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Development of Attenuated Furoxans as Novel Therapies for Alzheimer's Disease

开发减毒呋喃酮作为阿尔茨海默病的新疗法

基本信息

批准号：
10337296
负责人：
Isaac T Schiefer
金额：
$ 38.63万
依托单位：
UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10337296
关键词：
3-nitrotyrosine 3xTg-AD mouse ABCB1 gene AD transgenic mice ADME Study Alzheimer&apos s Disease Alzheimer&apos s disease therapy Amyloid beta-42 Amyloid beta-Protein Animals Attenuated Biological Availability Biological Markers Brain Brain-Derived Neurotrophic Factor Cell Culture Techniques Cells Cerebrovascular Circulation Clinical Cognition Cyclic AMP-Dependent Protein Kinases Cyclic AMP-Responsive DNA-Binding Protein Cyclic GMP Cytoprotection Data Development Disease Dose Drug Design Drug Kinetics Electrophysiology (science)Engineering Exhibits Failure Glucose Glutamates Goals Growth High Pressure Liquid Chromatography Hippocampus (Brain)Histopathology Hypotensives Immunohistochemistry In Vitro Infrastructure Institutes Lead Learning Long-Term Potentiation MAPK3 gene Measures Mediating Medical Memory Memory Loss Memory impairment Metabolic Metabolism Modeling Modernization Molecular Analysis Molecular Structure Monitor Mus Names Neurodegenerative Disorders Neurons Nitrates Nitric Oxide Oral Oxidative Stress Oxygen PC12 Cells Pathway interactions Penetration Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Pharmacotherapy Phase Phosphorylation Plasma Prevalence Production Property Proteins Research Route Science Short-Term Memory Signal Transduction Signaling Protein Slice Soluble Guanylate Cyclase Sulfhydryl Compounds Survival Rate Synaptic Transmission Synaptic plasticity Synthesis Chemistry Systemic blood pressure Testing Therapeutic Intervention Thioflavin S Toxic effect Transgenic Mice Transgenic Organisms Universities Up-Regulation Validation Western Blotting Work acute toxicity analog behavioral outcome blood-brain barrier penetration calmodulin-dependent protein kinase II cholinergic cognitive function cohort combat cost deprivation design drug development efficacy study efficacy validation experimental study fear memory frontier furoxans gene product immunocytochemistry improved in vivo insight intraperitoneal lead optimization mimetics neuroprotection neuroregulation neurorestoration novel novel therapeutics oAβ pharmacokinetics and pharmacodynamics primary outcome scale up screening sex side effect small molecule success synaptic function targeted treatment therapy development transcription factor

项目摘要

Project Summary/Abstract Significant effort has been put toward developing therapies targeted at amyloid-β peptide (Aβ), the hallmark toxic aggregatory protein associated with AD. Unfortunately, Aβ targeted therapies have resulted in several costly Phase III clinical failures. This research focuses on developing novel cognition enhancing agents which do not directly target Aβ but may reverse the effects of Aβ on cognitive function and provide neurorestorative effects by up-regulating neurogenic gene products. Nitric oxide (NO) mimetics activate an intracellular 2nd messenger known as soluble guanylyl cyclase (sGC) leading to increased cyclic GMP (cGMP) production and increased phosphorylation/activation of cAMP response element binding protein- CREB (pCREB). CREB phosphorylation is recognized as being a crucial regulator of synaptic plasticity, resulting in the production of pro-growth gene products, such as brain derived neurotrophic factor (BDNF), and enhanced synaptic transmission. NO/cGMP/CREB signaling is disrupted in AD via Aβ-mediated inhibition of NO-induced CREB phosphorylation and synaptic plasticity. Reversal of Aβ induced memory impairment via agents which activate NO/cGMP signaling results in improved cognitive function. Hence, NO/cGMP activating agents show potential for the treatment of AD. Furoxans are a class of thiol-dependent NO mimetics which may hold potential as novel neurorestorative therapies. Furoxans are distinct because they exhibit `tunable' NO mimetic effects. A unique molecular structure distinguishes furoxans from classical NO mimetic nitrates and makes it possible to engineer molecules with significantly reduced rates of NO mimetic activity. HPLC-MS/MS analysis reveals that furoxan reactivity can be manipulated in a predictable manner to avoid the adverse systemic hypotensive side-effects associated with transient fluxes of NO. Preliminary studies indicate furoxans have good brain penetration, neuroprotective activity, and cognition enhancing effects via NO/cGMP/CREB signaling. This project represents a hit-to-lead optimization campaign for the development of furoxans as novel agents for AD. Our approach includes- 1) synthesis of novel analogs and preliminary screening in PC12 cells for protection against oxidative stress; 2) Counter screening active analogs in a focused in vitro pharmacokinetic battery; 3) validating efficacy to improve synaptic function (ex vivo LTP experiments) and protect primary cortical neurons from Aβ induced toxicity; 4) a focused PK/PD study to define a relationship between orally administered furoxan, unbound furoxan in the hippocampus, and engagement of NO/cGMP signaling. A brief dose escalation study will confirm that furoxans do not affect systemic blood pressure or possess acute toxicity prior to conducting a pilot in vivo efficacy in 3xTg transgenic AD mice. Primary outcomes focus on the ability to improve spatial working and contextual fear memory in 3xTg mice.

