Al-Romaiyan Altaf, Masocha Willias
Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, Safat, Kuwait.
Front Pharmacol. 2022 Aug 9;13:944502. doi: 10.3389/fphar.2022.944502. eCollection 2022.
Triterpenes such as euphol and pristimerin, which are plant secondary metabolites, were the first to be characterized as monoacylglycerol lipase (MAGL) inhibitors. MAGL inhibitors alleviate chemotherapy-induced neuropathic pain (CINP) in rodent models. Pristimerin has been shown to have additive anticancer activity with paclitaxel, a chemotherapeutic drug. However, the activity of pristimerin on CINP has not been evaluated. The aims of this study were to evaluate whether various triterpenes had activity against recombinant human MAGL and MAGL activity in mouse tissues, and whether pristimerin could prevent development of paclitaxel-induced mechanical allodynia. The effects of four triterpenes betulinic acid, cucurbitacin B, euphol, and pristimerin on the activity human recombinant MAGL and MAGL activity of mice brain and paw skin tissues were evaluated using MAGL inhibitor screening and MAGL activity assay kits. The effects of treatment of female BALB/c mice with pristimerin intraperitoneally on the development of paclitaxel-induced mechanical allodynia were assessed using the dynamic plantar aesthesiometer and on nuclear factor-2 erythroid related factor-2 () gene expression in the paw skin were evaluated by real time polymerase chain reaction. Pristimerin inhibited the human recombinant MAGL activity in a concentration-dependent manner like JZL-195, a MAGL inhibitor. Betulinic acid, cucurbitacin B and euphol inhibited human recombinant MAGL activity but their effects were not concentration dependent and were less to that of pristimerin. Pristimerin inhibited both mouse brain and paw skin MAGL activity in a concentration-dependent manner. Paclitaxel induced mechanical allodynia and increase in MAGL activity in the paw skin. Treatment with pristimerin prevented the development of paclitaxel-induced mechanical allodynia and the paclitaxel-induced increase in MAGL activity. Pristimerin significantly upregulated mRNA expression of a regulator of endogenous antioxidant defense. These results indicate that triterpenes inhibit human recombinant MAGL activity with varying degrees. Pristimerin inhibits both mouse brain and paw skin MAGL activity in a concentration-dependent manner, prevents both the development of paclitaxel-induced mechanical allodynia and the associated increase in MAGL activity in the paw skin, and might protect against paclitaxel-induced oxidative stress. Co-treatment with pristimerin and paclitaxel could be useful in the treatment of cancer and prevention of CINP.
大戟醇和扁蒴藤素等三萜类化合物是植物次生代谢产物，它们最早被鉴定为单酰甘油脂肪酶（MAGL）抑制剂。MAGL抑制剂可减轻啮齿动物模型中化疗引起的神经性疼痛（CINP）。已证明扁蒴藤素与化疗药物紫杉醇具有相加的抗癌活性。然而，扁蒴藤素对CINP的活性尚未评估。本研究的目的是评估各种三萜类化合物是否对重组人MAGL和小鼠组织中的MAGL活性有作用，以及扁蒴藤素是否能预防紫杉醇诱导的机械性异常性疼痛的发生。使用MAGL抑制剂筛选和MAGL活性检测试剂盒评估了四种三萜类化合物桦木酸、葫芦素B、大戟醇和扁蒴藤素对人重组MAGL活性以及小鼠脑和爪皮肤组织中MAGL活性的影响。使用动态足底麻醉仪评估腹腔注射扁蒴藤素对雌性BALB/c小鼠紫杉醇诱导的机械性异常性疼痛发生的影响，并通过实时聚合酶链反应评估爪皮肤中核因子-2红细胞相关因子-2（）基因的表达。扁蒴藤素像MAGL抑制剂JZL-195一样以浓度依赖性方式抑制人重组MAGL活性。桦木酸、葫芦素B和大戟醇抑制人重组MAGL活性，但其作用不呈浓度依赖性且小于扁蒴藤素。扁蒴藤素以浓度依赖性方式抑制小鼠脑和爪皮肤中的MAGL活性。紫杉醇诱导爪皮肤出现机械性异常性疼痛并使MAGL活性增加。用扁蒴藤素治疗可预防紫杉醇诱导的机械性异常性疼痛的发生以及紫杉醇诱导的爪皮肤中MAGL活性增加。扁蒴藤素显著上调内源性抗氧化防御调节因子的mRNA表达。这些结果表明三萜类化合物不同程度地抑制人重组MAGL活性。扁蒴藤素以浓度依赖性方式抑制小鼠脑和爪皮肤中的MAGL活性，预防紫杉醇诱导机械性异常性疼痛的发生以及爪皮肤中相关的MAGL活性增加，并且可能预防紫杉醇诱导的氧化应激。扁蒴藤素与紫杉醇联合治疗可能对癌症治疗和预防CINP有用。
