CN115887619A - 中脑星形胶质细胞源性神经营养因子的用途及药物组合物 - Google Patents
中脑星形胶质细胞源性神经营养因子的用途及药物组合物 Download PDFInfo
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- CN115887619A CN115887619A CN202111166282.9A CN202111166282A CN115887619A CN 115887619 A CN115887619 A CN 115887619A CN 202111166282 A CN202111166282 A CN 202111166282A CN 115887619 A CN115887619 A CN 115887619A
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- neurotrophic factor
- astrocyte
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Abstract
本发明属于医药技术领域，具体涉及中脑星形胶质细胞源性神经营养因子的用途及药物组合物。本发明提供中脑星形胶质细胞源性神经营养因子在制备预防和/或治疗库欣病的药物中的用途。本发明还进一步提供以中脑星形胶质细胞源性神经营养因子为活性成分的药物组合物。该药物组合物为库欣病的临床治疗提供了新的选择，具有很好的应用前景。
Description
技术领域
本发明属于医药技术领域，具体涉及中脑星形胶质细胞源性神经营养因子的用途及药物组合物。
背景技术
促肾上腺素腺瘤是一种较为常见的垂体瘤。病变垂体组织丧失原有的负反馈调节机制及昼夜节律，阿黑皮素源(POMC)作为前体物质高表达且高功能、自主分泌大量促肾上腺皮质激素(ACTH)，致使肾上腺组织分泌过量的糖皮质激素，继而引发以高皮质醇血症为特征的库欣病。库欣病患者常出现糖、脂及电解质代谢异常，以向心性肥胖、血糖、血压异常等为特征，出现一系列代谢综合征，严重影响患者的预期寿命及生存质量。目前，针对该病的治疗有手术治疗、放射治疗及药物治疗。
根据国内外专家的共识(J Clin Endocrinol Metab,July 2008,93(7):2454–2462；《中华医学杂志》2016年96卷11期835-840页)，手术切除为首选治疗方式。常用经鼻蝶内镜或经颅入路。但因手术切除难度大，可能发生垂体功能低下等严重并发症，手术治疗效果与术者操作技术及经验密切相关。经过手术切除后，仍有约15％的患者未达缓解，长期随访的累计复发率近35％。
放射治疗为手术残留或术后复发的辅助治疗措施。但因术后常发生垂体功能低下，且起效所需时间较长等问题，导致放射治疗促肾上腺素腺瘤治疗中的应用受到限制。
药物治疗因简单、便捷、经济等特点已成为促肾上腺素腺瘤的一种重要的辅助治疗方式。术前辅以药物治疗可降低高皮质醇血症对机体造成的影响，是手术治疗的有效过渡措施。其次，若患者术后未达激素缓解目标，药物治疗也是针对库欣病的补救治疗措施。目前临床常用的治疗药物包括类固醇生成抑制剂及中枢活性药物，但这些均有不同程度的弊端。此外，也有文献提出，促使ACTH的分泌正常化的药物，也可用于治疗促肾上腺素腺瘤引发的库欣病(J Clin Endocrinol Metab,July 2008,93(7):2454–2462)。
类固醇生成抑制剂为较为常用的库欣病药物治疗选择，主要包括酮康唑、甲吡酮、米托坦等。该类药物通过抑制合成酶，影响肾上腺甾体合成而导致皮质醇合成减少。但使用类固醇生成抑制剂时易引起肾上腺功能低下，引发肾上腺危象而造成严重后果。针对促肾上腺素腺瘤的中枢活性药物主要为多巴胺2型(D2)受体激动剂卡麦角林和生长激素抑制素受体(SSTR)激动剂帕瑞肽。卡麦角林主要为治疗高泌乳素血症的药物，部分研究发现卡麦角林对促肾上腺素腺瘤的治疗作用较为有限。此外，帕瑞肽及长效缓释剂为已获批的针对手术失败或不适宜手术患者的治疗。但帕瑞肽及长效制剂可致胃肠道反应及心动过缓。同时，帕瑞肽易引起高血糖，需密切监测血糖。
因此，开发新的库欣病治疗药物是非常有意义的，能够为治疗促肾上腺素腺瘤治疗提供新选择，改善难以手术、多次手术及难治性患者的预后。
中脑星形胶质细胞源性神经营养因子(mesencephalic astrocyte-derivedneurotrophic factor，MANF)属于进化保守的神经营养因子(neurotrophic factors，NTFs)家族成员。除具有神经营养功能，MANF还参与内质网应激与炎症反应等过程，在糖尿病、肥胖等代谢性疾病中均扮演着重要的角色。
