Multiple actions of the novel anticonvulsant drug topiramate in the rat subiculum in vitro

University of Rome Tor Vergata, Roma, Latium, Italy
Brain Research (Impact Factor: 2.84). 11/1998; 807(1-2):125-134. DOI: 10.1016/S0006-8993(98)00785-9


We used an in vitro slice preparation to study whether and how the anticonvulsant drug topiramate (TPM, 50–500 μM) modulates the excitability of rat subicular neurons that generate action potential bursts mainly caused by voltage-dependent, Na+-electrogenesis. Subiculum is a gating structure for outputs originating from the hippocampus proper, and thus it may play a role in limbic seizures. In 28/45 neurons, TPM induced a steady hyperpolarization of the resting membrane potential (RMP) that ranged between −2 and −16 mV and was associated with a 24–62% decrease of the apparent membrane input resistance. TPM also depressed the ability of these cells to generate action potential bursts in response to brief (5–150 ms) depolarizing pulses; such an effect was characterized by an increase in the amount of intracellular depolarizing current required for eliciting action potential bursts, and it also occurred when the TPM-induced steady hyperpolarization was compensated by injecting steady depolarizing current. In addition TPM reduced by approx. 50% the regular action potential firing elicited by prolonged (350–1000 ms) depolarizing pulses (n=15 of 27 neurons). Recovery of the TPM-induced changes was not seen during washout for periods of 20–80 min (n=7). Both the steady hyperpolarization of the RMP and the input resistance decrease elicited by TPM were markedly reduced by the GABAA receptor antagonists bicuculline methiodide (10 μM; n=6) or picrotoxin (100 μM; n=2); such an effect was associated with a reduction, but not with blockade of the depressant action exerted by TPM on burst generation. Our findings indicate that TPM reduces subicular cell excitability, and modifies bursting ability and repetitive firing properties. These effects may be ascribed to actions on voltage-gated, Na+ electrogenesis and GABAA receptors. We propose that these changes in excitability may all contribute to the anticonvulsant action of TPM in limbic seizures that occur in temporal lobe epilepsy patients.

