Can a permanent damaged brain be repairable in the phase of chronic stroke
Can a permanent damaged brain be repairable in the phase of chronic stroke
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慢性中风阶段永久性受损的大脑可以修复吗
DOI：
10.4172/2168-975x.s1.003
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Zhao LiRu
中科院分区：
文献类型：
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作者：
Zhao LiRu
S 和创伤性脑损伤 (TBI) 是全球人类死亡和残疾的主要原因。不幸的是，针对中风和创伤性脑损伤患者的有效治疗方法很少。大多数先前和当前的实验治疗都集中在影响一种信号通路、调节单个膜蛋白/通道/受体（例如 NMDA 受体）或针对一种类型的细胞死亡机制（例如细胞凋亡）。近年来，许多使用这些方法的临床试验均以失败告终，人们达成了这样的共识：一种疗法要想有效治疗脑缺血和创伤性脑损伤等复杂的中枢神经系统疾病，就需要对多种途径和多种细胞类型产生压倒性的保护作用。迄今为止，对于急性中风/TBI患者还没有真正多方面且临床可行的治疗方法。然而，一种潜在的疗法因其对大脑、心脏和其他器官的多功能保护作用而脱颖而出：低温疗法。在动物和人类研究中，轻至中度低温显示出显着的针对脑缺血的神经保护作用（梗塞减少高达 90%）。现有的物理降温技术的一些缺点是速度慢（约 3 小时）且不实用，这阻碍了低温治疗的临床应用。因此，长期以来一直在寻求可用于低温治疗的化合物用于临床治疗。使用药物诱导的低温，预计即使体温小幅下降（1-2°C）也有利于预防有害的损伤后高热，延缓继发性损伤的发展，并随后延长其他干预措施的治疗窗口。我们开发了ABS201、ABS601和ABS363等新型神经降压素衍生物，它们可以穿过血脑屏障诱导“调节性低温”，在30分钟左右将身体和大脑温度降低3-5°C，而不会引起颤抖。系统研究、血液测试和尸检显示这些化合物没有毒性或副作用。缺血后施用这些化合物可显着减轻缺血引起的神经细胞死亡、血脑屏障损伤并改善功能恢复。在小鼠出血性中风模型中，中风发作 24 小时后施用 ABS201 仍显示出显着的神经保护和功能益处。我们最近的研究还显示了药物引起的低温对 TBI 的保护作用。因此，这些化合物提供了一种充分利用低温治疗但没有明显副作用的新疗法。药物低温有望成为全球脑保护药物的新类别，有助于将化学/药物低温疗法转化为临床应用。
S and traumatic brain injury (TBI) are leading cause of human death and disability across the globe. Unfortunately, there are very few effective therapies for stroke and TBI patients. Most previous and current experimental treatments have focused on affecting one signaling pathway, regulating an individual membrane protein/channel/receptor (e.g. NMDA receptor) or targeting one type of cell death mechanism (e.g. apoptosis). The failure of many clinical trials that have used these approaches in recent years has generated the consensus that for a therapy to be effective against complicated CNS disorders such as cerebral ischemia and TBI, it requires overwhelming protective effects on multiple pathways and multiple cell types. So far, there has been no therapy that is truly multifaceted and clinically feasible for acute stroke/TBI patients. One potential therapy, however, stands out for its versatile protective effects on the brain, heart and other organs: Hypothermia therapy. Mild-to-moderate hypothermia has shown remarkable neuroprotective effects (up to 90% infarct reduction) against brain ischemia in animal and human studies. Some of the drawbacks to available cooling techniques of physical means are that they are slow (3 hrs) and not practical, which have hampered clinical applications of hypothermia therapy. Thus, chemical compounds that can be utilized for hypothermia therapy have long been sought after for clinical treatments. Using drug-induced hypothermia, it is expected that even a small drop in body temperature (1-2°C) is beneficial for preventing the detrimental post-injury hyperthermia, delay the evolution of the secondary injury, and thereafter extend the therapeutic window for other interventions. We have developed novel neurotensin derivatives such as ABS201, ABS601, and ABS363 that can pass through the blood-brain barrier to induce “regulated hypothermia”, reducing body and brain temperature by 3-5°C in around 30 min without causing shivering. Systemic studies, blood tests, and autopsy examinations showed no toxic or adverse effects of these compounds. Post-ischemic administration of these compounds markedly attenuates ischemiainduced neuronal cell death, blood-brain barrier damage and improved functional recovery. In a hemorrhagic stroke model of the mouse, ABS201 administration 24 hrs after the onset of stroke still showed significant neuroprotection and functional benefits. Our recent investigation also showed protective effects of drug-induced hypothermia against TBI. These compounds thus provide a novel therapy that takes full advantage of therapeutic hypothermia but with no obvious side effects. It is expected that drug-induced hypothermia can be developed as a new category of global brain protection drugs and help to translate the chemical/pharmacological hypothermic therapy into clinical applications.