CN117045652B - 犬尿喹啉酸在制备缓解和/或治疗神经性贪食症的药物中的应用 - Google Patents
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Abstract
本发明属于医药技术领域，涉及犬尿喹啉酸在制备缓解和/或治疗神经性贪食症的药物中的应用。本发明在小鼠上建立BN发病的动物模型，通过小鼠粪便微生物代谢组测序，发现KYNA在BN小鼠肠道内显著降低。WB检测发现BN小鼠肠道中KYNA合成酶KAT I/II/III的蛋白表达水平也显著降低，说明肠道内KYNA合成受阻。通过对BN患者粪便进行靶向代谢物质谱检测，发现BN患者肠道内KYNA相较于正常被试也呈现下降变化。最后，对BN小鼠进行为期11天的口饲KYNA处理，发现该处理可改善BN小鼠的贪食症状。因此，口服补充KYNA恢复肠道代谢物水平可以达到从根源机制上治疗BN的目的，为临床治疗BN提供了新的方法。
Description
技术领域
本发明涉及医药技术领域，具体地，涉及犬尿喹啉酸在制备缓解和/或治疗神经性贪食症的药物中的应用。
背景技术
神经性贪食症(Bulimia nervosa,BN)是一类由不良饮食习惯发展而成的饮食失调疾病，发病特征主要表现为反复发作且不可抗拒的冲动性暴饮暴食，并伴随不当的补偿行为来缓解摄入过量的身心不适，如催吐、导泻、禁食及过度运动等。一项基于2019年全球疾病负担研究的评估分析显示，过去三十年来中国BN的发病率和伤残调整寿命年均显著增长，截至2019年，中国BN患病人数超过150万人，预计到2030年，这一数字将会增加到200万人。BN发病患者中年轻女性居多。除遗传因素外，压力因素对于BN的发病起到关键作用，包括生活压力、社会文化压力及心理压力等。BN的长期后果包括落齿、手麻手抖、晕厥、消化道损伤及心率失常等症状，严重情况下甚至有可能发生休克和心脏骤停。BN患者罹患各种癌症的风险因素也显著增加，包括结直肠癌、食管癌、肝癌和卵巢癌等。此外，BN患者也往往伴随出现一些神经精神障碍，如焦虑症、抑郁症、双相情感障碍及边缘型人格障碍等。据统计，BN患者的死亡率在所有精神类疾病(包括重型抑郁症)中是最高的。总之，BN对健康有较大危害，且逐渐成为当今社会环境下的一个普遍问题。
BN的治疗目标是减少患者暴饮暴食的频率并建立健康的饮食习惯。现阶段临床上对BN的治疗手段包括心理治疗及药物治疗，包括：(1)认知行为疗法(CBT)，也是最早用于BN治疗的方法，该方法侧重帮助患者树立正常的体重认知，了解BN的负面影响，纠正对体重及形体的过分关注，以及合理的规划一日三餐，CBT对于有着强烈治疗愿望的患者来说短期内预后效果较好，但复发率较高；(2)人际关系疗法(IPT)，这种方法侧重于改善BN患者的人际关系，通过建立更多的社交活动分散患者对食物的关注，因此IPT治疗周期长，见效时间较慢，容易出现患者依从性越来越差的问题；(3)行为治疗(BT)，该方法侧重于提高患者的压力耐受程度，调节情绪以此降低暴饮暴食的欲望。与CBT和IPT相比，BT治疗患者的复发率最高。现阶段临床上没有针对BN的特效治疗药物，主要通过使用抗抑郁药(如各类5-HT再摄取抑制剂)、抗惊厥药物(如托吡酯)等去缓解BN症状。但这些药物往往伴有头痛、异常镇静、失眠、嗜睡、注意力不集中及心率和血压升高等不良反应。很多患者由于药物产生的副作用选择终止治疗，且在停药后，复发率依旧较高。由此可以看出，以上这些治疗方法均无法做到从根源机制上对BN的发病“对症下药”，导致治疗效果欠佳且容易反复。
