JZL 195 is a highly selective and irreversible dual inhibitor of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), with IC50 values of 2nM and 4nM, respectively[1]. In vivo, JZL 195 elevates the levels of endogenous cannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG)[2]. JZL 195 is commonly used to alleviate neuropathic and inflammatory pain, manage chemotherapy-induced peripheral neuropathy, and investigate potential antihypertensive effects, among other applications[3,4].
In vitro, pretreatment of immortalized human renal proximal tubular HK-2 cells with 250nM JZL 195 for 24h indirectly activated CB1R and significantly increased the mRNA and protein expression levels of erythropoietin (EPO)[5].
In vivo, oral administration of JZL 195 (20mg/kg) for 15 days in a streptozotocin-induced sporadic Alzheimer's disease mouse model significantly reversed the elevated levels of Aβ1-42 in hippocampal tissue[6]. Intraperitoneal injection of JZL 195 (3mg/kg) 2h after nitroglycerin (NTG) administration in Sprague-Dawley rats, with tissue sampling following behavioral tests, significantly reduced the NTG-induced increase in calcitonin gene-related peptide (CGRP) levels[7]. Intraperitoneal administration of JZL 195 (10mg/kg) 45min before bilateral carotid artery occlusion surgery in C3H mice significantly ameliorated ischemia-induced neurological deficits[8].
References:
[1] LONG J Z, NOMURA D K, VANN R E, et al. Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo[J]. Proceedings of the National Academy of Sciences, 2009, 106(48): 20270-20275.
[2] MANDUCA A, MORENA M, CAMPOLONGO P, et al. Distinct roles of the endocannabinoids anandamide and 2-arachidonoylglycerol in social behavior and emotionality at different developmental ages in rats[J]. European Neuropsychopharmacology, 2015, 25(8): 1362-1374.
[3] ANDERSON W B, GOULD M J, TORRES R D, et al. Actions of the dual FAAH/MAGL inhibitor JZL195 in a murine inflammatory pain model[J]. Neuropharmacology, 2014, 81: 224-230.
[4] TOCZEK M, RYSZKIEWICZ P, REMISZEWSKI P, et al. Weak hypotensive effect of chronic administration of the dual FAAH/MAGL inhibitor JZL195 in spontaneously hypertensive rats as revealed by area under the curve analysis[J]. International Journal of Molecular Sciences, 2023, 24(13): 10942.
[5] BARAGHITHY S, SOAE Y, ASSAF D, et al. Renal proximal tubule cell cannabinoid-1 receptor regulates bone remodeling and mass via a kidney-to-bone axis[J]. Cells, 2021, 10(2): 414.
[6] BAJAJ S, ZAMEER S, JAIN S, et al. Effect of the MAGL/FAAH dual inhibitor JZL-195 on streptozotocin-induced Alzheimer’s disease-like sporadic dementia in mice with an emphasis on Aβ, HSP-70, neuroinflammation, and oxidative stress[J]. ACS Chemical Neuroscience, 2022, 13(7): 920-932.
[7] GRECO R, DEMARTINI C, FRANCAVILLA M, et al. Dual inhibition of FAAH and MAGL counteracts migraine-like pain and behavior in an animal model of migraine[J]. Cells, 2021, 10(10): 2543.
[8] MITROSHINA E V, ABOGESSIMENGANE B Z, URAZOV M D, et al. The influence of Glial cell line-derived neurotrophic factor and modulated activity of endocannabinoid system on с3h mice sustainability to ischemic brain injury in vivo[J]. Opera Medica et Physiologica, 2016(S1): 83-84.
JZL 195是一种具有高效选择性、不可逆的脂肪酸酰胺水解酶（FAAH）和单酰甘油脂肪酶（MAGL）双重抑制剂，IC50值分别为2nM和4nM[1]。JZL 195在体内可提升内源性大麻素anandamide（AEA）和2-花生四烯酰甘油（2-AG）的水平[2]，通常用于减轻神经病理性和炎症性疼痛、管理化疗诱发的周围神经病变以及研究潜在的降压效果等领域[3,4]。
在体外，JZL 195（250nM）预处理永生化人肾近端小管HK-2细胞24h，通过间接激活CB1R，显著提高了红细胞生成素（EPO）的mRNA和蛋白表达水平[5]。
在体内，JZL 195（20mg/kg）通过口服治疗由Streptozotocin诱导的散发性阿尔茨海默病模型小鼠15天，显著逆转了海马组织中Aβ1-42水平升高[6]。JZL 195（3mg/kg; i.p.）于硝酸甘油（NTG）注射2h后处理Sprague-Dawley大鼠，在行为测试结束后取样，显著降低了NTG引起的降钙素基因相关肽（CGRP）水平升高[7]。JZL 195（10mg/kg）于双侧颈动脉闭塞手术前45min通过腹腔注射处理C3H小鼠，显著改善了由脑缺血导致的神经功能缺陷[8]。