Gabapentin Increases the Hyperpolarization‐activated Cation Current I_h in Rat CA1 Pyramidal Cells

Abstract

Summary: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 I h substantially contributes to the intrinsic membrane properties of neurons, the effects of GBP on the I h 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 I h amplitude in a concentrationdependent manner mainly by increasing the conductance, without significant changes in the activation properties or in the time course of I h . The effects ranged from ∼20% at 50 M, ∼25% at 75 M, to ∼35% at 100 M GBP (at -110 mV). In the presence of intracellular cyclic adenosine monophosphate (cAMP), the effects of GBP on I h were similar to those obtained in the absence of cAMP.Conclusions: These results suggest that GBP increases the I h 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.

Choosing the Correct Antiepileptic Drugs: From Animal Studies to the Clinic

“…The H-channel (hyperpolarization induced, cyclic nucleotide gated), has a high permeability to K + and tends to stabilize the membrane potential toward the resting potential against both hyperpolarizing and depolarizing inputs. AEDs, such as lamotrigine [9] and gabapentin [10] target the H-channels by increasing the hyperpolarization-activated cation current.…”

Antiepileptic Drugs and Pregnancy Outcomes

“…It has been described that GBP increased the non-activating cation current (IH) in the pyramidal neurons in the hippocampal area CA1, through a cAMP-independent mechanism, producing a decreased dendritic excitability of the neurons, and interneurons It also inhibits highvoltage calcium channels in central neurons in the rat brain. [Peng et al, 2011;Stefani et al, 1998;Surges et al, 2003].…”

Effects of the Ih Blockers CsCl and ZD7288 on Inherited Epilepsy in Mongolian Gerbils

“…Poolos has reviewed the dual (Yin and Yang) characteristics of Ih channels [34]. The Yin (=inhibitory) aspects include upregulation of Ih by antiepileptic drugs, which suggests that Ih exerts a fundamentally anti-convulsant effect [33,41]. In a recent study using genetically modified mice in which HCN2 had been deleted, the mice exhibited spontaneous absence seizures, suggesting that the absence of HCN2 is strongly proconvulsive [24].…”

“…Ih channels play important roles in regulating neuronal excitability, and have recently been shown to be altered by seizures [5,6,33,34,41,43]. Unlike other channels implicated in epilepsy, which either excite or inhibit normal neurons, the unique biphasic aspects of Ih cause it to be involved in both increased and decreased excitability of neurons.…”

“…The role of Ih in epilepsy remains controversial. The finding that antiepileptic drugs upregulate Ih suggests that Ih exerts a fundamentally anticonvulsant effect [33,41]. In a recent study using genetically modified mice in which HCN2 was deleted, the mice had spontaneous absence seizures, suggesting that a lack of HCN2 has a strongly proconvulsive effect [24].…”