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    • "To validate that our retinal SD was suitable for a subtypecontaining GABA A receptor pharmacology, we examined the effect of topiramate, a a subtype-selective GABA A receptor-positive modulator (Kawasaki et al., 1998) that was previously reported to elevate the cortical SD threshold (Green et al., 2013) and to reduce cortical SD frequency and propagation in rats (Unekawa et al., 2012). "
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    ABSTRACT: Cortical spreading depression (SD) is a transient propagating neuronal excitation followed by depression, which is generally accepted as the underlying cause of migraine. The inhibitory γ-aminobutyric acid type A (GABAA) receptor activation not only reduces cortical SD frequency and propagation, but also relieves migraine headache. This study aims to further determine the role of major subtypes of GABAA receptor in mediating SD genesis and propagation using an efficient in vitro chick retinal model. We firstly demonstrated that abundant α2, to a lesser extent, α5 of GABAA receptor expression in the chick retina, enabling the tissue useful for studying GABAA receptor pharmacology and SD. Marked suppression of SD by SL651498 and TPA023 were observed at 10 μmol·L(-1) and 50 μmol·L(-1) respectively, suggesting a critical role of GABAA receptor α subtypes, in particular α2, in modulating retinal SD elicitation and propagation. The negative data on NS11394 at 3 μmol·L(-1) and the little positive selectivity of TPA023 for α5 did not support that α5 subtype is involved in SD genesis and propagation. Our data provides strong evidence that α2, but not α5 is involved in early stage of migraine, indicating that α2 subtype a possible drug target related to migraine with aura. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.
    Neuroscience 04/2015; 298. DOI:10.1016/j.neuroscience.2015.04.016 · 3.36 Impact Factor
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    • "Topiramate was identified in 1979 and approved by the FDA in January 1997 as an antiepileptic drug. Topiramate interacts with a seemingly multitudinous array of targets (Guerrini and Parmeggiani, 2006; Kawasaki et al., 1998) and its primary mechanism of action is still unknown. "
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    ABSTRACT: In mammals and birds, conservation of body heat at around 37 °C is vital to life. Thermogenesis is the production of this heat which can be obligatory, as in basal metabolic rate, or it can be facultative such as the response to cold. A complex regulatory system has evolved which senses environmental or core temperature and integrates this information in hypothalamic regions such as the preoptic area and dorsomedial hypothalamus. These areas then send the appropriate signals to generate and conserve heat (or dissipate it). In this review, the importance of the sympathetic nervous system is discussed in relation to its role in basal metabolic rate and adaptive thermogenesis with a particular emphasis to human obesity. The efferent sympathetic pathway does not uniformly act on all tissues; different tissues can receive different levels of sympathetic drive at the same time. This is an important concept in the discussion of the pharmacotherapy of obesity. Despite decades of work the medicine chest contains only one pill for the long term treatment of obesity, orlistat, a lipase inhibitor that prevents the absorption of lipid from the gut and is itself not systemically absorbed. The central controlling system for thermogenesis has many potential intervention points. Several drugs, previously marketed, awaiting approval or in the earlier stages of development may have a thermogenic effect via activation of the sympathetic nervous system at some point in the thermoregulatory circuit and are discussed in this review. If the balance is weighted to the "wrong" side there is the burden of increased cardiovascular risk while a shift to the "right" side, if possible, will afford a thermogenic benefit that is conducive to weight loss maintenance. This article is part of a Special Issue entitled 'Central Control Food Intake'
    Neuropharmacology 10/2011; 63(1):111-23. DOI:10.1016/j.neuropharm.2011.10.014 · 5.11 Impact Factor
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    • "Aging and Disease • Volume 2, Number 4, August 2011 338 Inhibition of pyramidal neuron action potential firing was observed by topiramate at concentrations previously shown to inhibit voltage-gated sodium channels and epileptiform activity in vitro [13] [14]. Notably, this was observed in only 50% of neurons tested, and this could have reflected age-associated differences in voltagegated sodium or potassium channel function, as topiramate can act on each of these [14] [15] [16] [17] [18]. However, given the relative paucity of pharmacological studies of topiramate in the aged brain, it is not possible to determine if the limited in vitro efficacy of topiramate in the current study resulted from age-associated neuronal changes or changes that resulted from the prolonged period of spontaneous recurrent seizures in this experimental group. "
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    ABSTRACT: Emerging data indicate that age-related brain changes alter seizure susceptibility, seizure-associated neurodegeneration, and responsiveness to AEDs. The present study assessed long-term animal survival in the Kainic Acid (KA) model along with in-vivo spontaneous seizure frequency, cellular hyperexcitability in CA1 in-vitro and in-vivo in subiculum, and responsiveness of in-vitro CA1 hyperexcitability to topiramate. Sprague-Dawley male rats were given KA to induce convulsive status epilepticus (KA-SE) at 2-3 months of age. The one-month mortality after KA-SE was 27%. One-month survivor rats had 37% sudden unexplained late mortality after KA-SE as compared to none in saline controls during their second year of life. In-vivo seizure frequency was examined prior to terminal experiments. The diurnal average seizure frequency in the KA-SE group at age 2 years was 1.06 ± 0.24 seizures/hour while no seizures were observed in the saline age-matched controls (p<0.001). In-vitro recordings of CA1 pyramidal neurons revealed that depolarizing current injection from -60 mV evoked an increased number of action potentials in the aged KA-SE group compared to controls (p<0.002). Topiramate exhibited dose-dependent inhibition of action potential firing evoked by current injections into CA1 pyramidal neurons of KA-SE rats. In subiculum, KA-SE rats had frequent interictal spikes associated with high frequency oscillations while only rare spontaneous EPSPs were recorded in saline controls. Our experiments revealed that the hippocampal formation of aged epileptic rats shares features of hyperexcitability previously described in young adult epileptic rats using the KA model.
    Aging and Disease 08/2011; 2(4):332-8. · 3.07 Impact Factor
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