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J Neurosci：CRISPR介入抑郁症疗法，将开发副作用更小的药物

2018-08-23 浮苏 生物探索

CRISPR介入抑郁症副作用药物
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据估计，13 %的美国人服用抗抑郁药物对抗抑郁、焦虑、慢性疼痛或睡眠问题。然而对于1400万患有临床抑郁症的美国人来说，近三分之一得不到相关药物的缓解。近日，华盛顿大学医学院的研究人员正尝试一种基于CRISPR技术的新方法来缓解抑郁症。


图为大脑海马区的一个染有染料的神经元。研究人员正在测试神经甾体药物如何与这些神经元上的GABA受体结合，以开发更好的抗抑郁药物。神经甾体药物brexanolone是FDA批准的治疗产后抑郁症的药物。图片来源： Mennerick实验室

这一最新研究以“Chemogenetic isolation reveals synaptic contribution of δ GABAA receptors in mouse dentate granule neurons”为题发表在《Journal of Neuroscience》杂志上。精神病学教授Steven Mennerick说:“30多年前，FDA批准了最常用的抗抑郁药物，例如百忧解、帕罗西汀和左洛复。然而自那以后，新的抗抑郁药物就一直缺乏。因此开发更有效的抗抑郁药物势在必行。”



血清素是一种被认为可以调节情绪和社会行为的化学物质，大多数抗抑郁药物都通过靶向血清素受体来增强血清素水平。使用CRISPR技术，科学家能够靶向一种称为δ型的GABA受体。

GABA是中枢神经系统里的一种主要的递质，可能有助于减缓一些导致重度消极想法和感觉的认知过程。一些类型的GABA受体与焦虑有关，瞄准δ型GABA受体有助于缓解抑郁，尽管许多科学家已经将这些受体视为抑郁的潜在靶标，但是开发选择性结合特定类型GABA受体的化合物使研究变得复杂。

在这项新研究中，科学家们使用一种名为神经甾体的物质来靶向GABA受体，前者自然存在于大脑中，参与情感和动机的大脑网络。Mennerick解释道，“神经甾体被认为有选择地与δ型受体相互作用，有证据表明神经类固醇药物可能有助于抑郁症患者。”

Mennerick及其同事关注位于大脑海马体（大脑中参与学习和记忆的一部分）神经元上的GABA受体。使用CRISPR，他们突变了δ型GABA受体，以分离和测试它们在大脑功能中的作用。

早期研究表明，靶向这些受体可以减轻患有严重产后抑郁症的妇女的抑郁症状。去年夏天，《柳叶刀》杂志发表了一项治疗产后抑郁症的神经甾体类药物brexanolone的试验结果。对21名女性的研究表明，服用该药物的女性抑郁症状明显改善。



在目前的研究中，通过在细胞培养物和小鼠中测试相同的化合物，Mennerick的团队探索了这种药物是否通过δ型GABA受体发挥作用。

需要指出的是，这些药物能够影响GABA受体，但似乎也具有抗炎性质，研究人员认为这可能是在激活这些受体的同时减轻炎症的特殊组合，从而发挥抗抑郁作用。

Min-Yu Sun博士透露，研究小组下一步计划测量神经甾体对各种GABA受体亚型的作用。

“很难区分不同类型的GABA受体，因为它们有许多共同特性，”Sun说，“以前，科学家没有办法分离这些亚型，但是我们可以通过CRISPR / Cas9基因编辑技术来了解特定药物如何影响各个受体亚型。”

Mennerick解释说，如果进一步的研究证实激活δ型受体具有抗抑郁作用，下一步将是开发和测试更多激活这些受体的化合物。他指出，突变小鼠给了他们开发更有效的药物所需的工具，这些药物将更具选择性，副作用更少。

原始出处;

Min-Yu Sun, Hong-Jin Shu, Ann Benz, et.al. Chemogenetic isolation reveals synaptic contribution of δ GABAA receptors in mouse dentate granule neurons. Journal of Neuroscience 3 August 2018, 0799-18; DOI: https://doi.org/10.1523/JNEUROSCI.0799-18.2018

Stephen Kanes, Helen Colquhoun, et.al. Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial. The Lancet June 12, 2017

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    2019-01-12 showtest

    #副作用#

    0

  2. [GetPortalCommentsPageByObjectIdResponse(id=1824296, encodeId=e6c118242964f, content=<a href='/topic/show?id=56a932e7800' target=_blank style='color:#2F92EE;'>#副作用#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=32778, encryptionId=56a932e7800, topicName=副作用)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=8f0715, createdName=showtest, createdTime=Sat Jan 12 18:43:00 CST 2019, time=2019-01-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=342482, encodeId=fcac342482fd, content=学习一下, beContent=null, objectType=article, channel=null, level=null, likeNumber=58, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6KcicAVC1MwuOgo3iaicb1Imgk1yIfnvr6oXzibcAFB6puAyNJXbzWhNuLqaFYBVRWjh7rghkvFLPxMAfD5ib3nXwVD/0, createdBy=bed21972958, createdName=wxl882001, createdTime=Mon Sep 03 18:08:13 CST 2018, time=2018-09-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1276092, encodeId=adbb12e609282, content=<a href='/topic/show?id=755d5211a0' target=_blank style='color:#2F92EE;'>#CRISPR#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5211, encryptionId=755d5211a0, topicName=CRISPR)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=583c133, createdName=yuandd, createdTime=Sat Aug 25 04:43:00 CST 2018, time=2018-08-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1364372, encodeId=c12913643e263, content=<a href='/topic/show?id=7c5615628ad' target=_blank style='color:#2F92EE;'>#ROS#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=41, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=15628, encryptionId=7c5615628ad, topicName=ROS)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=acc3210, createdName=lsndxfj, createdTime=Sat Aug 25 04:43:00 CST 2018, time=2018-08-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=340368, encodeId=481034036862, content=抑郁症的药物治疗。, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://cdnapi.center.medsci.cn/medsci/head/2018/07/16/3b24606172648eea459125cb74754afe.jpg, createdBy=6c022216608, createdName=liumin1987, createdTime=Thu Aug 23 14:18:44 CST 2018, time=2018-08-23, status=1, ipAttribution=)]
    2018-09-03 wxl882001

    学习一下

    0

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    2018-08-25 yuandd

    #CRISPR#

    0

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    2018-08-25 lsndxfj

    #ROS#

    0

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    2018-08-23 liumin1987

    抑郁症的药物治疗。

    0

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使用CRISPR基因编辑技术在实验鼠中开发“基因驱动”，可用于消除对人类有害的动物群体。近日，一项颇具争议、能够改变整个物种基因组的技术首次被应用到哺乳动物身上。此次研究再次引来各路专家对基因驱动技术的热议。