Rainer Surges1, Thomas M Freiman, Thomas J Feuerstein. 1. Department of Neurology, Section of Clinical Neuropharmacology, Neurozentrum, University of Freiburg, Germany. surges@nz.ukl.uni-freiburg.de
Abstract
PURPOSE: Gabapentin (GBP) is a commonly used drug in the treatment of partial seizures, but its mode of action is still unclear. The genesis of seizures in temporal lobe epilepsy is thought to be crucially influenced by intrinsic membrane properties. Because the Ih substantially contributes to the intrinsic membrane properties of neurons, the effects of GBP on the Ih were investigated in CA1 pyramidal cells of rat hippocampus. METHODS: CA1 pyramidal cells in hippocampal slices were examined by using the whole-cell patch-clamp technique. RESULTS: GBP increased the Ih amplitude in a concentration-dependent manner mainly by increasing the conductance, without significant changes in the activation properties or in the time course of Ih. The effects ranged from approximately 20% at 50 microM, approximately 25% at 75 microM, to approximately 35% at 100 microM GBP (at -110 mV). In the presence of intracellular cyclic adenosine monophosphate (cAMP), the effects of GBP on Ih were similar to those obtained in the absence of cAMP. CONCLUSIONS: These results suggest that GBP increases the Ih through a cAMP-independent mechanism. Because the applied GBP concentrations were in a clinically relevant range, the observed effect may contribute to the anticonvulsant action of GBP in partial seizures and may represent a new concept of how this anticonvulsant drug works.
PURPOSE:Gabapentin (GBP) is a commonly used drug in the treatment of partial seizures, but its mode of action is still unclear. The genesis of seizures in temporal lobe epilepsy is thought to be crucially influenced by intrinsic membrane properties. Because the Ih substantially contributes to the intrinsic membrane properties of neurons, the effects of GBP on the Ih were investigated in CA1 pyramidal cells of rat hippocampus. METHODS:CA1 pyramidal cells in hippocampal slices were examined by using the whole-cell patch-clamp technique. RESULTS: GBP increased the Ih amplitude in a concentration-dependent manner mainly by increasing the conductance, without significant changes in the activation properties or in the time course of Ih. The effects ranged from approximately 20% at 50 microM, approximately 25% at 75 microM, to approximately 35% at 100 microM GBP (at -110 mV). In the presence of intracellular cyclic adenosine monophosphate (cAMP), the effects of GBP on Ih were similar to those obtained in the absence of cAMP. CONCLUSIONS: These results suggest that GBP increases the Ih through a cAMP-independent mechanism. Because the applied GBP concentrations were in a clinically relevant range, the observed effect may contribute to the anticonvulsant action of GBP in partial seizures and may represent a new concept of how this anticonvulsant drug works.