项目总结/摘要针对淀粉样β肽（Aβ）的治疗方法已经投入了大量的努力，与AD相关的标志性毒性聚集蛋白。不幸的是，Aβ靶向治疗导致了几次代价高昂的III期临床试验失败这项研究的重点是开发新的认知增强不直接靶向Aβ但可逆转Aβ对认知功能的影响并提供通过上调神经源性基因产物的神经恢复作用。一氧化氮（NO）模拟物激活细胞内第二信使，称为可溶性鸟苷酸环化酶 (sGC)导致增加的环GMP（cGMP）产生和增加的磷酸化/激活 cAMP反应元件结合蛋白- CREB（pCREB）。CREB磷酸化被认为是突触可塑性的重要调节器，导致促生长基因产物的产生，如脑衍生的神经营养因子（BDNF）和增强的突触传递。NO/cGMP/CREB信号传导在AD中通过Aβ介导的抑制NO诱导的CREB磷酸化和突触可塑性而被破坏。通过激活NO/cGMP信号传导的药物抑制Aβ诱导的记忆障碍，改善认知功能。因此，NO/cGMP激活剂显示出治疗AD的潜力。呋咱类药物是一类巯基依赖的NO模拟物，可能具有作为新型神经修复剂的潜力治疗呋咱是独特的，因为它们表现出“可调”的NO模拟效应。独特的分子结构将氧化呋咱与经典的NO模拟硝酸盐区分开来，具有显著降低的NO模拟活性速率的分子。HPLC-MS/MS分析表明，可以以可预测的方式操纵氧化呋咱反应性，与NO瞬时通量相关的副作用。初步研究表明，氧化呋咱具有良好的脑通过NO/cGMP/CREB信号传导的渗透、神经保护活性和认知增强作用。该项目代表了一个命中领先的优化运动的发展，氧化呋咱作为新的代理AD。我们的方法包括：1）新类似物的合成和在PC 12中的初步筛选 2）在体外集中筛选活性类似物; 3）验证改善突触功能的功效（离体LTP实验）和保护原代皮质神经元免受Aβ诱导的毒性; 4）一项重点PK/PD研究，以确定口服氧化呋咱、海马体中未结合氧化呋咱与NO/cGMP参与之间的关系发信号。一项简短的剂量递增研究将证实，氧化呋咱不影响全身血压，在3xTg转基因AD小鼠中进行试验性体内功效之前具有急性毒性。初级结果集中在改善3xTg小鼠的空间工作和背景恐惧记忆的能力。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Fluoxetine as an anti-inflammatory therapy in SARS-CoV-2 infection.

DOI：
10.1016/j.biopha.2021.111437
发表时间：
2021-06
期刊：
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
影响因子：
0
作者：
Creeden JF;Imami AS;Eby HM;Gillman C;Becker KN;Reigle J;Andari E;Pan ZK;O'Donovan SM;McCullumsmith RE;McCullumsmith CB
通讯作者：
McCullumsmith CB

Subcellular partitioning of protein kinase activity revealed by functional kinome profiling.

DOI：
10.1038/s41598-022-21026-5
发表时间：
2022-10-15
期刊：
Scientific reports
影响因子：
4.6
作者：
通讯作者：

Kinome Array Profiling of Patient-Derived Pancreatic Ductal Adenocarcinoma Identifies Differentially Active Protein Tyrosine Kinases.

DOI：
10.3390/ijms21228679
发表时间：
2020-11-17
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Creeden JF;Alganem K;Imami AS;Brunicardi FC;Liu SH;Shukla R;Tomar T;Naji F;McCullumsmith RE
通讯作者：
McCullumsmith RE

The active kinome: The modern view of how active protein kinase networks fit in biological research.