CN114642730B - 一种抑制剂在缓解吗啡耐受中的应用 - Google Patents

一种抑制剂在缓解吗啡耐受中的应用 Download PDF

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CN114642730B
CN114642730B CN202210122547.3A CN202210122547A CN114642730B CN 114642730 B CN114642730 B CN 114642730B CN 202210122547 A CN202210122547 A CN 202210122547A CN 114642730 B CN114642730 B CN 114642730B
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姜春懿
刘文涛
万莉
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Abstract

本发明公开了一种抑制剂在缓解吗啡耐受中的应用，将用于癌症治疗的EZH2抑制剂转用于缓解吗啡耐受，扩展了吗啡耐受的治疗靶点。本发明有效确证了EZH2靶标与吗啡耐受之间的强关联性，通过EZH2抑制剂能够有效缓解吗啡耐受，获得了改善吗啡耐受的全新靶标EZH2，为后续筛选缓解吗啡耐受的药物打下基础。根据EZH2靶标与吗啡耐受之间的关联，将EZH2抑制剂成功应用于缓解吗啡耐受。

Description

一种抑制剂在缓解吗啡耐受中的应用
技术领域
本发明涉及镇痛药物研发领域，特别涉及一种抑制剂在缓解吗啡耐受中的应用。
背景技术
神经性病理性疼痛是由于影响外周或中枢躯体感觉神经系统的病变或疾病所致。神经病理性疼痛的例子包括疼痛性多发性神经病、带状疱疹后神经痛、三叉神经痛和中风后疼痛。临床上，神经病理性疼痛的特征是自发的持续性或射痛，并在有害或非有害刺激后诱发放大的疼痛反应。外周神经损伤可导致慢性疼痛并最终导致神经病理性疼痛，神经病理性疼痛仍然是全世界最常见的疼痛疾病之一。慢性压迫性损伤(CCI,chronicconstriction injury)模型为更深入了解神经病理性疼痛提供了模型。
吗啡作为阿片类药物的代表药物具有强大的镇痛作用，是治疗剧烈、围手术期和慢性疼痛的主要药物(1,2)。随着疼痛的盛行，吗啡在疼痛管理中的使用在过去几十年显著增加。然而，吗啡的大量、频繁使用会带来严重的副作用，例如耐受性，即随着药物的重复使用，药效降低，需要加大用药剂量或者缩短给药间隔，才能维持原有药效。吗啡耐受是目前临床面临的极具挑战的问题。目前有大量关于吗啡耐受机制的报道，主要包括阿片受体数量下调(3)、抑制性神经元的变化(4)以及神经炎症(5)等。越来越多的研究表明，吗啡耐受是一种包含多重行为和细胞适应性的现象，其中包括中枢神经系统中的细胞、突触和网络水平的神经元可塑性的改变。尽管吗啡镇痛作用是通过与疼痛神经回路中的μ受体的结合和信号传导产生的，但是介导耐受性的具体细胞类型和受体仍然备受争议。长期给予吗啡能够通过影响受体的磷酸化、信号传导以及多聚化来调节神经元上μ受体的功能(6)。此外，已有另外一些研究表明，胶质细胞尤其是小胶质细胞是吗啡耐受重要的驱动力，吗啡通过与小胶质细胞所表达的μ受体结合激活小胶质细胞进而参与吗啡耐受。然而，与之相悖的研究称，小胶质细胞中缺乏μ受体，吗啡通过结合并激活小胶质细胞表面TLR4-MD2信号参与吗啡耐受，更令人困惑的是，吗啡耐受并没有因为TLR4的敲除而得到改善(7)。因此，神经元和胶质细胞在促发吗啡耐受中的贡献和分子机制仍然未得到解决，在基础研究中，缓解吗啡耐受的药物主要有二甲双胍(8)、利多卡因(9)、文拉法辛(10)以及雷帕霉素(10)等。但是目前在临床上，并没有公认的治疗吗啡耐受的特效药。因此寻找一个安全有效的药物缓解吗啡耐受成为亟待解决的问题。吗啡多用于癌症治疗引起的疼痛，然而随着使用吗啡时间的延长，吗啡的镇痛效果逐渐减弱从而影响癌症的治疗，令人欣喜的是，除了已有FDA批准上市的EZH2抑制剂(EPZ6438)用于治疗癌症，此外，多种EZH2抑制剂处于临床二期研发阶段，如CPI-1205、CPI-0209等。因此，若EZH2抑制剂既能治疗癌症也能缓解吗啡耐受，将解决临床一大难点。
