文献精读｜鼻内神经生长因子预防和恢复创伤性脑损伤的结果
文摘
健康
2024-09-26 16:00
湖北
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题目译名：鼻内神经生长因子预防和恢复创伤性脑损伤的结果发表期刊：Neural Regeneration Research.（神经再生研究）1.创伤性脑损伤的结果目前无法通过药物治愈，只能缓解治疗。2.神经生长因子是一种靶向神经元和非神经元细胞的神经营养因子，可能有助于预防/限制创伤性脑损伤的继发性损伤的结果。
3.神经生长因子经鼻给药可以绕过血脑屏障并确保药物通过脑实质快速广泛扩散，到达大脑中的神经营养因子靶点。
4.神经生长因子可以有效作用于创伤后脑损伤进展相关的分子功能障碍。
创伤性脑损伤 （TBI） 是由外部机械力（例如冲击、严重加速/减速和钝力）对大脑造成的突然损伤。迄今为止，还没有针对治疗TBI多种结局的药物治疗方案。根据世界卫生组织的定义，只有缓解治疗的方法通过早期识别、评估和治疗疼痛以及身体、社会心理和精神问题来预防和减轻痛苦，从而改善面临与危及生命疾病有关的问题患者的生活质量。神经生长因子 （NGF） 是一种神经营养肽，主要因其调节外周感觉、交感神经和中枢胆碱能神经元的生长和存活的能力而被发现。五十年的研究表明，NGF还针对中枢神经系统（CNS）中的非神经元细胞群，调节其行为。NGF的这种特性为广泛的临床前和临床研究奠定了基础，旨在研究其治疗神经退行性和神经创伤性疾病的药理学潜力。在过去的二十年中，这种潜力进一步增加，因为已经证明可以通过鼻内给药到达大脑中的神经营养因子靶点，这允许绕过血脑屏障并确保药物通过脑实质快速广泛扩散。自 1980 年以来，临床研究一直在寻求将 NGF 用于治疗周围神经病或 AD 等疾病，为周围和中枢神经系统受损的、NGF 反应性神经元提供营养支持。尽管这些尝试相对失败，主要与药理递送方法的侵入性和潜在有害副作用的发展有关，但最近已经研究了NGF的药理学潜力，首先是眼科病理学，然后是神经创伤的结果。对于后者，开发基于 NGF 的治疗方案的基本原理是基于：NGF 对中枢胆碱能神经元（即神经胶质细胞、免疫细胞和血管内皮细胞）以外的中枢神经系统细胞靶点的作用；内源性NGF对TBI的神经保护作用的临床前和临床证据;使用递送方法（即鼻内接种）靶向中枢神经系统结构的可能性，这保证了低侵入性与令人满意的安全性。
有临床前和临床证据表明，NGF 治疗如何积极影响继发于 TBI 的临床症状的演变。近年来，NGF给药的鼻内途径变得越来越重要，以至于目前它不仅是临床前研究的主题，而且是TBI患者临床试验的主题。表1总结了所有研究鼻内给药NGF对TBI结局影响的手稿。鼻内施用NGF通过嗅神经的前通路和通过三叉神经的后通路有效地扩散到脑实质中。最近的研究已经表明，通过鼻内输送NGF，可以有效地作用于目前所描述的一些与创伤后脑损伤进展相关的分子功能障碍，对于其他一些人来说，仍然有必要开发一条适当的临床前研究路径，然而，这条路径建立在坚实的理性假设之上，这些假设将在下面立即揭示。
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Aβ：β淀粉样蛋白;APP：淀粉样蛋白前体蛋白;Bcl2：B细胞淋巴瘤2;NFT：神经原纤维缠结;NGF：神经生长因子;p75NTR：p75神经营养因子受体;
ROS活性氧：活性氧;TLR4：Toll样受体4;TrkA：原肌球蛋白受体激酶A;VEGF：血管内皮生长因子。
鼻内NGF通过调节不同的神经细胞类型来执行其功能：小胶质细胞（绿细胞），星形胶质细胞（蓝细胞）和神经元（黄色细胞）。
（A）NGF对小胶质细胞（黑色实线）的TrkA攻击促进Aβ肽的清除，减少Aβ积累和斑块介导的细胞毒性作用。此外，TrkA / NGF信号传导（黑色实线）抑制TLR4介导的NF-κB途径的激活（灰色虚线），从而下调促炎细胞因子的释放。
（B）NGF介导的p75激活新台币通过阻断（黑色实线）细胞周期蛋白 D1 介导的细胞周期进展到 S 期（灰色虚线）来干扰星形胶质细胞增殖。
（C）NGF具有促血管生成活性，刺激VEGF的产生和释放。
（D）NGF的细胞膜TrkA激发促进Bcl-2的上调和半胱天冬酶-3的下调，限制线粒体介导的细胞凋亡（黑色实线）。此外，暴露于线粒体膜的TrkA受体的挑战会对Ca产生负面影响2+线粒体进入和ROS生产/释放。
（E） NGF 信号传导限制 tau 超磷酸化，抑制神经原纤维缠结 （NFT） 中的聚集。此外，NGF调节APP磷酸化水平，从而控制APP/TrkA结合，进而通过掩盖β和α分泌酶切割位点，限制Aβ斑块的形成。黑色实线表示NGF对受体攻击的直接作用;灰色虚线表示由NGF作用改变的途径。
鼻内给药NGF （IN-NGF）在TBI临床前模型中（表1）表明，通过这种药理学工具，可以改变疾病的进程，并可能避免不仅折磨患者而且折磨其家人和护理人员的残疾和痛苦的发展。如表1中总结，只有四分之一的临床前研究发现IN-NGF不能有效改善TBI诱导的缺陷。相反，在接受TBI的大鼠中进行IN-NGF可以改善Aβ沉积，运动活性和空间记忆，以减轻脑水肿的形成，同时减少炎性细胞因子的产生和由线粒体对创伤的反应介导的细胞凋亡，以及通过抑制糖原合酶激酶激酶-3β活性来抵消tau的过度磷酸化. 在所有这些研究中，NGF 是在创伤附近（紧接在创伤之前或之后）施用的。到目前为止报告的临床数据是通过治疗创伤几个月后的稳定和慢性症状获得的。该研究强调了IN-NGF如何改善灌注，代谢和脑功能的参数（通过分析脑电图测量），即使在脑损伤和严重残疾的发展之后也是如此。然而，希望未来基于NGF的TBI药理学将被开发为重症监护病房的工具，其中可以利用NGF的神经保护潜力来避免创伤损伤的扩散以及随之而来的严重残疾的发展。迄今为止发表的临床数据显示了IN-NGF如何恢复脑灌注，以及重新激活脑细胞的代谢活动，这种活动在创伤后被削弱。尽管有这些有希望的数据，但单纯的代谢再激活可能不足以恢复连接，从而不足以恢复损伤所涉及的电路的功能。因此，有必要探索鼻内NGF与旨在激活连接特定皮质区域与其皮质下对应物（其中包括皮质纹状体丘脑-皮质环）的回路的疗法之间的关联，以避免或恢复运动和/或认知功能的丧失。目前，通过电流（经颅直流电刺激）或磁电流（经颅磁刺激）的刺激似乎是有希望的，能够改变和/或刺激皮层和特定皮层下区域之间连接的恢复，这种效应可以通过NGF促进的脑代谢和灌注，线粒体功能，神经胶质表型和活性的恢复来促进。
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