Aim To investigate the synergistic effect of the combination of pinellia total alkaloid （PTA） and uncaria total alkaloid （UTA）, and explore the mechanism of anticonvulsant action. Methods Anticonvulsant and toxic effect profiles of combinations of PTA with UTA, alone and at three fixed ratios of 1：4, 1 ：1, 4：1, were evaluated in maximal electroshock （MES）-induced seizures and acute toxicity test in mice. Respective ED50 and LD50 were calculated with Bliss＇s method. Their synergistic effect were evaluated by isobolographic analysis and allowed the determination of benefit indices （BI） for respective combinations. The model of convulsive rats kindled by penicillin topically injected into cortex was used to investigated the content of Glu, Asp, Gly and GABA in hippocampus using high performance liquid chromatography （HPLC）. Results Combinations of PTA and UTA at the ratio of 4：1 were synergistic in MES test and antagonistic in acute toxicity test, showing the best profile for combinations of PTA with UTA. In contrast, the ratios of 1 ：4 and 1 ： 1, despite synergistic in MES test, were additive in acute toxicity test. The 4：1 combination and two drugs alone significantly decreased Glu level and increased GABA level in the hippocampus, but the GABA level in the 4：1 combination group was higher than that in the two drugs alone groups. They did not have significant influence on the levels of ASp and Gly. Conclusion Combinations of PTA and UTA at 4：1 ratio demonstrated synergistic effect in anticonvulsant action and antagonistic effect in toxicity. The anticonvulsant mechanism might be related to decreasing the excitability of Glutamatergic neurons and increasing the inhibition of GABAergic neurons.
