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

ABSTRACT

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.

KEYWORDS:

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

Acknowledgements

The authors thank Dr Chia-Hsiang Chen (Chang Gung Memorial Hospital) for providing the vectors with the cDNA of NMDAR subtypes and Dr A-Min Huang (National Cheng-Kung University) for offering the lentiviral related plasmid DNA. C. P. H., H. H C., M. H. C. conceived the study and are responsible for experimental design; C. P. H. performed cell MTT, calcium image, electrophysiology experiments and data analysis; L. C. participated in the neuronal culture; W. T. C. prepared cells expressing NMDAR; C. P. H. prepared the figures and drafted the manuscript; M. H. C., H. H C. edited the manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Ethics approval

All experiments in animal studies were approved by Institutional Animal Care and Use Committee of the National Health Research Institutes (NHRI-IACUC-102038-A).

Additional information

Funding

This work was supported by National Health Research Institutes [grant number NP-106-PP05].