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Neuroprotection of paeoniflorin as antidepressant candidate
Yuh-Fung Chen1,2, Yi-Jui Chen1, Jai-Sing Yang3
1Department of Pharmacology, China Medical University, Taichung City 404328, Taiwan, ROC.
Background:
Depression is one of the common mental disorders worldwide, and currently used antidepressants have undesirable effects; therefore, the development of new antidepressants without side effects is urgently needed. Paeoniflorin (PF) exhibits various pharmacological activities, including anti-inflammatory, antioxidant, and neuroprotective effects. NMDA receptors in the hippocampus play a vital role in the pathophysiology of depression. Due to the scarcity of reports on the neuroprotection of PF on NMDA-induced excitotoxicity in the hippocampus, the present study aims to investigate the effects of PF on NMDA-mediated EPSP and calcium influx in the hippocampus to evaluate the potential of PF as an antidepressant.
Methods:
In order to investigate the effects of PF on the NMDA receptor in the hippocampus, the hippocampal slices, primary-cultured hippocampal neurons, and in silico molecular docking analysis of PF with the NMDA receptor were used.
Results:
PF (2 μM) significantly depressed the NMDA-mediated EPSPs, resulting in a 50 % inhibition. The intracellular calcium level in primary-cultured hippocampal neurons was 102.67 nM, and 520.36 nM after NMDA (125 μM) treatment. With NMDA and PF co-treatment, the calcium level was 204.58 μM, showing a 60.68 % decrease. After NMDA was co-treated with 1 μM ruthenium red (RuR), the calcium level increased (from 534.58 nM to 665.68 nM). Additionally, co-treatment with PF significantly decreased the calcium level (468.05 nM, representing a 29.50 % decrease). In the presence of NMDA and 1 μM ω-conotoxin MVIIC (ω-Cono) co-treatment, the calcium level was 496.29 nM. In the presence of NMDA, ω-Cono, and RuR, the calcium level was 568.5 nM. Additionally, NMDA, ω-Cono, RuR, and PF co-treatment significantly decreased the calcium level to 270.94 nM. In silico molecular docking analysis revealed a binding energy of -48.5188 kcal/mol for PF with the NMDA receptor.
Conclusions:
PF binds to the NMDA receptor, exhibits neuroprotection, and contributes to its potential as an antidepressant.
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