Rendeiro Catarina, Foley Andrew, Lau Vera C, Ring Rebecca, Rodriguez-Mateos Ana, Vauzour David, Williams Claire M, Regan Ciaran, Spencer Jeremy P E
Molecular Nutrition Group, School of Chemistry, Food and Pharmacy, University of Reading, Reading RG6 6AP, UK; School of Psychology and Clinical Language Sciences, University of Reading, Reading RG6 6AL, UK.
Berand Neuropharmacology, NovaUCD, Belfield Innovation Park, UCD, Belfield, Dublin 4, Ireland.
Neuropharmacology. 2014 Apr;79(100):335-44. doi: 10.1016/j.neuropharm.2013.12.003. Epub 2013 Dec 11.
The increase in incidence and prevalence of neurodegenerative diseases highlights the need for a more comprehensive understanding of how food components may affect neural systems. In particular, flavonoids have been recognized as promising agents capable of influencing different aspects of synaptic plasticity resulting in improvements in memory and learning in both animals and humans. Our previous studies highlight the efficacy of flavonoids in reversing memory impairments in aged rats, yet little is known about the effects of these compounds in healthy animals, particularly with respect to the molecular mechanisms by which flavonoids might alter the underlying synaptic modifications responsible for behavioral changes. We demonstrate that a 3-week intervention with two dietary doses of flavonoids (Dose I: 8.7 mg/day and Dose II: 17.4 mg/day) facilitates spatial memory acquisition and consolidation (24 recall) (p < 0.05) in young healthy rats. We show for the first time that these behavioral improvements are linked to increased levels in the polysialylated form of the neural adhesion molecule (PSA-NCAM) in the dentate gyrus (DG) of the hippocampus, which is known to be required for the establishment of durable memories. We observed parallel increases in hippocampal NMDA receptors containing the NR2B subunit for both 8.7 mg/day (p < 0.05) and 17.4 mg/day (p < 0.001) doses, suggesting an enhancement of glutamate signaling following flavonoid intervention. This is further strengthened by the simultaneous modulation of hippocampal ERK/CREB/BDNF signaling and the activation of the Akt/mTOR/Arc pathway, which are crucial in inducing changes in the strength of hippocampal synaptic connections that underlie learning. Collectively, the present data supports a new role for PSA-NCAM and NMDA-NR2B receptor on flavonoid-induced improvements in learning and memory, contributing further to the growing body of evidence suggesting beneficial effects of flavonoids in cognition and brain health.
神经退行性疾病发病率和患病率的上升凸显了更全面了解食物成分如何影响神经系统的必要性。特别是，黄酮类化合物已被认为是有前景的物质，能够影响突触可塑性的不同方面，从而改善动物和人类的记忆与学习能力。我们之前的研究强调了黄酮类化合物在逆转老年大鼠记忆损伤方面的功效，但对于这些化合物在健康动物中的作用知之甚少，尤其是关于黄酮类化合物可能改变导致行为变化的潜在突触修饰的分子机制。我们证明，对年轻健康大鼠进行为期3周的两种膳食剂量黄酮类化合物干预（剂量I：8.7毫克/天和剂量II：17.4毫克/天）可促进空间记忆的获取和巩固（24小时回忆）（p<0.05）。我们首次表明，这些行为改善与海马齿状回（DG）中神经黏附分子多唾液酸化形式（PSA-NCAM）水平的升高有关，而PSA-NCAM是建立持久记忆所必需的。我们观察到，对于8.7毫克/天（p<0.05）和17.4毫克/天（p<0.001）的剂量，含有NR2B亚基的海马NMDA受体同时增加，这表明黄酮类化合物干预后谷氨酸信号增强。海马ERK/CREB/BDNF信号的同时调节以及Akt/mTOR/Arc通路的激活进一步加强了这一点，这些在诱导海马突触连接强度变化（学习的基础）方面至关重要。总体而言，目前的数据支持了PSA-NCAM和NMDA-NR2B受体在黄酮类化合物诱导的学习和记忆改善中的新作用，进一步为越来越多表明黄酮类化合物对认知和大脑健康有益的证据做出了贡献。
