Protective Effect of 2′,3′-Dihydroxy-4′,6′-dimethoxychalcone on Glutamate-Induced Neurotoxicity in Primary Cortical Cultures

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We have previously isolated 2′,3′-dihydroxy-4′,6′-dimethoxychalcone (DDC) from green perilla leaves as the activator of the nuclear factor erythroid 2-related factor 2 (Nrf2)–antioxidant response element (ARE) pathway. This study aims to evaluate the effects of DDC against glutamate neurotoxicity using rat primary cortical cultures. Treatment of cultures with DDC for 24 h before glutamate exposure significantly inhibited glutamate neurotoxicity in a concentration-dependent manner. The involvement of hemeoxygenase-1 (HO-1) and reduced glutathione (GSH) in the protective effects of DDC on cortical cultures was also evaluated. While an HO-1 inhibitor did not have a significant effect on DDC-induced neuroprotection, a γ-glutamylcystein synthetase (γ-GCS) inhibitor significantly suppressed the protective effect of DDC. In an astrocyte culture, DDC induced a marked increase in the levels of intracellular reduced GSH. These results suggest that DDC mainly activates the Nrf2–ARE pathway of astrocytes, resulting in the increased extracellular release of reduced GSH, protecting neurons from glutamate neurotoxicity.