犬尿喹啉酸(Kynurenic acid,KYNA)是色氨酸(Trp)的代谢产物之一。广泛分布于哺乳动物的体液和中枢神经系统中，能拮抗兴奋性氨基酸(EAA)和烟碱受体，与某些神经系统、眼科、肾脏、免疫性等疾病都有关联。由于BN的发病机制及治疗方案较复杂，相关科研人员尚未完全研究清楚，目前还未有通过服用KYNA来缓解或治疗BN的相关报道。
发明内容
本发明的目的是为了克服现有技术的上述不足，提供犬尿喹啉酸在制备缓解和/或治疗神经性贪食症的药物中的应用。
本发明的另一目的在于提供一种缓解和/或治疗神经性贪食症的药物。
本发明的另一目的在于提供含有犬尿喹啉酸的食品、饮品、保健品、肠内营养剂、膳食补充剂、兽药和/或饲料添加剂。
为了实现上述目的，本发明是通过以下方案予以实现的：
本发明前期以啮齿类动物为研究对象，在小鼠上建立BN发病的动物模型，用于模拟BN患者的临床症状；通过小鼠粪便微生物代谢组测序，发现一种代谢物犬尿喹啉酸(KYNA)，其水平在BN小鼠肠道内显著降低。Western blot检测发现BN小鼠肠道中KYNA合成酶KAT I/II/III的蛋白表达水平也显著降低，说明肠道内KYNA合成受阻。通过对BN患者粪便进行靶向代谢物质谱检测，发现BN患者肠道内KYNA相较于正常被试也呈现下降变化。最后，对BN小鼠进行为期11天的口饲KYNA处理，发现该处理可改善BN小鼠的贪食症状。因此，相较于易复发的心理治疗与副作用大的药物治疗，口服补充KYNA恢复肠道代谢物水平可以达到从根源机制上治疗BN的目的，为临床推广治疗BN提供了新的方法。
因此，本发明请求保护犬尿喹啉酸在制备缓解和/或治疗神经性贪食症的药物中的应用。
本发明还请求保护一种缓解和/或治疗神经性贪食症的药物，所述药物中含有犬尿喹啉酸。
在一种具体的实施方式中，所述犬尿喹啉酸的浓度为4mg/mL。
在一种更具体的实施方式中，所述犬尿喹啉酸的口饲剂量为每只鼠每天0.8mgKYNA溶于0.2ml饮水中，连续口饲11天。
优选地，所述药物还含有药物辅料。
更优选地，所述药物辅料包含抗黏合剂、渗透促进剂、缓冲剂、增塑剂、表面活性剂、消泡剂、增稠剂、包合剂、吸收剂、保湿剂、溶剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、pH值调节剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、整合剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、发泡剂、助悬剂、包衣材料、芳香剂、稀释剂、絮凝剂与反絮凝剂、助滤剂或释放阻滞剂。
优选地，所述药物的剂型为颗粒剂、胶囊剂、片剂、丸剂或口服液。
优选地，所述药物的应用对象包括但不限于人类或小鼠。
本发明还请求保护含有犬尿喹啉酸的食品、饮品、保健品、肠内营养剂、膳食补充剂、兽药和/或饲料添加剂。
优选地，所述的食品、饮品、保健品、肠内营养剂、膳食补充剂、兽药和/或饲料添加剂中，所述犬尿喹啉酸的浓度为4mg/mL。
优选地，所述的食品、饮品、保健品、肠内营养剂、膳食补充剂、兽药和/或饲料添加剂可改善神经性贪食症相关症状。
与现有技术相比，本发明具有以下有益效果：
本发明发现KYNA能有效缓解神经性贪食症，具体体现在：对BN小鼠进行为期11天的口饲KYNA处理，发现该处理可改善BN小鼠的贪食症状。因此，口服补充KYNA恢复肠道代谢物水平可以达到从根源机制上治疗BN的目的。与心理治疗相比，补充KYNA无需患者住院，节省人力物力财力，无需担心疗程结束后复发；与现有采用不对症的抗抑郁药或抗惊厥药相比，补充KYNA产生的副作用远小于抗抑郁药或抗惊厥药带来的副作用。综上所述，KYNA在制备预防和/或治疗神经性贪食症的产品中具有广阔的应用前景。
