.
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DOI：
10.1167/iovs.16-19356
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发表时间：
2016-06-01
影响因子：
4.4
通讯作者：
Straiker A
中科院分区：
文献类型：
--
作者：
Miller S;Leishman E;Hu SS;Elghouche A;Daily L;Murataeva N;Bradshaw H;Straiker A
大麻素，如Δ9-THC，通过脊椎动物眼睛中的内源性信号传导系统起作用，其通过CB 1受体降低IOP。内源性大麻素（eCB）配体，2-花生四烯酰甘油（2-AG），同样激活CB 1，并通过单酰基甘油脂肪酶（MAGL）代谢。我们研究了眼2-AG及其通过MAGL的调节以及利用eCB降低IOP的治疗潜力。我们测试了局部应用2-AG和MAGL阻断剂对血压正常小鼠的影响，并使用高效液相色谱/串联质谱法（HPLC/MS/MS）检查了MAGL敲除（MAGL−/−）小鼠眼睛和脊髓中eCB相关脂质种类的变化。我们还研究了MAGL在小鼠前房中的蛋白分布。2-花生四烯酰甘油以CB 1和浓度依赖性方式可靠地降低IOP。单酰基甘油脂酶在无色素睫状体上皮中显著表达。MAGL阻断剂KML 29而非JZL 184降低IOP。CB 1降低IOP的能力在MAGL−/−小鼠中没有脱敏。眼单酰基甘油，包括2-AG，在MAGL−/−小鼠中升高，但与脊髓相反，花生四烯酸和野牡丹素没有变化。我们的数据证实了MAGL在眼2-AG和相关脂质物质代谢中的核心作用，并且内源性2-AG可用于降低IOP。MAGL阻断剂KML 29有望作为治疗剂，而JZL 184可能难以穿过角膜。这些数据，结合MAGL对眼部单酰基甘油的相对特异性和MAGL−/−小鼠中缺乏脱敏作用，表明优化的MAGL阻滞剂的开发为治疗IOP升高提供了治疗潜力。
Cannabinoids, such as Δ9-THC, act through an endogenous signaling system in the vertebrate eye that reduces IOP via CB1 receptors. Endogenous cannabinoid (eCB) ligand, 2-arachidonoyl glycerol (2-AG), likewise activates CB1 and is metabolized by monoacylglycerol lipase (MAGL). We investigated ocular 2-AG and its regulation by MAGL and the therapeutic potential of harnessing eCBs to lower IOP. We tested the effect of topical application of 2-AG and MAGL blockers in normotensive mice and examined changes in eCB-related lipid species in the eyes and spinal cord of MAGL knockout (MAGL−/−) mice using high performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS). We also examined the protein distribution of MAGL in the mouse anterior chamber. 2-Arachidonoyl glycerol reliably lowered IOP in a CB1- and concentration-dependent manner. Monoacylglycerol lipase is expressed prominently in nonpigmented ciliary epithelium. The MAGL blocker KML29, but not JZL184, lowered IOP. The ability of CB1 to lower IOP is not desensitized in MAGL−/− mice. Ocular monoacylglycerols, including 2-AG, are elevated in MAGL−/− mice but, in contrast to the spinal cord, arachidonic acid and prostaglandins are not changed. Our data confirm a central role for MAGL in metabolism of ocular 2-AG and related lipid species, and that endogenous 2-AG can be harnessed to reduce IOP. The MAGL blocker KML29 has promise as a therapeutic agent, while JZL184 may have difficulty crossing the cornea. These data, combined with the relative specificity of MAGL for ocular monoacylglycerols and the lack of desensitization in MAGL−/− mice, suggest that the development of an optimized MAGL blocker offers therapeutic potential for treatment of elevated IOP.