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(-)-Phenserine tartrate (PhenT) as a treatment for traumatic brain injury.
CNS Neuroscience & Therapeutics ( IF 4.8 ) Pub Date : 2019-12-11 , DOI: 10.1111/cns.13274
Nigel H Greig,Daniela Lecca,Shih-Chang Hsueh,Carlos Nogueras-Ortiz,Dimitrios Kapogiannis,David Tweedie,Elliot J Glotfelty,Robert E Becker,Yung-Hsiao Chiang,Barry J Hoffer

AIM Traumatic brain injury (TBI) is one of the most common causes of morbidity and mortality of both young adults and the elderly, and is a key contributing factor in about 30% of all injury-associated deaths occurring within the United States of America. Albeit substantial impact has been made to improve our comprehension of the mechanisms that underpin the primary and secondary injury stages initiated by a TBI incident, this knowledge has yet to successfully translate into the development of an effective TBI pharmacological treatment. Developing consent suggests that a TBI can concomitantly trigger multiple TBI-linked cascades that then progress in parallel and, if correct, the multifactorial nature of TBI would make the discovery of a single effective mechanism-targeted drug unlikely. DISCUSSION We review recent data indicating that the small molecular weight drug (-)-phenserine tartrate (PhenT), originally developed for Alzheimer's disease (AD), effectively inhibits a broad range of mechanisms pertinent to mild (m) and moderate (mod)TBI, which in combination underpin the ensuing cognitive and motor impairments. In cellular and animal models at clinically translatable doses, PhenT mitigated mTBI- and modTBI-induced programmed neuronal cell death (PNCD), oxidative stress, glutamate excitotoxicity, neuroinflammation, and effectively reversed injury-induced gene pathways leading to chronic neurodegeneration. In addition to proving efficacious in well-characterized animal TBI models, significantly mitigating cognitive and motor impairments, the drug also has demonstrated neuroprotective actions against ischemic stroke and the organophosphorus nerve agent and chemical weapon, soman. CONCLUSION In the light of its tolerability in AD clinical trials, PhenT is an agent that can be fast-tracked for evaluation in not only civilian TBI, but also as a potentially protective agent in battlefield conditions where TBI and chemical weapon exposure are increasingly jointly occurring.

中文翻译:

(-)-Phenserine tartrate (PhenT) 作为外伤性脑损伤的治疗方法。

AIM 创伤性脑损伤 (TBI) 是导致年轻人和老年人发病和死亡的最常见原因之一,并且是美国境内发生的所有与伤害相关的死亡中约 30% 的关键促成因素。尽管对提高我们对由 TBI 事件引发的原发性和继发性损伤阶段的机制的理解产生了重大影响,但这些知识尚未成功转化为有效的 TBI 药物治疗的开发。发展同意表明 TBI 可以同时触发多个 TBI 相关级联,然后并行进展,如果正确,TBI 的多因素性质将使发现单一有效机制靶向药物的可能性不大。讨论 我们回顾了最近的数据,表明最初为阿尔茨海默病 (AD) 开发的小分子量药物 (-)-酒石酸苯丝氨酸 (PhenT) 可有效抑制与轻度 (m) 和中度 (mod) TBI 相关的广泛机制,这结合起来支持随之而来的认知和运动障碍。在临床可转化剂量的细胞和动物模型中,PhenT 减轻了 mTBI 和 modTBI 诱导的程序性神经元细胞死亡 (PNCD)、氧化应激、谷氨酸兴奋性毒性、神经炎症,并有效逆转了导致慢性神经变性的损伤诱导基因通路。除了在充分表征的动物 TBI 模型中证明有效,显着减轻认知和运动障碍,该药物还显示出对缺血性中风和有机磷神经毒剂和化学武器索曼的神经保护作用。结论 鉴于其在 AD 临床试验中的耐受性,PhenT 是一种不仅可以在民用 TBI 中进行快速评估的药剂,而且在 TBI 和化学武器暴露越来越多地同时发生的战场条件下也可以作为潜在的保护剂.
更新日期:2019-12-11
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