Effects of lamotrigine and conventional antiepileptic drugs on amygdala- and hippocampal-kindled seizures in rats

Otsuki, Kenro; Morimoto, Kiyoshi; Satô, Keiko; Yamada, Norihito; Kuroda, Shigetoshi

doi:10.1016/s0920-1211(98)00018-7

Cited by 65 publications

(29 citation statements)

References 30 publications

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“…Carbamazepine (20 -40 mg/kg) attenuated kindled seizures in rats (Otsuki et al, 1998), and the ED 50 for maximal electroshock seizures was 12.2 to 14.5 mg/kg (Borowicz et al, 1995); 10 to 30 mg/kg/day is given in pediatric therapy (Suzuki et al, 1991). The relatively high threshold for a proapoptotic action of carbamazepine is consistent with the safety profile of this drug as monotherapy during pregnancy (Meador, 2004).…”

Section: Discussionmentioning

confidence: 52%

Antiepileptic Drug-Induced Neuronal Cell Death in the Immature Brain: Effects of Carbamazepine, Topiramate, and Levetiracetam as Monotherapy versus Polytherapy

Kim

Kondratyev²,

Gale³

2007

J Pharmacol Exp Ther

123

126

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The aim of this study was to test the potential neurotoxicity of three antiepileptic drugs (AEDs), carbamazepine (5H-dibenzepine-5-carboxamide), topiramate [2,3:4,5-bis-O-(1-methylethylidene)-␤-D-fructopyranose sulfamate], and levetiracetam [2-(2-oxopyrrolidin-1-yl)butanamide], in the developing rat brain, when given alone or in combinations. The extent of cell death induced by AEDs was measured in several brain regions of rat pups (postnatal day 8) by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay 24 h after drug treatment. Carbamazepine alone did not increase neurodegeneration when given in doses up to 50 mg/kg, but it induced significant cell death at 100 mg/kg. When combined with phenytoin, carbamazepine, 50 but not 25 mg/kg, significantly exacerbated phenytoin-induced cell death. Although topiramate (20 -80 mg/ kg) alone caused no neurodegeneration, all doses exacerbated phenytoin-induced neurodegeneration. Levetiracetam (250 -1000 mg/kg) alone did not induce cell death, nor did it exacerbate phenytoin-induced neurodegeneration. Of the combinations examined, only that of levetiracetam (250 mg/kg) with carbamazepine (50 mg/kg) did not induce neurodegeneration. Our data underscore the importance of evaluating the safety of combinations of AEDs given during development and not merely extrapolating from the effects of exposure to single drugs. Although carbamazepine and topiramate alone did not induce neuronal death, both drugs exacerbated phenytoin-induced cell death. In contrast, because cotreatment with levetiracetam and carbamazepine did not enhance cell death in the developing brain, it may be possible to avoid proapoptotic effects, even in polytherapy, by choosing appropriate drugs. The latter drugs, as monotherapy or in combination, may be promising candidates for the treatment of women during pregnancy and for preterm and neonatal infants.

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Section: Discussionmentioning

confidence: 52%

Antiepileptic Drug-Induced Neuronal Cell Death in the Immature Brain: Effects of Carbamazepine, Topiramate, and Levetiracetam as Monotherapy versus Polytherapy

Kim

Kondratyev²,

Gale³

2007

J Pharmacol Exp Ther

123

126

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“…Specifically, we tested the effects on use-dependent plasticity of (i) lorazepam (LZ), a drug that enhances ␥-aminobutyric acid type A (GABA A ) receptor function by acting as a positive allosteric modulator (12) and that blocks the induction of LTP (10); (ii) dextromethorphan (DM), a drug that blocks N-methyl-Daspartate (NMDA) receptors (11,13), required for LTP in the motor cortex (7,11), and experience-dependent plasticity in the somatosensory cortex (14); and (iii) lamotrigine (LG), a drug that modifies the gating of voltage-activated Na ϩ and Ca 2ϩ channels (15) without affecting LTP induction (16,17).…”

