# Neuroprotection of paeoniflorin as antidepressant candidate

## TL;DR

Paeoniflorin shows neuroprotective effects by reducing NMDA-induced excitotoxicity in the hippocampus, suggesting it could be a promising antidepressant.

## Contribution

This study demonstrates paeoniflorin's neuroprotective potential against NMDA-induced excitotoxicity in the hippocampus.

## Key findings

- Paeoniflorin significantly inhibits NMDA-mediated EPSPs by 50%.
- Paeoniflorin reduces intracellular calcium influx by up to 60.68% in hippocampal neurons.
- Molecular docking analysis shows strong binding of paeoniflorin to the NMDA receptor with a binding energy of −48.5188 kcal/mol.

## Abstract

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.

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.

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.

PF binds to the NMDA receptor, exhibits neuroprotection, and contributes to its potential as an antidepressant.