The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
Harrington Discovery Institute, University Hospital Case Medical Center, Department of Psychiatry Case Western Reserve University, Geriatric Research Education and Clinical Centers, Louis Stokes Cleveland VAMC, Cleveland, OH, 44106, USA.
Neuropharmacology. 2019 Feb;145(Pt B):268-282. doi: 10.1016/j.neuropharm.2018.09.024. Epub 2018 Sep 17.
Traumatic brain injury (TBI) is a significant public health problem around the world. A promising area of research is the characterization of small, drug-like molecules that have potent clinical properties. One pharmacotherapeutic agent in particular, an aminopropyl carbazole called P7C3, was discovered using an in vivo screen to identify new agents that augmented the net magnitude of adult hippocampal neurogenesis. P7C3 greatly enhanced neurogenesis by virtue of increasing survival rates of immature neurons. The potent neuroprotective efficacy of P7C3 is likely due to enhanced nicotinamide phosphoribosyltransferase (NAMPT) activity, which supports critical cellular processes. The scaffold of P7C3 was found to have favorable pharmacokinetic properties, good bioavailability, and was nontoxic. Preclinical studies have shown that administration of the P7C3-series of neuroprotective compounds after TBI can rescue and reverse detrimental cellular events leading to improved functional recovery. In several TBI models and across multiple species, P7C3 and its analogues have produced significant neuroprotection, axonal preservation, robust increases in the net magnitude of adult neurogenesis, protection from injury-induced LTP deficits, and improvement in neurological functioning. This review will elucidate the exciting and diverse therapeutic findings of P7C3 administration in the presence of a complex and multifactorial set of cellular and molecular challenges brought forth by experimental TBI. The clinical potential and broad therapeutic applicability of P7C3 warrants much needed investigation into whether these remedial effects can be replicated in the clinic. P7C3 may serve as an important step forward in the design, understanding, and implementation of pharmacotherapies for treating patients with TBI. This article is part of the Special Issue entitled "Novel Treatments for Traumatic Brain Injury".
创伤性脑损伤（TBI）是全球范围内一个重大的公共卫生问题。一个有前途的研究领域是对具有潜在临床特性的小分子药物的特征描述。特别是一种叫做 P7C3 的氨基丙基咔唑的药物，是通过体内筛选发现的，目的是鉴定能增加成年海马神经发生净幅度的新药物。P7C3 通过提高不成熟神经元的存活率，极大地增强了神经发生。P7C3 具有强大的神经保护作用，可能是由于其增强了烟酰胺磷酸核糖转移酶（NAMPT）的活性，从而支持了关键的细胞过程。发现 P7C3 的支架具有良好的药代动力学特性、良好的生物利用度和非毒性。临床前研究表明，TBI 后给予 P7C3 系列神经保护化合物可以挽救和逆转导致功能恢复的有害细胞事件。在几种 TBI 模型和多个物种中，P7C3 及其类似物已产生显著的神经保护、轴突保存、成年神经发生净幅度的显著增加、防止损伤诱导的长时程增强缺陷以及神经功能的改善。这篇综述将阐明 P7C3 在实验性 TBI 引起的复杂和多因素的细胞和分子挑战下的给药的令人兴奋和多样化的治疗发现。P7C3 的临床潜力和广泛的治疗适用性需要进一步研究，以确定这些补救作用是否可以在临床上复制。P7C3 可能是设计、理解和实施治疗 TBI 患者的药物治疗的重要一步。本文是“创伤性脑损伤的新疗法”特刊的一部分。
