Biological signatures of the cognitive effects of Centella asiatica

积雪草认知影响的生物学特征

• 批准号: 9563219
• 负责人: JOSEPH F QUINN
• 金额: $ 30.2万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9563219
• 关键词: Acids; Adverse effects; Adverse event; Age; Alzheimer' s Disease; Alzheimer' s disease model; Antioxidants; Biogenesis; Biological; Biological Assay; Biological Availability; Blood; Botanicals; Brain; Brain region; Cell Line; Clinical; Clinical Trials; Cognition; Cognitive; Coupled; Creatine; Custom; Deoxyguanosine; Disease Progression; Dose; Drug Kinetics; Elderly; Electron Transport; F2-Isoprostanes; Female; Frequencies; Gender; Gene Expression; Goals; Gotu kola; Half-Life; Hour; Human; Impaired cognition; Impairment; In Vitro; Individual; Ingestion; Institutional Review Boards; Intake; Interview; Liquid Chromatography; Magnetic Resonance Spectroscopy; Maximum Tolerated Dose; Measures; Memory; Memory Loss; Mitochondria; Moods; Mus; N-acetylaspartate; Neurons; Oral; Oral Administration; Outcome Measure; Oxidative Phosphorylation; Oxidative Stress; Participant; Patients; Phase; Phosphocreatine; Placebos; Plasma; Reporting; Response Elements; Rodent; Safety; Sampling; Signal Transduction; Standardization; Testing; Tg2576; Time; Triterpenes; Urine; Water; Wild Type Mouse; amnestic mild cognitive impairment; clinical effect; cognitive testing; dosage; gender difference; improved; in vitro Model; in vivo; inorganic phosphate; magnetic resonance spectroscopic imaging; male; mild cognitive impairment; mitochondrial dysfunction; mouse model; neuroblastoma cell; non-demented; placebo group; preclinical study; spectroscopic imaging; tandem mass spectrometry; treatment group

Centella asiatica (CA) is a botanical remedy, reputed to enhance memory and brain function. Cognitive effects of CA have been reported in rodents and in humans. In our preclinical studies, CA water extract (CAW) improved cognition in both the Tg2576 mouse model of Alzheimer's Disease (AD) and in wild type (WT) mice. CAW upregulated mitochondrial electron transport chain (ETC) gene expression in multiple brain regions of treated mice. In vitro, CAW increased ETC gene expression, ATP levels and oxidative phosphorylation in human neuroblastoma cells and mouse primary neurons. CAW also upregulated antioxidant response element gene expression in these in vivo and in vitro models. Since mitochondrial dysfunction and oxidative stress are strongly associated with disease progression in AD, we hypothesize that CA will reduce cognitive decline in AD patients by increasing brain mitochondrial biogenesis and/or function, and reducing oxidative stress. Active compounds in CA include triterpenes and caffeoylquinic acids (CQAs). Our ultimate goal is to develop a CA product standardized to these actives, as a botanical agent to slow cognitive decline in AD. Towards this goal, the present proposal seeks to (a) identify biological signatures of target engagement by CA in humans (R61 phase) and (b) demonstrate an association of these signatures with a clinical effect on cognition (R33 phase). The R61 project will first examine the pharmacokinetics of CA triterpenes and CQAs, and changes in plasma total antioxidant capacity, following oral intake of a CA product (with known triterpene and CQA content) in 10 cognitively normal, elderly subjects (age 65-85). This will confirm bioavailability of CA compounds and inform dosage decisions. CA product will then be administered, at three escalating doses for four weeks each, to elderly subjects with normal cognition (n=16) and others (n=16) with either amnesic mild cognitive impairment (MCI) or mild AD. Tolerability and adverse events at each CA product dose will be noted. Brain mitochondrial activity will be assessed by measuring N-acetylaspartate and high energy phosphate metabolites using 1H and 31P magnetic resonance spectroscopic imaging (MRSI). Antioxidant status will be measured as plasma and urine 8-hydroxy-2-deoxyguanosine levels. Significant changes from baseline in MRSI signals and/or oxidative status will be considered a biological signature of CA's activity. The subsequent R33 project will compare CA product and placebo, in subjects with MCI/mild AD (n=24 per treatment group). Subjects will receive the maximum tolerated dose giving a biological signal in the R61 study (or placebo) for 24 weeks. Cognitive assessments and plasma F2-isoprostane levels (for antioxidant status) will be evaluated in addition to the R61 biological signatures. We will compare changes in biological signatures induced by CA product versus placebo, and determine their strength of association with any cognitive effects observed. The R61 and R33 phases will include equal numbers of male and female subjects, to assess gender dependent effects of CA. If successful, this project will lead to a larger clinical trial of the cognitive effects of the CA product in MCI or AD subjects.

积雪草（Centella asiatica， CA）是一种植物疗法，以增强记忆和大脑功能而闻名。认知效果