Nat Commun:针对“隐形口袋”治疗中风和癫痫

2019-01-30 佚名 生物通

理想的药物只影响确切的细胞和神经元,而不产生不必要的副作用。这一概念对治疗精致复杂的人脑尤为重要。冷泉港实验室的科学家揭示了一种机制,为中风和癫痫特异性治疗指出了一条明路。

理想的药物只影响确切的细胞和神经元,而不产生不必要的副作用。这一概念对治疗精致复杂的人脑尤为重要。冷泉港实验室的科学家揭示了一种机制,为中风和癫痫特异性治疗指出了一条明路。

负责这项研究的资深科学家Hiro Furukawa教授说:“这真的归结于化学。”

当人类大脑受伤时,例如中风,大脑的某些部分就开始酸化,这种酸化导致谷氨酸大量释放。“在NMDA受体受到撞击的部位突然得到更多谷氨酸,导致NMDA受体开始大量燃烧,”Furukawa说。

在健康的大脑中NMDA(N-甲基,D-天冬氨酸)受体负责控制带电原子或离子进出神经元。这些信号的“放电”对学习和记忆形成至关重要。然而,过度活跃的神经元会导致灾难性的后果,如中风、癫痫、抑郁症和阿尔兹海默症,我们在遗传突变个体重,经常观察到异常的NMDA受体活性。

Furukawa团队与埃默里大学的科学家合作,寻找一种在不影响大脑正常区域的情况下防止NMDA受体过度放电的方法。以前的工作确定了一些有希望的化合物,名为93系列。这些化合物在酸性环境中渴望与NMDA受体结合,即使在谷氨酸存在的情况下也可以下调受体活性,从而防止神经元过度放电。

然而,93系列化合物有时会抑制大脑健康部位的NMDA受体,这就是Furukawa和同事们想要改进它的原因。

利用X射线晶体学,研究人员观察到93系列化合物可以插槽入NMDA受体的以前从未被注意到的小口袋,实验表明,这个口袋对周围的酸碱度变化特别敏感。“我们看到了NMDA受体内的酸碱敏感口袋,从而重新设计出了名为94系列的化合物,这样它就可以更有效地适合那个口袋,并且可以获得更高的pH敏感性。”

原始出处:Regan MC, Zhu Z, Yuan H, et al. Structural elements of a pH-sensitive inhibitor binding site in NMDA receptors. Nat Commun. 2019 Jan 18;

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    2020-01-06 liuli5079
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    2019-08-01 liye789132251
  3. [GetPortalCommentsPageByObjectIdResponse(id=2087509, encodeId=11d7208e50950, content=<a href='/topic/show?id=490750196b' target=_blank style='color:#2F92EE;'>#COMMUN#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5019, encryptionId=490750196b, topicName=COMMUN)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7931272, createdName=liuli5079, createdTime=Mon Jan 06 07:57:00 CST 2020, time=2020-01-06, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1883567, encodeId=7668188356e22, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=27, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Thu Aug 01 20:57:00 CST 2019, time=2019-08-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1045832, encodeId=9a36104583211, content=中风是俗称,应该称为缺血性卒中吧, beContent=null, objectType=article, channel=null, level=null, likeNumber=43, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=guging, createdTime=Wed Jan 30 21:57:00 CST 2019, time=2019-01-30, status=1, ipAttribution=)]
    2019-01-30 guging

    中风是俗称,应该称为缺血性卒中吧

    0