附图说明
图1为在小鼠上建立BN模型的示意步骤。其中，图1A为电击后不同时间段(post2h,8h,24h)后小鼠消耗chow和Oreo的重量；图1B为对照小鼠和BN小鼠在不同时间段chow/Oreo消耗重量的比值；图1C为对照小鼠和BN小鼠在不同时间段的热量摄入；图1D为对照小鼠和BN小鼠电击后靠近Oreo所需的潜伏时间。
图2为对照小鼠和BN小鼠肠道微生物代谢组测序分析。其中，图2A为对照小鼠与BN小鼠基于肠道微生物代谢组分析的t-SNE聚类分析，表明两组小鼠代谢组存在显著差异；图2B为对照小鼠与BN小鼠上升与下调的肠道代谢物数目；图2C为对照小鼠与BN小鼠肠道KYNA相对水平的统计，以及口饲健康小鼠粪便后BN小鼠肠道KYNA相对水平的恢复情况；图2D为包括KYNA在内的多种肠道代谢物在对照小鼠与BN小鼠中的相对水平热图统计，其中BN小鼠KYNA水平显著低于对照小鼠。
图3为对照小鼠和BN小鼠肠道内三种亚型KYNA合成酶的蛋白表达水平分析。其中，图3A为对照小鼠和BN小鼠肠道内三种亚型KYNA合成酶的蛋白WB电泳条带；图3B为图3A的量化统计，表明BN小鼠肠道内三种亚型KYNA合成酶的蛋白表达水平均显著低于对照小鼠。
图4为BN病人肠道KYNA的表达水平分析，表明与小鼠上发现的差异一致，BN患者肠道内KYNA水平也呈现下降变化。
图5为对照小鼠、BN小鼠以及BN小鼠口饲KYNA后贪食程度的分析。其中，图5A为对照小鼠、BN小鼠以及给及KYNA的BN小鼠第11天口饲结束后不同时间段chow/Oreo消耗重量的比值；图5B为对照小鼠、BN小鼠以及给及KYNA的BN小鼠第11天口饲结束后不同时间段的热量摄入统计，这些结果表明口饲KYNA能显著缓解BN小鼠的贪食症状。
具体实施方式
下面结合说明书附图及具体实施例对本发明作出进一步地详细阐述，所述实施例只用于解释本发明，并非用于限定本发明的范围。下述实施例中所使用的试验方法如无特殊说明，均为常规方法；所使用的材料、试剂等，如无特殊说明，为可从商业途径得到的试剂和材料。
实施例1在C57BL/6J小鼠上建立BN模型
整个模型由三个循环组成，每个循环11天，前4天为节食期，小鼠每天获得少于日均消耗量的鼠粮chow(约日均消耗量的60％)；随后2天小鼠获得充足chow，并额外获得不限量的Oreo饼干；接下来撤去Oreo，小鼠进入4天的chow自由饮食期；在第11天对小鼠进行0.45mA足底电击，并记录电击后不同时间段(post 2h,8h,24h)后小鼠消耗chow和Oreo的重量(图1A)。通过计算chow/Oreo消耗重量的比值来反应其对高能食物的偏爱程度：chow/Oreo值越低，偏爱度越高，反之chow/Oreo值越高，偏爱度越低；以及摄入总卡路里数来反应贪食程度：卡路里值越高，贪食程度越强(图1B-D)。
实施例2BN小鼠肠道微生物代谢物KYNA水平下降
收集对照小鼠与BN小鼠粪便并进行肠道微生物代谢组测序分析。t-SNE分簇结果表明BN组小鼠与对照组小鼠代谢组存在显著差异(图2A、2B)。深度分析发现BN小鼠组犬尿喹啉酸KYNA的含量远低于对照组(图2C、2D)。而当向BN小鼠移植对照小鼠的粪便浸出液后，BN小鼠肠道内KYNA水平得以恢复(图2C)，这说明KYNA确实来源于肠道微生物。
实施例3BN小鼠肠道中KYNA合成酶KAT I/II/III的蛋白表达水平显著降低
通过western blot检测BN小鼠肠道内KYNA合成酶的表达水平，发现相较于对照组，BN小鼠肠道内三种KYNA合成酶亚型的蛋白表达水平均呈现下降趋势(图3A、3B)，说明BN小鼠肠道内KYNA合成通路受阻。