目前，现有技术中尚未有MANF对库欣病作用的相关研究。
发明内容
针对现有技术中的问题，本发明提供中脑星形胶质细胞源性神经营养因子的用途及药物组合物。目的在于提供一种新的药物组合物，该药物组合物能够抑制POMC的表达，进而抑制ACTH分泌，实现对库欣病的预防和治疗。
中脑星形胶质细胞源性神经营养因子在制备预防和/或治疗库欣病的药物中的用途。
优选的，所述药物用于抑制阿黑皮素源表达和/或用于抑制促肾上腺皮质激素分泌。
优选的，所述药物用于预防和/或治疗促肾上腺皮质激素依赖性的库欣病。
本发明中所述中脑星形胶质细胞源性神经营养因子可以是所有的中脑星形胶质细胞源性神经营养因子。优选的，所述中脑星形胶质细胞源性神经营养因子为重组中脑星形胶质细胞源性神经营养因子或天然中脑星形胶质细胞源性神经营养因子。其中，重组中脑星形胶质细胞源性神经营养因子的氨基酸序列如SEQ ID NO.1或SEQ ID NO.2所述。
本发明还提供一种用于预防和/或治疗库欣病的药物组合物，它是以中脑星形胶质细胞源性神经营养因子为活性物质，加上药物上可接受的辅料或者辅助性成分制备而成。
优选的，所述药物组合物用于抑制阿黑皮素源表达和/或用于抑制促肾上腺皮质激素分泌。
优选的，所述药物组合物用于预防和/或治疗促肾上腺皮质激素依赖性的库欣病。
优选的，所述中脑星形胶质细胞源性神经营养因子为重组中脑星形胶质细胞源性神经营养因子或天然中脑星形胶质细胞源性神经营养因子。
本发明通过实验证明了在不影响细胞增殖的情况下，MANF能够恢复垂体细胞对糖皮质激素的反应性并重建负反馈调节机制，达到抑制POMC的表达和ACTH分泌的作用。降低ACTH的分泌可以治疗和预防库欣病是本领域的共识，具体作用机理是：当血液中ACTH降低后，影响其靶腺——肾上腺，相应地致使肾上腺分泌皮质激素减少，从而缓解由过量糖皮质激素所带来的库欣病的相关病理生理学改变。POMC是ACTH的前体物质。因此，通过抑制POMC的表达和ACTH分泌，MANF最终能够达到治疗库欣病的目的。
本发明还提供一种以MANF为活性物质的药物组合物，该药物组合物能够抑制POMC的表达，进而抑制ACTH分泌，实现对库欣病的预防和治疗。为临床治疗提供了新的选择。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为实施例1中CCK-8法检测不同浓度MANF对AtT-20细胞活性影响的结果；
图2为实施例1中qPCR检测不同浓度MANF对AtT-20细胞POMC水平影响的结果；
图3为实施例1中Western Blot检测MANF处理后AtT-20细胞POMC变化的结果；
图4为实施例2中ELISA法测定细胞上清中ACTH含量的结果。
具体实施方式
以下实施例和实验例中，所用的试剂和材料均为市售品。
实施例1MANF对POMC表达的抑制作用
一、实验方法
1、细胞培养：
(1)在5％CO2、37℃恒温细胞培养箱中以Ham’s F12K完全培养基培养AtT-20细胞。
(2)取对数生长期细胞，1500rpm离心3min后，加适量Ham’s F12K完全培养基重悬，分别以1×10^4/孔密度及1×10^6/孔密度接种细胞至96孔及6孔板中。连续培养24h。
(3)分别以4.0,2.0,1.0,0.5,0.25,0.12,0.06,0.03及0(μg/mL)浓度MANF(购自北京义翘神州生物技术有限公司，产品编号50954-M08H，其序列如SEQ ID NO.2所述)处理AtT-20细胞24h后，以CCK-8法检测AtT-20活性。
2、细胞处理
以地塞米松(Dex，GLP Bio,GC40775)构建促肾上腺素腺瘤体外模型，分别以下表所示组别加入Dex及MANF：
上述步骤1(2)中培养AtT-20细胞24h后。以1500rpm离心3min后，PBS清洗重悬3次后。提取不同组AtT-20细胞RNA并逆转录，通过qPCR法检测POMC表达。提取不同组AtT-20细胞蛋白质，经BCA法定量后以Western Blot法检测POMC表达。
3、CCK-8法检测MANF对AtT-20细胞活性影响
(1)取步骤1中处理后细胞，分别加入CCK8(APExBio，货号K1018)10μL，5％CO2、37℃恒温细胞培养箱中孵育3h。
(2)使用全波长酶标仪(Molecular Detector，
190)测量450nm处吸光度(O.D.)。
(3)以O.D.值计算细胞存活率。
细胞存活率(％)＝[(As-Ab)/(Ac-Ab)]×100
As＝实验孔吸光度(含有细胞，培养基，CCK-8和MANF)
Ab＝空白孔吸光度(含有培养基和CCK-8)
Ac＝对照孔吸光度(含有细胞，培养基和CCK-8)
