Using the patch-clamp technique, we studied the modulation of ionotropic gamma-aminobutyric acid (GABA) and glutamate neurotransmission by apigenin, a flavonoid with sedative and antidepressant activity. Apigenin reversibly reduced GABA-evoked currents mediated by alpha1beta2gamma2 receptors expressed in HEK293 cells. Amplitude and frequency of spontaneous postsynaptic inhibitory currents (sIPSCs) mediated by GABA(A) receptors were also decreased by apigenin in cultured cortical neurons. The flavonoid was almost inactive on alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA) mediated currents while it reduced N-methyl-D-aspartate (NMDA) receptor mediated responses with a half maximal inhibiting concentration (IC50) of 10 microM. The flavonoid inhibited also peak amplitude and frequency of spontaneous postsynaptic excitatory currents (sEPSCs). Finally, apigenin is neuroprotective against glutamate-induced neurotoxicity in cerebellar and cortical neurons in culture. Our data reveal the antagonistic effect of apigenin on GABA and NMDA channels. While the inhibition on GABA receptor cannot explain the effects of the drug in vivo our data on NMDA channels reveal a new target of apigenin. A reduction of the network excitability could thus account for the sedative effects. Furthermore, our data suggest a potential neuroprotective activity of apigenin.