Synergistic protection of allopregnanolone and phenobarbital against maximal electroshock seizures in mice
Abstract
Aim: To examine the interactions of allopregnanolone and phenobarbital for the protection against seizures.
Methods: The protective activity of allopregnanolone and/or phenobarbital against seizures was studied in the C57 mice, using the maximal electroshock seizure (MES) test. The modulations by allopregnanolone and/or phenobarbital at the GABA(A) receptor were also characterized using the [3H]flunitrazepam binding in the membrane preparation of mouse cerebral cortex.
Results: Pretreatment with phenobarbital produced a dose-dependent protective effect against seizures. The ED50 value of phenobarbital was 2.61 (95 % confidence limits: 1.59 - 4.26) mg . kg-1. Likewise, the ED50 value of allopregnanolone was 0.11 (0.06 - 0.18) mg . kg-1. The combination of allopregnanolone and phenobarbital (1:20) resulted in an ED50 value of 0.73 (0.44 - 1.21) mg . kg-1 with the Q value smaller than 1. In measuring the enhancement of [3H]flunitrazepam binding, we found that the pattern for the concentration-effect curves of phenobarbital with or without allopregnanolone was consistent with that of the theoretical curves of functional synergism.
Conclusion: There was a synergism between allopregnanolone and phenobarbital for the protective activity against seizures. Also there was a functional synergism between these two agents for the enhancement of [3H]flunitrazepam binding to the GABAA receptor complex in the brain.
Keywords:
Methods: The protective activity of allopregnanolone and/or phenobarbital against seizures was studied in the C57 mice, using the maximal electroshock seizure (MES) test. The modulations by allopregnanolone and/or phenobarbital at the GABA(A) receptor were also characterized using the [3H]flunitrazepam binding in the membrane preparation of mouse cerebral cortex.
Results: Pretreatment with phenobarbital produced a dose-dependent protective effect against seizures. The ED50 value of phenobarbital was 2.61 (95 % confidence limits: 1.59 - 4.26) mg . kg-1. Likewise, the ED50 value of allopregnanolone was 0.11 (0.06 - 0.18) mg . kg-1. The combination of allopregnanolone and phenobarbital (1:20) resulted in an ED50 value of 0.73 (0.44 - 1.21) mg . kg-1 with the Q value smaller than 1. In measuring the enhancement of [3H]flunitrazepam binding, we found that the pattern for the concentration-effect curves of phenobarbital with or without allopregnanolone was consistent with that of the theoretical curves of functional synergism.
Conclusion: There was a synergism between allopregnanolone and phenobarbital for the protective activity against seizures. Also there was a functional synergism between these two agents for the enhancement of [3H]flunitrazepam binding to the GABAA receptor complex in the brain.