4、RNA提取及PCR
(1)取步骤2中处理后细胞。通过TRIzol TM试剂(Thermo ScientificTM，155960-26)提取RNA。
(2)使用超微量核酸蛋白测定仪(Thermo ScientificTM，ND-ONEC-W)测定RNA浓度后，使用RevertAid RT(Thermo ScientificTM，K1691)进行逆转录。
(3)使用2X SYBR GreenqPCR Master Mix(Bimake，B21202)及POMC引物进行qPCR反应。Pomc引物序列如下表所示：
| 序列表编号 | 序列 | |
| 正向链 | SEQUENCE NO.3 | ATGCCGAGATTCTGCTACAGT |
| 反向链 | SEQUENCE NO.4 | TCCAGCGAGAGGTCGAGTTT |
5、蛋白质提取及Western Blot检测
(1)取步骤2中处理后细胞，以全蛋白提取试剂盒(Solarbio Life Science,BC3710)提取蛋白后，通过BCA法(Beyotime，P0010)测定蛋白浓度。
(2)使用InstantViewTM SDS-PAGE蛋白染色及上样缓冲液(5X)(Beyotime，P0280)将蛋白变性。
(3)以Western Blot法测定POMC表达情况。
二、实验结果
1、CCK-8法检测MANF对AtT-20细胞活性影响
CCK-8法检测MANF对AtT-20细胞活性影响的结果如图1所示，结果表明，不同浓度MANF对AtT-20细胞活性无显著影响。
2、RNA提取及PCR
PCR结果如图2(*p<0.05)所示，结果表明，不同浓度MANF均可致AtT-20中POMC在转录水平降低。其中予以1.0μg/mL时，效果最明显。
3、蛋白质提取及Western Blot检测
选择1.0μg/ml MANF处理后的AtT-20细胞，通过Western Blot法检测POMC变化。结果如图3(*p<0.05)所示，经MANF及Dex联合处理后，AtT-20细胞中POMC表达明显降低，具有统计学差异。
本实施例的实验表明，MANF能够在不影响细胞增殖的情况下，抑制POMC的表达。
实施例2MANF对ACTH分泌的抑制作用
一、实验方法
1、细胞培养及细胞处理的步骤与实施例1相同；
2、细胞上清ACTH检测
(1)取上述步骤处理后细胞，取细胞培养上清。
(2)通过ELISA法(Elabscience，E-EL-M0079c)测定细胞上清中ACTH。
二、实验结果
通过ELISA法测定细胞上清可见不同浓度MANF联合Dex处理AtT-20细胞后，其ACTH均可降低，且呈现出浓度依赖效应。即随着MANF浓度增加，AtT-20培养所用细胞上清中ACTH含量逐渐降低。如图4所示。
本实施例的实验表明，MANF能够抑制ACTH的分泌。
通过上述实施例可见，在不影响细胞增殖的情况下，MANF能够恢复垂体细胞对糖皮质激素的反应性并重建负反馈调节机制，达到抑制POMC的表达和抑制ACTH分泌的作用。因此，以MANF为活性物质的药物能够预防和治疗POMC表达、ACTH分泌导致的库欣病。本发明为库欣病的临床治疗提供了新的选择，具有很好的应用前景。
SEQUENCE LISTING
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Claims (8)
1.中脑星形胶质细胞源性神经营养因子在制备预防和/或治疗库欣病的药物中的用途。
2.按照权利要求1所述的用途，其特征在于：所述药物用于抑制阿黑皮素源表达和/或用于抑制促肾上腺皮质激素分泌。
3.按照权利要求1所述的用途，其特征在于：所述药物用于预防和/或治疗抑制促肾上腺皮质激素依赖性的库欣病。
4.按照权利要求1所述的用途，其特征在于：所述中脑星形胶质细胞源性神经营养因子为天然中脑星形胶质细胞源性神经营养因子或重组中脑星形胶质细胞源性神经营养因子。
5.一种用于预防和/或治疗库欣病的药物组合物，其特征在于：它是以中脑星形胶质细胞源性神经营养因子为活性物质，加上药物上可接受的辅料或者辅助性成分制备而成。
6.按照权利要求5所述的药物组合物，其特征在于：所述药物组合物用于抑制阿黑皮素源表达和/或用于抑制促肾上腺皮质激素分泌。
7.按照权利要求5所述的药物组合物，其特征在于：所述药物组合物用于预防和/或治疗促肾上腺皮质激素依赖性的库欣病。
8.按照权利要求5所述的药物组合物，其特征在于：所述中脑星形胶质细胞源性神经营养因子为重组中脑星形胶质细胞源性神经营养因子或天然中脑星形胶质细胞源性神经营养因子。
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