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confidence: 99%

Mechanisms of use-dependent plasticity in the human motor cortex

Bütefisch¹

2000

Proceedings of the National Academy of Sciences

298

363

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Practicing movements results in improvement in performance and in plasticity of the motor cortex. To identify the underlying mechanisms, we studied use-dependent plasticity in human subjects premedicated with drugs that influence synaptic plasticity. Usedependent plasticity was reduced substantially by dextromethorphan (an N-methyl-D-aspartate receptor blocker) and by lorazepam [a ␥-aminobutyric acid (GABA) type A receptor-positive allosteric modulator]. These results identify N-methyl-D-aspartate receptor activation and GABAergic inhibition as mechanisms operating in use-dependent plasticity in intact human motor cortex and point to similarities in the mechanisms underlying this form of plasticity and long-term potentiation.

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“…We do not typically observe this degree of variability when the rats are stimulated with suprathreshold current intensities of 600-800 A. However, because LTG has been shown to increase the AD and seizure thresholds in fully kindled rats (41,42), we decided to use the lower-intensity stimulation to maximize our likelihood of finding an antiepileptogenic effect of this drug.…”

Section: Discussionmentioning

confidence: 99%

“…LTG, administered intraperitoneally (i.p.) in doses of 10 mg/kg or more, suppresses generalized amygdalakindled seizures and increases the afterdischarge (AD) and seizure thresholds in fully kindled animals (40)(41)(42)(43). However, the effects of LTG on kindled seizure development have not yet been reported.…”

mentioning

confidence: 99%

Lamotrigine Treatment During Amygdala‐Kindled Seizure Development Fails to Inhibit Seizures and Diminishes Subsequent Anticonvulsant Efficacy

2000

Epilepsia

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Summary:Purpose: Lamotrigine (LTG) is an anticonvulsant that is currently in use for the treatment of various seizure disorders and that shows promise in the treatment of affective illness. LTG is also effective in the suppression of amygdalakindled seizures. Because many drugs show a differential efficacy profile as a function of the phase of kindling evolution, we evaluated LTG for its potential antiepileptogenic effects on the development of amygdala-kindled seizures.Methods: In two separate studies, LTG (5 or 15 mg/kg versus vehicle) was administered before each daily amygdala stimulation (biphasic square wave pulses, 100 pulse pairs per second for a total of 0.5 second, 1-millisecond pulse width) at an intensity of 50 A over the AD threshold. Seizure development was assessed, as well as the effect of this pretreatment on subsequent efficacy of LTG on completed kindled seizures.Results: LTG at 5 mg/kg failed to block seizure development. At 15 mg/kg, LTG paradoxically enhanced seizure development and produced running fits in four of the nine animals tested. Animals previously treated with either dose of LTG during kindling development showed a diminished response to the anticonvulsant effects of LTG on fully kindled seizures compared with the vehicle-treated controls.Conclusions: Although LTG possesses potent anticonvulsant effects on completed amygdala-kindled seizures, it is either without effect (5 mg/kg) or facilitates (15 mg/kg) the initial phase of kindling development. In addition, exposure to LTG during kindled seizure development leads to a reduced subsequent response to the drug in fully kindled animals. These observations parallel those with carbamazepine and suggest that different stages of kindling (epileptogenesis versus fully manifest seizures) may have different underlying neural mechanisms that require distinct pharmacotherapies.

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Effects of lamotrigine and conventional antiepileptic drugs on amygdala- and hippocampal-kindled seizures in rats

Cited by 65 publications

References 30 publications

Antiepileptic Drug-Induced Neuronal Cell Death in the Immature Brain: Effects of Carbamazepine, Topiramate, and Levetiracetam as Monotherapy versus Polytherapy

Antiepileptic Drug-Induced Neuronal Cell Death in the Immature Brain: Effects of Carbamazepine, Topiramate, and Levetiracetam as Monotherapy versus Polytherapy

Mechanisms of use-dependent plasticity in the human motor cortex

Lamotrigine Treatment During Amygdala‐Kindled Seizure Development Fails to Inhibit Seizures and Diminishes Subsequent Anticonvulsant Efficacy

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