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Nutr Neurosci. 2019 Jul 22:1-16. doi: 10.1080/1028415X.2019.1641995. [Epub ahead of print]

Differential inhibitory effects of resveratrol on excitotoxicity and synaptic plasticity: involvement of NMDA receptor subtypes.

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a Center for Neuropsychiatric Research, National Health Research Institutes , Zhunan , Taiwan.
b Institute of Molecular Medicine, National Tsing Hua University , Hsinchu , Taiwan.
c Institute of Neuroscience, National Chengchi University , Taipei , Taiwan.
d Research Center for Mind, Brain and Learning, National Chengchi University , Taipei , Taiwan.


Objectives: The neuroprotective effects of resveratrol against excitatory neurotoxicity have been associated with N-methyl-D-aspartate receptor (NMDAR) inhibition. This study examined the differential inhibitory effects of resveratrol on NMDAR-mediated responses in neuronal cells with different NMDAR subtype composition. Methods: The effects of resveratrol on NMDA-induced cell death and calcium influx in immature and mature rat primary cortical neurons were determined and compared. Moreover, the potencies and efficacies of resveratrol to inhibit NR1/NR2A, NR1/NR2B, NR1/NR2C, and NR1/NR2D NMDAR expressed in HEK 293 cells were evaluated. Results: Resveratrol significantly attenuated NMDA-induced cell death in mature neurons, but not in immature neurons. Resveratrol also concentration-dependently reduced NMDA-induced calcium influx among all NMDAR subtypes, but displayed NR2 subunit selectivity, with a potency rank order of NR2B = NR2D > NR2A = NR2C and an efficacy rank order of NR2B = NR2C > NR2A = NR2D. Data show the stronger inhibitory effects of resveratrol on NR1/NR2B than other subtypes. Moreover, resveratrol did not affect hippocampal long-term potentiation (LTP), but impaired long-term depression (LTD). Discussion: These findings reveal the specific NMDAR modulating profile of resveratrol, providing further insight into potential mechanisms underlying the protective effects of resveratrol on neurological disorders.


Cortical neuron; LTD; LTP; NMDAR subtypes; calcium; hippocampus; neurotoxicity; resveratrol

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