增强子和启动子处组蛋白共价组蛋白修饰的动态调节在基因表达的调节中起着关键作用，人类癌症基因组测序工作发现表明，编码修饰组蛋白的染色质调节因子的各种基因经常在各种癌症中发生突变(11)，研究强调了zeste同源物2的染色质修饰增强子(EZH2,enhancer of zeste homolg 2)与癌症之间的联系。EZH2是抑制复合物2(PRC2,Polycomb repressive complex2)的酶亚基，是一种组蛋白甲基转移酶，该亚基可使组蛋白H3的27位赖氨酸(H3K27)发生三甲基化，通过表观遗传机制促进基因转录沉默。研究表明，EZH2在多种肿瘤或者癌症发生中均高表达，如乳腺癌、胰腺癌、肝癌、肺癌以及NK/T细胞淋巴瘤等(12)。许多研究表明，EZH2能够促进癌细胞的存活、增殖、上皮到间充质、侵袭和耐药性。目前，已经开发出多种EZH2抑制剂并进入临床研究，他泽司他(Tazemetostat，EPZ6438)是一种已开发的表观遗传药物，是全球首个获美国FDA批准的EZH2抑制剂，最初是用于治疗有转移性或者局部不可切除的上皮样肉瘤患者。除了在癌症中，已有文献报道，在蛛网膜下腔出血(SHA)后的脑损伤中，EZH2及其介导的H3K27me3的上调在炎症发生发展中至关重要，并且EPZ6438(EZH2抑制剂)能够显著抑制H3K27me3的表达，并上调抑炎蛋白SOCS3(细胞因子信号转导抑制分子3，suppressors-of-cytokine-signaling 3)，下调炎症信号通路相关分子的表达，如肿瘤坏死因子相关受体家族6(TRAF6)、核转录因子(nuclear factor-κB，NF-κBp65)以及白激素-1β(IL-1β)等，而EPZ6438的作用能够被SOCS3小干扰RNA(SOCS3siRNA)取消(13)。然而，目前EZH2在吗啡耐受的作用并没有相关报道。在吗啡耐受过程中，众多基因的表达发生了变化，EZH2或许参与其中。
由此我们猜想EPZ6438是否能够通过抑制H3K27me3的表达缓解吗啡耐受，参考文献如下：
1.Carroll IR,Angst MS,and Clark JD.Management of perioperative painin patients chronically consuming opioids.Reg Anesth Pain Med.2004；29(6):576-91.
2.Kalso E,Edwards JE,Moore AR,and McQuay HJ.Opioids in chronic non-cancer pain:systematic review of efficacy and safety.Pain.2004；112(3):372-80.
3.Cahill CM,Walwyn W,Taylor AMW,Pradhan AAA,and Evans CJ.AllostaticMechanisms of Opioid Tolerance Beyond Desensitization andDownregulation.Trends Pharmacol Sci.2016；37(11):963-76.
4.Bobeck EN,Chen Q,Morgan MM,and Ingram SL.Contribution of adenylylcyclase modulation of pre-and postsynaptic GABA neurotransmission to morphineantinociception and tolerance.Neuropsychopharmacology.2014；39(9):2142-52.
5.Mélik Parsadaniantz S,Rivat C,Rostène W,and Réaux-Le GoazigoA.Opioid and chemokine receptor crosstalk:a promising target for paintherapy？Nat Rev Neurosci.2015；16(2):69-78.
6.Christie MJ.Cellular neuroadaptations to chronic opioids:tolerance,withdrawal and addiction.Br J Pharmacol.2008；154(2):384-96.
7.Fukagawa H,Koyama T,Kakuyama M,and Fukuda K.Microglial activationinvolved in morphine tolerance is not mediated by toll-like receptor 4.JAnesth.2013；27(1):93-7.
8.Pan Y,Sun X,Jiang L,Hu L,Kong H,Han Y,et al.Metformin reducesmorphine tolerance by inhibiting microglial-mediated neuroinflammation.JNeuroinflammation.2016；13(1):294.
9.Zhang Y,Tao GJ,Hu L,Qu J,Han Y,Zhang G,et al.Lidocaine alleviatesmorphine tolerance via AMPK-SOCS3-dependent neuroinflammation suppression inthe spinal cord.J Neuroinflammation.2017；14(1):211.
