摘要
背景:脑震荡(轻度)和其他中度创伤性脑损伤(TBI)和阿尔茨海默病(AD)有重叠的神经疾病,包括神经元预程序化细胞死亡(Pppd),以及临床损伤和残疾。基于AD的淀粉样蛋白假说的多项临床试验迄今未获成功,表明新药开发是谨慎的。O还寻求与淀粉样蛋白假说无关的机制。为了解决这些问题,我们建议使用脑震荡/TBI动物模型作为AD转基因小鼠的补充。AD候选药物在预防PPCD和导致AD痴呆进展方面的潜力。 方法:对AD的神经病理学进展及其对药物靶识别的影响进行了检索,检索了检索到的Medline/MEDLINE,并参考了所识别的文献。用于评估疾病改变结果的临床试验标准,与AD和脑震荡/TBI相关的血浆生物标志物,神经病理学,特别是PPCD,以及AD等神经精神病学临床试验方法。 结果:我们确定并解决了七个问题,并突出了Thal-Sano AD‘开始损害的时间’设计,以便在我们的临床试验中应用。多样而重要的病理在脑震荡/TBI、缺氧和AD动物模型中发现了自身诱发神经元PPCD的AL级联和指征。AD及脑震荡/脑损伤的外周标志物缺乏的探讨GY和PPCD我们评估了细胞外小泡(EVS)丰富的神经元来源,包括外显子。在我们的脑震荡/TBI,缺氧和AD动物模型中,我们发现了与预期一致的证据。时间依赖性PPCD的NCE和(-)-苯丝氨酸抑制神经元自身诱导的PPCD。因此,我们开发了一种(-)-苯丝氨酸的扩展控释制剂,以提供个性化的剂量素。g和稳定的治疗脑浓度,以药理学审问PPCD作为药物开发的靶点。解决已查明的问题,可能会使任何临床试验面临以下风险:失败后,我们进行了探索性AD和脑震荡/TBI临床试验设计。 结论:我们的发现为神经代代患者的病理目标进展提供了生物标记,并通过神经元保护提出了一种新的方法来满足这些条件。NST自身诱导PPCD。
关键词: 阿尔茨海默病、创伤性脑损伤、脑震荡、细胞外囊泡生物标志物、程序性细胞死亡、(-)-苯丝氨酸、神经变性、神经退行性疾病临床试验设计N,外显子,凋亡。
Current Alzheimer Research
Title:(-)-Phenserine and Inhibiting Pre-Programmed Cell Death: In Pursuit of a Novel Intervention for Alzheimer’s Disease
Volume: 15 Issue: 9
关键词: 阿尔茨海默病、创伤性脑损伤、脑震荡、细胞外囊泡生物标志物、程序性细胞死亡、(-)-苯丝氨酸、神经变性、神经退行性疾病临床试验设计N,外显子,凋亡。
摘要: Background: Concussion (mild) and other moderate traumatic brain injury (TBI) and Alzheimer's disease (AD) share overlapping neuropathologies, including neuronal pre-programmed cell death (PPCD), and clinical impairments and disabilities. Multiple clinical trials targeting mechanisms based on the Amyloid Hypothesis of AD have so far failed, indicating that it is prudent for new drug developments to also pursue mechanisms independent of the Amyloid Hypothesis. To address these issues, we have proposed the use of an animal model of concussion/TBI as a supplement to AD transgenic mice to provide an indication of an AD drug candidate’s potential for preventing PPCD and resulting progression towards dementia in AD.
Methods: We searched PubMed/Medline and the references of identified articles for background on the neuropathological progression of AD and its implications for drug target identification, for AD clinical trial criteria used to assess disease modification outcomes, for plasma biomarkers associated with AD and concussion/TBI, neuropathologies and especially PPCD, and for methodological critiques of AD and other neuropsychiatric clinical trial methods.
Results: We identified and address seven issues and highlight the Thal-Sano AD ‘Time to Onset of Impairment' Design for possible applications in our clinical trials. Diverse and significant pathological cascades and indications of self-induced neuronal PPCD were found in concussion/TBI, anoxia, and AD animal models. To address the dearth of peripheral markers of AD and concussion/TBI brain pathologies and PPCD we evaluated Extracellular Vesicles (EVs) enriched for neuronal origin, including exosomes. In our concussion/TBI, anoxia and AD animal models we found evidence consistent with the presence of time-dependent PPCD and (-)-phenserine suppression of neuronal self-induced PPCD. We hence developed an extended controlled release formulation of (-)-phenserine to provide individualized dosing and stable therapeutic brain concentrations, to pharmacologically interrogate PPCD as a drug development target. To address the identified problems potentially putting any clinical trial at risk of failure, we developed exploratory AD and concussion/TBI clinical trial designs.
Conclusions: Our findings inform the biomarker indication of progression of pathological targets in neurodegenerations and propose a novel approach to these conditions through neuronal protection against self-induced PPCD.
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Cite this article as:
(-)-Phenserine and Inhibiting Pre-Programmed Cell Death: In Pursuit of a Novel Intervention for Alzheimer’s Disease, Current Alzheimer Research 2018; 15 (9) . https://dx.doi.org/10.2174/1567205015666180110120026
DOI https://dx.doi.org/10.2174/1567205015666180110120026 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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