Therapeutic endocannabinoid augmentation for mood and anxiety disorders: comparative profiling of FAAH, MAGL and dual inhibitors.
Therapeutic endocannabinoid augmentation for mood and anxiety disorders: comparative profiling of FAAH, MAGL and dual inhibitors.
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DOI：
10.1038/s41398-018-0141-7
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发表时间：
2018-04-26
影响因子：
6.8
通讯作者：
Patel S
中科院分区：
文献类型：
--
作者：
Bedse G;Bluett RJ;Patrick TA;Romness NK;Gaulden AD;Kingsley PJ;Plath N;Marnett LJ;Patel S
最近的研究已经证明了药理学内源性大麻素（eCB）增强方法在各种临床前模型中的抗焦虑潜力。内源性大麻素降解酶（如脂肪酸酰胺水解酶（FAAH）和单酰基甘油脂肪酶（MAGL））的药理学抑制在啮齿动物模型中引起有希望的抗焦虑作用，不良行为影响有限，然而，双重FAAH/MAGL抑制的功效尚未研究。在本研究中，我们比较了FAAH（PF-3845）、MAGL（JZL 184）和FAAH/MAGL（JZL 195）双重抑制剂对（1）非应激和应激条件下的焦虑样行为、（2）自发活动和体温、（3）脑中脂质水平和（4）认知功能的影响。行为分析表明，PF-3845或JZL 184，但不是JZL 195，能够防止约束应激诱导的焦虑在光-暗盒试验中，当压力暴露前给药。此外，JZL 195治疗不能逆转在高架零迷宫或明暗箱中足电击诱导的焦虑样行为。JZL 195，而不是PF-3845或JZL 184，在旷场试验中降低体温和增加焦虑样行为。总体而言，JZL 195未显示出抗焦虑功效，并且在所检查的模型中，JZL 184的作用比PF-3845更稳健。这些结果表明，增加内源性AEA或2-AG分别产生抗焦虑作用的压力条件下，但同样的效果并没有获得从同时增加AEA和2-AG。
Recent studies have demonstrated anxiolytic potential of pharmacological endocannabinoid (eCB) augmentation approaches in a variety of preclinical models. Pharmacological inhibition of endocannabinoid-degrading enzymes, such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), elicit promising anxiolytic effects in rodent models with limited adverse behavioral effects, however, the efficacy of dual FAAH/MAGL inhibition has not been investigated. In the present study, we compared the effects of FAAH (PF-3845), MAGL (JZL184) and dual FAAH/MAGL (JZL195) inhibitors on (1) anxiety-like behaviors under non-stressed and stressed conditions, (2) locomotor activity and body temperature, (3) lipid levels in the brain and (4) cognitive functions. Behavioral analysis showed that PF-3845 or JZL184, but not JZL195, was able to prevent restraint stress-induced anxiety in the light–dark box assay when administered before stress exposure. Moreover, JZL195 treatment was not able to reverse foot shock-induced anxiety-like behavior in the elevated zero maze or light–dark box. JZL195, but not PF-3845 or JZL184, decreased body temperature and increased anxiety-like behavior in the open-field test. Overall, JZL195 did not show anxiolytic efficacy and the effects of JZL184 were more robust than that of PF-3845 in the models examined. These results showed that increasing either endogenous AEA or 2-AG separately produces anti-anxiety effects under stressful conditions but the same effects are not obtained from simultaneously increasing both AEA and 2-AG.
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影响因子：
3.6
作者：
Hasanein, Parisa;Far, Massoud Teimuri
通讯作者：
Far, Massoud Teimuri
影响因子：
3.1
作者：
Henry MS;Gendron L;Tremblay ME;Drolet G
通讯作者：
Drolet G
影响因子：
3.4
作者：
Curran, HV;Brignell, C;Henry, J
通讯作者：
Henry, J
影响因子：
5.8
作者：
Dale, Elena;Bang-Andersen, Benny;Sanchez, Connie
通讯作者：
Sanchez, Connie
50 年来抗焦虑药物发现的障碍和希望。
DOI：
10.1038/nrd4075
发表时间：
2013-09
期刊：
Nature reviews. Drug discovery
影响因子：
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作者：
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