Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA.
J Neurosci. 2012 Apr 11;32(15):5144-50. doi: 10.1523/JNEUROSCI.6437-11.2012.
While polyphenolic compounds have many health benefits, the potential development of polyphenols for the prevention/treatment of neurological disorders is largely hindered by their complexity as well as by limited knowledge regarding their bioavailability, metabolism, and bioactivity, especially in the brain. We recently demonstrated that dietary supplementation with a specific grape-derived polyphenolic preparation (GP) significantly improves cognitive function in a mouse model of Alzheimer's disease (AD). GP is comprised of the proanthocyanidin (PAC) catechin and epicatechin in monomeric (Mo), oligomeric, and polymeric forms. In this study, we report that following oral administration of the independent GP forms, only Mo is able to improve cognitive function and only Mo metabolites can selectively reach and accumulate in the brain at a concentration of ∼400 nM. Most importantly, we report for the first time that a biosynthetic epicatechin metabolite, 3'-O-methyl-epicatechin-5-O-β-glucuronide (3'-O-Me-EC-Gluc), one of the PAC metabolites identified in the brain following Mo treatment, promotes basal synaptic transmission and long-term potentiation at physiologically relevant concentrations in hippocampus slices through mechanisms associated with cAMP response element binding protein (CREB) signaling. Our studies suggest that select brain-targeted PAC metabolites benefit cognition by improving synaptic plasticity in the brain, and provide impetus to develop 3'-O-Me-EC-Gluc and other brain-targeted PAC metabolites to promote learning and memory in AD and other forms of dementia.
虽然多酚化合物有许多健康益处，但多酚作为预防/治疗神经紊乱的潜在药物，其发展受到复杂性的限制，且有关其生物利用度、代谢和生物活性的知识有限，特别是在大脑中。我们最近证明，用特定的葡萄来源的多酚制剂（GP）进行饮食补充，可显著改善阿尔茨海默病（AD）小鼠模型的认知功能。GP 由原花青素（PAC）儿茶素和表儿茶素的单体（Mo）、低聚体和聚合物形式组成。在这项研究中，我们报告说，口服独立的 GP 形式后，只有 Mo 能够改善认知功能，只有 Mo 代谢物才能以约 400 nM 的浓度选择性地到达并积累在大脑中。最重要的是，我们首次报道了一种生物合成的表儿茶素代谢物，3'-O-甲基-表儿茶素-5-O-β-葡萄糖醛酸苷（3'-O-Me-EC-Gluc），这是 Mo 处理后在大脑中发现的 PAC 代谢物之一，可通过与 cAMP 反应元件结合蛋白（CREB）信号相关的机制，在海马切片中以生理相关浓度促进基础突触传递和长时程增强。我们的研究表明，选择性的大脑靶向 PAC 代谢物通过改善大脑中的突触可塑性来改善认知，为开发 3'-O-Me-EC-Gluc 和其他大脑靶向 PAC 代谢物以促进 AD 和其他形式痴呆症的学习和记忆提供了动力。
