Effects of Phenytoin, Carbamazepine, and Gabapentin on Calcium Channels in Hippocampal Granule Cells from Patients with Temporal Lobe Epilepsy

Abstract

Summary: Purpose:The anticonvulsants phenytoin (PHT), carbamazepine (CBZ), and gabapentin (GBP) are commonly used in the treatment of temporal lobe epilepsy. Ca" current modulation has been proposed to contribute to the antiepileptic activity of these drugs. The purpose of this study was to determine the effects of these anticonvulsants on voltage-dependent calcium channels in pathologically altered neurons from patients with chronic temporal lobe epilepsy.Methods: Acutely isolated human hippocampal granule cells were examined by using the whole-cell configuration of the patch-clamp technique.Results: PHT and CBZ produced a reversible, concentrationdependent inhibition of high-voltage-activated (HVA) Ca2' currents without affecting voltage-dependent activation. The concentration-response curves of PHT and CBZ indicated maximal inhibition of 35 and 65%, respectively, with halfmaximal inhibition being obtained at 89 and 244 ph4, respectively. At therapeutic cerebrospinal fluid (CSF) concentrations, HVA currents were not significantly altered by PHT and CBZ. However, PHT but not CBZ showed a reduction of HVA currents of 16% at a therapeutic whole-brain concentration of 80 FM. In contrast to CBZ, PHT produced a small hyperpolarizing shift in the voltage dependence of steady-state inactivation. PHT, 80 ph4, shifted the potential of half-maximal inactivation by -3.1 f 0.5 mV (p < 0.05). GBP, which was recently found to bind to the a$ subunit of a neuronal Ca" channel, showed no modulation of Ca2+ conductances.Conclusions: These results suggest that, in contrast to GBP and CBZ, modulation of postsynaptic Ca2+ channels can contribute to the anticonvulsant action of PHT in human hippocampal granule cells.

Carbamazepine inhibits L-type Ca2+ channels in cultured rat hippocampal neurons stimulated with glutamate receptor agonists

“…These data indicate that CBZ, at least at higher concentrations, can affect L-type Ca 2 + channels, and agree with other findings indicating that CBZ could have Ca 2 + antagonistic properties (Elliott, 1990;Schirrmacher et al, 1993;Mark et al, 1995;Vonwegerer et al, 1997;Schumacher et al, 1998). Moreover, Schirrmacher et al (1995) also suggested that CBZ reduces Ca 2 + currents presumably by inhibiting L-type Ca 2 + channels in rat sensory spinal ganglion cells.…”

“…However, the mechanisms underlying the effects of this AED have not been completely identified, and are still a matter of debate. It has been shown that CBZ can inhibit Ca 2 + channels (Elliott, 1990;Schirrmacher et al, 1993;Schumacher et al, 1998), enhance 4-aminopyridine-sensitive potassium currents in cortical neurons (Olpe et al, 1991), acts as an antagonist of adenosine A 1 receptors (Biber et al, 1996), attenuates cAMP production (Chen et al, 1996), induces the release of serotonin (Dailey et al, 1997a,b), and inhibits the release of glutamate (Waldmeier et al, 1996;Okada et al, 1998). Preischemic treatment with CBZ also tends to reduce the cerebral damage and neurological deficit (Minato et al, 1997).…”

Modulation of Calcium Channels by Group I and Group II Metabotropic Glutamate Receptors in Dentate Gyrus Neurons from Patients with Temporal Lobe Epilepsy

“…Six neurons remained unidentified. HVA Ca2+ currents were evoked every 10 sec with a 50-msec depolarizing voltage step to -10 mV from a holding potential of -60 mV using Ba2+ (5 mM) as the charge carrier (29). The peak current amplitudes at -10 mV ranged from 360 pA to 2.50 nA (mean 1.48 f 0.49 nA, n = 47), producing a mean current density of 149 f 70 pA/pF.…”

“…Dissociated neurons from the dentate gyrus were obtained from human specimens as described previously (29,30). Briefly, surgical specimens were dissected into 400-pm-thick coronal hippocampal slices with the use of a vibratome (Ted Pella Inc., Redding, Calif, U.S.A.).…”

<b>Spontaneous absence-like activity in Wistar rats: Behavioral and electrographic characteristics and the effects of antiepileptic drugs

“…In the past 30 years, many types of spontaneous or pharmacologically induced animal "absence-like" epilepsy have been reported (HOSFORD et al, 1995;MAXSON et al, 1983;SIDMAN, 1979;SERIKAWA et al, 1987;COENEN, 1986;VERGNES et al, 1982VERGNES et al, , 1986, with cortical spike-and-wave discharge, associated with various behavioral phenomena, as common denominator. A presumably new type of spontaneous epilepsy, resembling human absence seizures, was identified in a fraction of Wistar rats used in our laboratory.…”