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Dose-Dependent Modulation of Nmda Receptors: Neuroprotective Mechanisms Against Oxidative Stress in Hippocampal Neurons Publisher



M Nikbakhtzadeh MARJAN ; A Behboudian ASAL ; Ms Mohammadnia Maryam SALEH ; Z Yaghoobi ZAHRA ; S Hosseindoost SAEREH ; A Kheradmand AFSHIN ; G Ashabi GHORBANGOL
Authors

Source: International Journal of Molecular and Cellular Medicine Published:2025


Abstract

N-Methyl-D-Aspartate (NMDA) receptors are involved in synaptic plasticity and neuronal communication. They have various responses to oxidative stress based on the dosage of agonists or antagonists that may be applied. This study focuses on modulation of NMDA receptors in primary hippocampal neurons in oxidative stress condition to understand the effects of NMDA receptor activation and inhibition. In our experiments, primary hippocampal neurons were treated with NMDA and MK-801 to assess their effect on cell viability and apoptosis. Oxidative stress was induced at different concentrations, to evaluate NMDA receptor activity and the neuroprotective effects of MK-801. Apoptosis rates were specified by applying flow cytometry, and assaying caspase-3 activity. Intracellular calcium levels were monitored using fluorescent dye Fura-2 AM. NMDA at 200 μM significantly prevented the cytotoxic effect induced by H2O2 (P<0.001). MK-801 with concentrations of 5 to 20 μM, could reverse the cytotoxic effect of H2O2. As a result, it significantly inhibited the toxicity of H2O2 on neuronal cells (P<0.001), while 40 μM could not reverse its effects. NMDA (200 μM) increased neuronal survival to 88.3% in the presence of H2O2 and prevented apoptosis. MK-801 (5 μM) also elevated cell survival to 87.2%. Treatment with NMDA (200 µM) + H2O2 also did not show any changes in the Fura-2AM fluorescence compared to the H2O2 group (P>0.05). However, MK-801+ H2O2 reduced the effects of H2O2 on the fluorescence ratio and calcium influx considerably in comparison with the H2O2 group (P<0.01). Treatment with MK-801 (5 μM) effectively mitigated the effects of H2O2 on caspase-3 activity compared to the H2O2 group (P<0.001). Importantly, the dose-dependent effects of NMDA receptors offer a new path into finding therapeutic strategies for neurodegenerative diseases. © 2025 Elsevier B.V., All rights reserved.
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