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神经炎症:自闭症癫痫的新的治疗思路

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发表于 2019-1-3 01:09:59 | 显示全部楼层 |阅读模式
背景

自闭症谱系障碍(Asd)是一种普遍存在的神经发育障碍,影响1/100的儿童,在社交技巧上有困难,语言、学习障碍、注意力不集中和刻板行为,约有22-30%的自闭症儿童有无特定病理基础的癫痫发作,没有明显或典型的脑电图改变. 这些自闭症发作率比一般人群高出约十倍。然而这种高比率在其他神经系统疾病如精神分裂症中缺没有发现.

最近的证据表明,神经炎症可能导致癫痫发作。最近研究认为,这可能与环境或应激触发引起的脑肥大细胞活化导致的过敏有关。过敏能导致血脑屏障的局部破坏和神经炎症,从而促发癫痫的发病,当抗癫痫药物无效时,治疗神经炎症可能是有用的。

事实上,ASD与某些免疫功能紊乱有关,例如针对胎儿大脑的抗体水平升高,提示血脑屏障破裂。最近的一篇孤独症项目的文章报道有42%的3岁自闭症儿童存在小脑神经元GABA蛋白血浆抗体,提示它们可能构成ASD的易感亚型。此外,ASD患者大脑中IL-6的表达增高,血清IL-6升高与小鼠孤独症表型的表达有关。

有新的证据表明环境对ASD发病机制有重要意义 .许多ASD患者患有食物过敏. 此外,25%的儿童患有“过敏样”症状。但非过敏触发激活肥大细胞的实验研究 ,包括汞,往往没有积极的皮肤或RAST测试结论。

许多研究表明肥大细胞在先天免疫和获得性免疫中的重要性, 包括炎症 . 来自肠道和大脑的物质可触发肥大细胞释放过敏介质这可能会破坏肠道屏障和血脑屏障(BBB),从而有助于自闭症的发病机制 . 许多介质,如IL-6,可以“选择性”地从肥大细胞中释放出来, 进行组织学评价是不可能的

更重要的是,肥大细胞与癫痫的发病机制有关。一项使用老鼠模型的研究表明非过敏肥大细胞化合物显著增加电击致小鼠的惊厥率,这种效应在肥大细胞缺失小鼠中被消除 . 此外,肥大细胞触发神经降压素(NT) 能促进N-甲基-D-天冬氨酸(NMDA)刺激皮层神经元导致啮齿类动物的癫痫发作.而自闭症儿童神经降压素NT升高, 并被认为是自闭症的一个可能的治疗靶点.
肥大细胞增多症的儿童,皮肤过敏、腹泻、学习障碍,多动症、聚焦困难症(雾脑)并存在,这让人联想到ASD . 事实上,肥大细胞增多症儿童比一般人多10倍的ASD患病率(肥大细胞增多症儿童为1/10的ASD患病率,一般人为1/100.

有趣的是,肥大细胞增多症患者也有较高的血清IL-6水平,这与癫痫发作和发展正相关.此外,肥大细胞瘤会产生类似于癫痫发作的症状.

假说

免疫功能障碍和炎症出现改变血脑屏障完整性。最近的证据表明,血脑屏障的完整性,尤其是白细胞-内皮细胞粘附也可能参与癫痫的发病机制,一种被称为“免疫学:电风暴障碍”的现象.而肥大细胞被认为是“通往大脑的门”.

ASD患者容易受到压力影响,产前压力与自闭症的风险有关. 大脑,特别是下丘脑,含有许多肥大细胞,这些肥大细胞位于血脑屏障周围,这种压力激活大脑肥大细胞导致BBB破坏.此外,应激下分泌的促肾上腺皮质激素释放激素(CRH),能激活肥大细胞。脑肥大细胞也有助于偏头痛的发病机制,这增加了癫痫发作的可能性。脑肥大细胞的局部活化可能导致血脑屏障的局灶性破坏,局灶性神经炎症可能成为致痫部位(图1 ).这个过程可能通过神经元相应受体 (FcgRI) 激活,该受体经红藻氨酸刺激后致痫并导致大脑细胞死亡。

再者FcεRI受体,通常认为只存在于肥大细胞和嗜碱性粒细胞表面,而最近在神经元上也被发现提示过敏性刺激甚至可能直接影响神经元,一旦血脑屏障被破坏,免疫球蛋白即可进入大脑,最近发表的一篇文章报道,自闭症患者血清高迁移率族蛋1 (HMGB1) 水平升高 . HMGB1在神经毒性刺激后由神经元释放。最近证明它是一种促癫痫的途径,通过激活小鼠Toll样受体(TLR-4) 。

研究也发现肥大细胞的激活会导致线粒体易位到细胞表面 ,在细胞外检测到线粒体mtDNA 研究也发现,自闭症儿童血清中存在细胞外线粒体DNA水平升高的现象 ,损伤相关的分子模式DAMPs,其中包括从受损的细胞释放的线粒体DNA,据报道,可以通过激活Toll样受体而导致自身炎症 .线粒体DNA也被认为是直接的神经毒性分子并且改变小鼠的行为 .

黄酮复合物在神经炎症中的应用

抗惊厥药物在ASD和肥大细胞增多症患者的发作往往是无效的 . 因此,使用针对ASD核心症状,或脑肥大细胞激活和炎症,的治疗方法是非常重要的 .研究发现,黄酮类,可能是有用的,因为他们的抗氧化和抗炎功效.

木犀草素是菊花和洋甘菊中的一种黄酮类化合物。越来越多的证据表明木犀草素具有很强的抗氧化作用,自由基清除剂,抗炎及肥大细胞抑制活性. 此外,木犀草素抑制小胶质细胞IL-6的释放,同时模仿脑源性神经营养因子的活性(BDNF) . 木犀草素还能抑制小鼠的类孤独症样行为.

木犀草素还能抑制肥大细胞对活化T细胞的刺激,以及抑制炎症性疾病多发性硬化患者外周血单个核细胞的活化. 此外,柑橘果肉和果皮中发现的结构与黄酮类似物,槲皮黄素,也是一种强效的肥大细胞抑制剂具有抗癫痫作用,

天然糖苷芦丁同样也具备这样的功能 .因此木犀草素,对于炎症的治疗可能是有用的,包括ASD儿童的癫痫发作,尤其在口服吸收生物有效性足够的配方中应用。



肥大细胞位于血管周围接近神经末梢和调节血脑屏障的通透性。过敏性和非免疫性刺激引起的刺激(如CRH、神经降压素、汞、线粒体DNA),肥大细胞释放血管舒张和炎症分子(IL-6、线粒体DNA、肿瘤坏死因子和血管内皮生长因子VEGF),其中一些增强了血管内皮细胞粘附分子的表达(VCAMs) 并允许排出脑内循环淋巴细胞,局灶性脑炎症可能导致或加重癫痫发作。

意义

总之,证据表明肥大细胞的活化,癫痫发作,炎症反应之间可能存在的关联,通过促炎症介质和分泌调节血脑屏障的渗透性肥大细胞功能抑制剂,尤其是抑制NT作用的抑制剂,如木犀草素,可能成为治疗孤独症和相关癫痫发作的新的治疗药物。


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