10.Mansouri MT,Naghizadeh B,Ghorbanzadeh B,Alboghobeish S,HoushmandG,and Amirgholami N.Venlafaxine Attenuates the Development of MorphineTolerance and Dependence:Role of L-Arginine/Nitric Oxide/cGMP Pathway.EndocrMetab Immune DisordDrug Targets.2018；18(4):362-70.
11.Dalgliesh GL,Furge K,Greenman C,Chen L,Bignell G,Butler A,etal.Systematic sequencing of renal carcinoma reveals inactivation of histonemodifying genes.Nature.2010；463(7279):360-3.
12.Kim KH,and Roberts CW.Targeting EZH2 in cancer.Nat Med.2016；22(2):128-34.
13.Luo Y,Fang Y,Kang R,Lenahan C,Gamdzyk M,Zhang Z,et al.Inhibitionof EZH2(Enhancer of Zeste Homolog 2)Attenuates Neuroinflammation viaH3k27me3/SOCS3/TRAF6/NF-κB(Trimethylation of Histone 3Lysine 27/Suppressor ofCytokine Signaling 3/Tumor Necrosis Factor Receptor Family 6/Nuclear Factor-κB)in a Rat Model of Subarachnoid Hemorrhage.Stroke.2020；51(11):3320-31.
发明内容
本发明所要解决的技术问题：目前临床上没有治疗吗啡耐受的特效药，寻找改善吗啡耐受的全新靶标。
为解决上述技术问题，本发明提供以下的技术方案：
一种抑制剂在缓解吗啡耐受中的应用，将EZH2抑制剂用于制备缓解吗啡耐受的药物。
优选地，所述EZH2抑制剂包括EPZ6438、CPI-1205、UNC1999或mircoRNA中的至少一种。
优选地，所述mircoRNA为miRshRNA(EZH2)，其序列为5’-ACTTGCCCACCTCGGAAATTT-3’。
优选地，所述药物中还包括药学上可接受的辅料。
一种阿片类药物组合物，包含上述EZH2抑制剂和阿片类镇痛药物。
优选地，所述阿片类镇痛药物为吗啡。
一种缓解吗啡耐受药物的筛选方法，以EZH2为靶点，通过体内外实验筛选EZH2抑制剂，将EZH2抑制剂用于制备缓解吗啡耐受的药物
本发明获得的有益效果：
本发明有效确证了EZH2靶标与吗啡耐受之间的强关联性，通过EZH2抑制剂能够有效缓解吗啡耐受，获得了改善吗啡耐受的全新靶标EZH2，为后续筛选缓解吗啡耐受的药物打下基础。根据EZH2靶标与吗啡耐受之间的关联，将EZH2抑制剂成功应用于缓解吗啡耐受。
附图说明
图1为EZH2抑制剂(EPZ6438)缓解吗啡耐受的行为学实验结果；
图2为两种EZH2抑制剂(CPI-1205或UNC1999)缓解吗啡耐受的行为学实验结果；
图3为miR30shRNA(EZH2)通过抑制EZH2缓解吗啡耐受的行为学实验结果。
图4为EZH2抑制剂(EPZ6438)能抑制吗啡引起的炎症反应。
具体实施方式
下面通过对实施例的描述，对本发明的具体实施方式作进一步详细的说明，以帮助本领域的技术人员对本发明的发明构思、技术方案有更完整、准确和深入的理解。
实施例1：EPZ6438购于selleck公司，为10mg粉末，化学名称为[1,1'-联苯]-3-甲酰胺，N-[(1,2-二氢-4,6-二甲基-2-氧代-3-吡啶基)甲基]-5-[乙基(四氢-2H-吡喃)-4-基)氨基]-4-甲基-4'-(4-吗啉基甲基)-，将其溶于1.11ml DMSO中得到浓度为10mM的母液。组别设置为对照组(生理盐水，saline)、吗啡组、吗啡和EPZ6438(EZH2抑制剂)共给药组、EPZ6438(EZH2抑制剂)组。其中将10mg/ml的吗啡母液用生理盐水稀释10倍得到10mg/10ml吗啡(溶液1)。将10mM的EPZ6438溶液溶于10mg/10ml吗啡，得到10μg/10μl吗啡中含有2μg/10μlEPZ6438(EZH2抑制剂)的溶液(溶液2)。