实施例4BN患者肠道内KYNA水平呈现下降变化
进一步招募了11名临床诊断为BN的女性患者，以及9名年龄、性别和体重指数相匹配的健康被试，并分别收集BN患者和健康被试的粪便进行靶向代谢物质谱检测。分析发现，与健康被试相比，BN患者肠道内KYNA水平也呈现下降变化(图4)。
实施例5口饲KYNA可缓解BN小鼠的贪食症状
以上这些结果提示，BN症状的出现可能与KYNA的缺失有关，因此在小鼠上进行验证，对BN小鼠给予为期11天的口饲KYNA处理(每只鼠每天0.8mg KYNA溶于0.2mL饮水中)，结果与预期一致，补充KYNA显著缓解了BN小鼠的贪食症状(图5A、5B)。综上所述，补充KYNA为BN临床治疗提供了一个新思路。
最后所应当说明的是，以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制，对于本领域的普通技术人员来说，在上述说明及思路的基础上还可以做出其它不同形式的变化或变动，这里无需也无法对所有的实施方式予以穷举。凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明权利要求的保护范围之内。
Claims (1)
1.犬尿喹啉酸作为唯一活性成分在制备缓解和/或治疗神经性贪食症的药物中的应用，其特征在于，所述犬尿喹啉酸的浓度为4mg/mL。
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| CN101563106A (zh) * | 2006-09-19 | 2009-10-21 | 埃斯蒂维实验室股份有限公司 | Nmda-受体配体和具有5-ht6受体亲合力的化合物的组合 |
| CN109223785A (zh) * | 2018-10-29 | 2019-01-18 | 中国药科大学 | 犬尿喹啉酸或其衍生物在制备改善慢性精神应激相关病理损伤药物中的应用 |
| CN113350342A (zh) * | 2021-06-01 | 2021-09-07 | 南京医科大学附属逸夫医院 | 犬尿喹啉酸在制备治疗骨质疏松相关疾病的药物中的用途 |
| CN114601832A (zh) * | 2021-12-01 | 2022-06-10 | 南方医科大学 | 犬尿喹啉酸在制备改善hiv-1相关神经认知功能障碍药物中的应用 |
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| CN101563106A (zh) * | 2006-09-19 | 2009-10-21 | 埃斯蒂维实验室股份有限公司 | Nmda-受体配体和具有5-ht6受体亲合力的化合物的组合 |
| CN109223785A (zh) * | 2018-10-29 | 2019-01-18 | 中国药科大学 | 犬尿喹啉酸或其衍生物在制备改善慢性精神应激相关病理损伤药物中的应用 |
| CN113350342A (zh) * | 2021-06-01 | 2021-09-07 | 南京医科大学附属逸夫医院 | 犬尿喹啉酸在制备治疗骨质疏松相关疾病的药物中的用途 |
| CN114601832A (zh) * | 2021-12-01 | 2022-06-10 | 南方医科大学 | 犬尿喹啉酸在制备改善hiv-1相关神经认知功能障碍药物中的应用 |
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