Rumex acetosa L. enhance learning and cognitive function by modulating NMDA receptor and BDNF pathways in vitro and in vivo.

Rumex acetosa L. (RA), a member of the Polygonaceae family, is called sorrel and has been used as a vegetable and traditional medicine. RA has various bioactive functions; however, its effects on cognitive function remain unclear. Herein, we investigated the learning- and memory-enhancing effects of RA in rats using the Morris Water Maze (MWM) test. In addition, we evaluated the effect of RA on cognitive function in the hippocampus, both in vitro and in vivo, to identify the underlying molecular mechanisms. RA showed cognitive enhancing effects by activating cyclic AMP-responsive element-binding protein (CREB) via N-methyl-d-aspartate (NMDA) receptor 2 subunits (NR2A and NR2B), postsynaptic density protein-95 (PSD-95) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit (GluA1) signaling in primary cultured rat hippocampal neurons. For the in vivo experiments, RA was orally administered to SD rats for 26 days. RA showed significantly decreased escape latency on the first (acquisition) and last (retention) trials on the 2nd and 3rd training days and increased entry into the platform quadrant of time and distance on the probe trial. Furthermore, RA significantly increased NR2A, NR2B, PSD-95, and GluA1 the following downstream signaling extracellular signal-regulated kinase 1/2 (ERK1/2), calcium/calmodulin-dependent protein kinase II (CaMKII) phosphorylation, and brain-derived neurotrophic factor (BDNF) in the hippocampus. These results demonstrate that RA improves cognitive function, including synaptic plasticity, by regulating the NMDA receptor-dependent and BDNF/CREB signaling pathways.