ICR小鼠分组，每组10只，各组连续7天分别每天鞘内注射10μl生理盐水、10μl溶液1、10μl溶液2、10μl EPZ6438(EZH2抑制剂)30min后通过甩尾试验(tail-flick trail)检测小鼠对疼痛的敏感性。行为学数据表明，EPZ6438(EZH2抑制剂)能够显著缓解慢性吗啡给药引起的耐受性。***p<0.001versus saline-treated group；###p<0.001versus morphine-treated group.(如图1所示)。
实施例2：CPI-1205(EZH2抑制剂)购于selleck公司，为5mg粉末，其化学名称1H-吲哚-3-甲酰胺，N-[(1,2-二氢-4-甲氧基-6-甲基-2-氧代-3-吡啶基)甲基]-2-甲基-1-[(1R)-1-[1-(2,2,2-三氟乙基)-4-哌啶基]乙基]-，将其溶于385.6μl的DMSO中，得浓度为10mM的母液。UNC1999(EZH2抑制剂)购于selleck公司，为5mg粉末，化学名称为1H-吲唑-4-甲酰胺，N-[(1,2-二氢-6-甲基-2-氧代-4-丙基-3-吡啶基)甲基]-1-(1-甲基乙基)-6-[6-[4-(1-甲基乙基)-1-哌嗪基]-3-吡啶基]-，将其溶于351μLDMSO中，得到浓度为10mM的母液。组别设置为对照组(生理盐水，saline)、吗啡组、吗啡和CPI-1205(EZH2抑制剂)共给药组、吗啡和UNC1999(EZH2抑制剂EPZ6438(EZH2抑制剂)组。其中将10mg/ml的吗啡母液用生理盐水稀释10倍得到10mg/10ml吗啡(溶液1)。将10mM CPI-1205、UNC1999溶液溶于10mg/10ml吗啡，分别得到10μg/10μl吗啡中含有2μg/10μl CPI-1205(EZH2抑制剂)(溶液2)或UNC1999(EZH2抑制剂)的溶液(溶液3)。
ICR小鼠分组，每组10只，各组连续7天分别每天鞘内注射10μl生理盐水、10μl溶液1、10μl溶液2、10μl溶液2、10μl EZH2抑制剂(2μg/10μl，CPI-1205)、10μl EZH2抑制剂(2μg/10μl，UNC1999)30min后，通过甩尾试验(tail-flick trail)检测小鼠对疼痛的敏感性。行为学数据表明，CPI-1205、UNC1999能够显著缓解慢性吗啡给药引起的耐受性。***p<0.001versus saline-treated group；#p<0.05，###p<0.001versus morphine-treatedgroup；$$$p<0.001versus morphine-treated group.(如图2所示)。
实施例3：组别设置为对照组(生理盐水，saline)、吗啡组、吗啡和慢病毒过表达miR30shRNA(EZH2)组，miR30shRNA序列为5’-ACTTGCCCACCTCGGAAATTT-3’。
ICR小鼠分组，每组10只，分别在第-7、0天给予用慢病毒过表达miR30shRNA(EZH2)以抑制EZH2，其中，以pSLenti-GAD67-EGFP-3xFLAG-WPRE空载体构建载有miR30shRNA(Ezh2)的质粒，即pSLenti-GAD67-EGFP-3xFLAG-miR30shRNA(Ezh2)-WPRE，每只小鼠鞘内注射10μl，随后各组连续7天分别每天鞘内注射10μg(给药量)/10μl(给药体积)吗啡30min后，通过甩尾试验(tail-flick trail)检测小鼠对疼痛的敏感性。行为学数据表明，抑制EZH2能够显著缓解慢性吗啡给药引起的耐受性。***p<0.001versus saline-treated group；###p<0.001versus morphine-treated group。(如图3所示)。
实施例4：组别设置为Saline组、Morphine组、Morphine+EPZ6438组以及EPZ6438组，在SH-SY5Y细胞中，给予(终浓度为1μM)EZH2抑制剂72h后，给予细胞吗啡(终浓度200μM)刺激12h后，检测炎症因子IL-1β、TNF-α的变化(如图4所示)，结果显示EZH2抑制剂(EPZ6438)能够显著缓解吗啡引起的炎症反应。
以上实施例仅为说明本发明的技术思想，不能以此限定本发明的保护范围，凡是按照本发明提出的技术思想，在技术方案基础上所做的任何改动，均落入本发明保护范围之内；本发明未涉及的技术均可通过现有技术加以实现。

Claims (2)

1.EZH2抑制剂在制备缓解吗啡耐受药物中的应用，所述缓解吗啡耐受的药物为组合物，包括EZH2抑制剂和阿片类镇痛药物；所述EZH2抑制剂为EPZ6438、CPI-1205、UNC1999或mircoRNA中的至少一种；所述mircoRNA的序列为5’-ACTTGCCCACCTCGGAAATTT-3’， 所述阿片类镇痛药物为吗啡。
2.根据权利要求1中所述的应用，其特征在于：所述药物中还包括药学上可接受的辅料。
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