Signal Transduct Target Ther:口服小檗碱改善帕金森

2021-04-04 MedSci原创 MedSci原创

BBR是肠球菌中TH的激动剂，并可导致肠道中左旋多巴的产生。口服BBR可通过肠道细菌增加血/粪中的左旋多巴。因此，BBR可能通过类似维生素的作用上调肠道微生物区系中左旋多巴的生物合成来改善大脑功能。

肠道微生物区系是影响大脑功能的一个越来越公认的因素，但其机制尚不清楚。多巴胺是一种主要的神经递质，其在大脑中的水平与大脑功能密切相关。人类多巴胺的主要合成途径是“L-苯丙氨酸(Phe) → L-酪氨酸(Tyr) → (S)-3，4-二羟基苯丙氨酸(左旋多巴) → 多巴胺(Phe-Tyr-多巴-多巴胺)”代谢途径。在这个过程中，第一阶段(Phe-Tyr步骤)由苯丙氨酸羟化酶催化。这种转化主要发生在肝脏和肾脏。肝脏(或肾脏)和/或血源性Tyr(来自饮食)可以通过血脑屏障进入大脑。酪氨酸-多巴-多巴胺转化是第二阶段，在大脑中由酪氨酸羟化酶(TH)和多巴脱羧酶(DDC)完成。该途径的阻断可导致神经系统疾病，如苯丙酮尿酸和帕金森病。TH是儿茶酚胺生物合成的限速酶，可将L-Tyr羟基化为L-多巴。这是一种含铁的单加氧酶，需要四氢生物蝶呤(BH₄)作为辅因子。当L-多巴产生时，BH₄被转化为7，8-二氢生物蝶呤(BH₂)，并在此过程中持续消耗BH₄。BH₄可以通过两种方式在细胞质中合成：来源合成和/或修复。在正常条件下，GTP-NH₂P₃(D-赤蝶呤-7，8-二氢蝶呤三磷酸)-PPH₄(6-丙酮酰四氢蝶呤)-BH₄途径可以合成BH₄，称为“源合成”；另一方面，BH₄可以通过墨嘌呤→BH₂ → BH₄和二氢叶酸还原的补救途径来补充。

在肠道菌群中已发现产生BH₄的细菌，微生物中也存在苯丙氨酸-酪氨酸-多巴-多巴胺代谢途径。这表明细菌可能含有哺乳动物用来产生多巴胺的酶基因的同源物。事实上，一些细菌可以被视为生产多巴胺/多巴胺的生物技术工厂。有趣的是，人体肠道中的细菌，如肠球菌，是多巴/多巴胺的制造者，在肠道和大脑之间提供了一种可能的化学联系。最近的研究表明，肠道微生物区系可以通过微生物衍生的代谢物，如5-羟色胺来调节大脑功能。因此，关键问题是如何才能以一种实用的方式调节大脑功能。

小檗碱(BBR)是一种天然化合物，分离自黄连、小檗属等草本植物。BBR在中国作为一种非处方药(OTC)用于治疗腹泻患者已有数十年的历史。BBR是一种安全有效的治疗高脂血症和2型糖尿病的药物，机制新颖。在过去的十年里，BBR在降血脂和降血糖方面的临床疗效得到了广泛的证实。此外，来自独立小组的BBR已多次报道对大脑功能有有益影响。在这些小组中，两个韩国实验室研究了BBR在动物身上的抗帕金森病效果。一组发现BBR治疗小鼠帕金森病有效，而另一组在大鼠身上获得阴性结果。在差异分析中，第一组给小鼠口服BBR，而第二组给BBR大鼠腹腔注射BBR(腹腔注射)。因此，肠道微生物区系可能是答案。另外，BBR口服给药在肠道吸收较差，且在肠道中浓度较高。想要探索BBR与肠道菌群之间的相互作用，以及BBR连接肠道微生物区系和中枢神经系统(CNS)的化学机制。左旋多巴等主要神经递质成为本研究的研究对象。口服BBR通过触发肠道微生物区系中BH₄的生物合成，提高血液和脑中多巴/多巴胺的浓度，从而增强TH产生L-多巴的活性，并最终改善动物的体能。对临床受试者的途径中间产物的检测证实了BBR在人类中的效果。这一结果可能会为控制肠道和大脑之间的串扰提供新的线索。

多巴胺可能是肠道和大脑之间相互作用的化学联系。BBR调节肠道菌群中苯基-酪氨酸-多巴胺的生物合成可改善脑功能

口服BBR的作用类似于维生素。肠道细菌产生的左旋多巴通过循环进入大脑，并转化为多巴胺。为了验证BBR效应激活的肠-脑轴，将粪肠球菌移植到帕金森病(PD)小鼠体内。细菌可显著增加小鼠脑多巴胺含量，改善帕金森病的临床表现，且BBR与细菌联合治疗效果优于单纯细菌治疗。此外，2，4，6-三甲基吡喃四氟硼酸盐(TMP-TFB)衍生基质辅助激光解吸质谱(MALDI-MS)多巴胺成像证实口服肠球菌感染小鼠脑内纹状体多巴胺水平升高，BBR增强了脑多巴胺的成像强度。这些结果表明，BBR是肠球菌中TH的激动剂，并可导致肠道中左旋多巴的产生。口服BBR可通过肠道细菌增加血/粪中的左旋多巴。因此，BBR可能通过类似维生素的作用上调肠道微生物区系中左旋多巴的生物合成来改善大脑功能。

原文出处：

Wang, Yan et al. “Oral berberine improves brain dopa/dopamine levels to ameliorate Parkinson's disease by regulating gut microbiota.” Signal transduction and targeted therapy vol. 6,1 77. 24 Feb. 2021, doi:10.1038/s41392-020-00456-5

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2022-01-16 楚秀娟

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2021-08-17 yaanren

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createdAvatar=, createdBy=46905128057, createdName=zy&kt, createdTime=Sun Apr 04 23:05:49 CST 2021, time=2021-04-04, status=1, ipAttribution=)]
2021-04-20 闆锋旦

#target#

117 0
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2021-05-22 bsmagic9140

#TRA#

73 0
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2021-04-07 wxy00780

学习了

145 0
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2021-04-06 angelxuqun

太厉害了！一药多用

106 0
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2021-04-05 病毒猎手

#小檗碱#就是#黄连素#，现在泛化，好象啥病都能治疗，事实上它的主要作用是调节#肠道微生物#的，并不能被人体吸收。从#中医#角度，是#清热解毒#作用，因此，慢性病中，凡有#热毒#的，似乎可能都有效，因为它确实可以让肠道微生物的菌**生改变。

240 0
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2021-04-04 zy&kt

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