The protective effect of magnolol, a component of Magnolia officinalis, against hypoxia-induced cell injury in cortical neuron-astrocyte mixed cultures was examined. Exposure of the cells to chemical hypoxia (0.5 mM KCN) produced morphological changes in neurons but not in astrocytes. KCN induced dose- and time-dependent increases in release of LDH and decreases in viable cell number. Treatment with magnolol (10 and 100 microM) significantly reduced the KCN-induced LDH release in a concentration-dependent manner. A higher concentration (750 microM) magnolol was toxic. Nuclear condensation was not observed in KCN-treated cells, suggesting that chemical hypoxia-induced cell death was via necrosis, rather than via apoptosis. This is the first report demonstrating that magnolol protects neurons against chemical hypoxic damage or necrotic cell death in cortical neuron-astrocyte mixed cultures.