Neurochemical and Behavioral Aspects of Lamotrigine

Leach, Michael J.; Baxter, M. G.; Critchley, M. A. E.

doi:10.1111/j.1528-1157.1991.tb05882.x

Cited by 137 publications

(65 citation statements)

References 10 publications

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“…LTG is believed to block voltage-sensitive sodium channels, with a resulting decrease in glutamate release (7,8). Antiepileptic drug ef- fects may be mediated by GABA receptors, but LTG is a less potent inhibitor of GABA release (28,29). The measurement of fEPSPs may provide evidence for a modulation of synaptic transmission by LTG.…”

Section: Discussionmentioning

confidence: 99%

Effects of Lamotrigine on Field Potentials and Long‐Term Potentiation in Guinea Pig Hippocampal Slices

Langosch¹,

Zhou²,

Frick³

et al. 2000

Epilepsia

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Summary:Purpose: To investigate the effects of lamotrigine (LTG), a new anticonvulsant, on neuronal excitability, synaptic transmission, and long-term potentiation (LTP) in guinea pig hippocampal slices.Methods: Electrically evoked field excitatory postsynaptic potentials (fEPSPs) and population spikes (PSs) were investigated in the CAI region of the hippocampus.Results: The concentration-response curves showed different actions of LTG in concentrations near therapeutic plasma levels (1 0 pM) on fEPSPs and PSs. The initial slopes of fEPSPs were not affected, whereas the amplitudes of PSs were significantly decreased. Higher concentrations of LTG decreased both fEPSP slopes and PS amplitudes; however, the effects on PSs were much stronger. Also, there were no differences in fEPSP slopes or PS amplitudes compared with controls when LTP was induced in the presence of LTG (10 pM).Conclusions: Our data are in contrast to previous findings that suggest LTG acts primarily on presynaptic sites by blocking the release of excitatory amino acids. The new antiepileptic drug lamotrigine [3,5-diamino-6-(2,3-dichlorophenyl)-1,2,3-trazine] (LTG) has been used in the treatment of focal epilepsies with or without secondary generalization (1,2). Also, several reports have indicated efficacy in the treatment of bipolar affective disorders (3-6). LTG is believed to block presynaptic voltage-sensitive sodium channels, inhibiting the release of excitatory amino acids (7,8). Further, antagonistic effects of LTG on calcium channels have been found in rat cortical neurons (9) and in the CAl/CA3 hippocampal area of guinea pigs (10). Recently, LTG has been shown to modulate the transient potassium outward current I , (1 l).Long-term potentiation (LTP) is a widely accepted model for synaptic plasticity, learning, and memory (12,13). Synaptic plasticity has been suggested to play an important role in epileptogenic mechanisms (14-16) as well as in the development and time course of affective disorders (6,17,18). LTG was found to have no influence on the induction of LTP in the dentate gyrus of urethaneAccepted May 11, 2000. Address correspondence and reprint requests to J. M. Langosch, Dept. of Psychiatry, University of Freiburg, Hauptstr. 5, Fr ei b u r g , Germ an y . E-mai 1 : j en s-1 a n g 0 s c h @ p s y a 1 I g . u kl .uni-freiburg.de anesthetized rats in vivo (1 9,20). In contrast, LTG inhibits tetraethylammonium-induced synaptic plasticity in rat amygdala (21). In the present study, we investigated the influence of LTG on field potentials and high frequency-induced synaptic plasticity in area CAI of guinea pig hippocampal slices. Parts of the results have been published in abstract form (22,23). METHODSHippocampal slices were prepared as described previously (24). In brief, white female guinea pigs (Charles River, Sulzfeld, Germany; 280-350 g) were anesthetized with ether, brains were removed, and transverse hippocampal slices (400 bm thick) were prepared in ice-cold medium. After preparation, all slices were incubated in a holding c...

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Section: Discussionmentioning

confidence: 99%

Effects of Lamotrigine on Field Potentials and Long‐Term Potentiation in Guinea Pig Hippocampal Slices

Langosch¹,

Zhou²,

Frick³

et al. 2000

Epilepsia

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“…In other experiments, LTG had no BZD-like effects on GABA-evoked chloride currents (10,45) and did not appear to be an NMDA (N-methy1-D-aspartate) antagonist, because it failed to inhibit NMDA-evoked cyclic GMP formation in a rat brain preparation (42). Because the clinical profile of LTG appears broader than would be expected based on the single mechanism thus far confirmed, the search for additional potential mechanisms continues.…”

Section: Ltgmentioning

confidence: 99%

Clinical Significance of Animal Seizure Models and Mechanism of Action Studies of Potential Antiepileptic Drugs

1997

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Summary: More than 50 million persons worldwide suffer from epilepsy, many of whom are refractory to treatment with standard antiepileptic drugs (AEDs Although epilepsy affects more than 50 million persons worldwide (l), the development of new pharmacologic interventions has lagged behind that of many other therapeutic categories. Until recently, physicians have had available a relatively limited armamentarium of antiepileptic drugs (AEDs) to treat patients with seizure disorders. This group of "standard" AEDs includes phenytoin (PHT), carbamazepine (CBZ), valproate (VPA), barbiturates such as phenobarbital (PB) and primidone (PRM), certain benzodiazepines (BZDs), and ethosuximide (ESM). Most of these agents have a limited spectrum of antiepileptic activity, and all have certain negative properties that limit their utility and complicate patient management. At least 25% of epilepsy patients remain refractory to these AEDs ( 2 ) . Seirecently been discovered. FBM appears to be active at the strychnine-insensitive glycine binding site of the NMDA receptor. TPM is active on the kainate/AMPA subtype of glutamate receptor and at a potentially novel site on the GABAA receptor. For several reasons, availability of a single AED with multiple mechanisms of action may be preferred over availability of multiple AEDs with single mechanisms of action. These reasons include ease of titration, lack of drugdrug interactions, and reduced potential for pharmacodynamic tolerance. Key Words: Anticonvulsants-Drug screening -Neurotransmitters -Phenytoin -Ethosuximide-Topiramate-Valproate-Benzodiazepines-Barbitu-zure control in many more patients is achieved only at the expense of various types and severities of AEDrelated adverse effects. The need for new AEDs with improved clinical profiles is therefore quite clear.Fortunately, the present decade has been marked by a number of advances in AED development. Since 1990, several novel AEDs have been commercialized in one or more countries and are in the process of evaluation for worldwide registrations. These include vigabatrin (VGB), lamotrigine (LTG), gabapentin (GBP), tiagabine (TGB), felbamate (FBM), and topiramate (TPM). This report briefly discusses the preclinical models supporting the clinical evaluation of these AEDs, reviews the presently proposed mechanisms of old and new AEDs, somewhat more closely examines the recently emerging mechanistic profile of the clinically promising new AED TPM, and offers some observations about the significance of mechanism findings from the scientific and the clinical perspective.

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“…1,22 On the other hand, tics, abnormal eye movements and movement disorders as observed in two patients are rare. [23][24][25] The mechanisms that cause abnormal eye movements and movement disorders are highly hypothetical. It has been postulated that AED may act on sodium channels causing such anomalies, by acting on dopaminergic metabolism with the inhibition of excitatory aminoacides (glutamine).…”

Section: Discussionmentioning

confidence: 99%

Late side-effects of valproate and lamotrigine

Moreira

Thomé‐Souza

Valente

2007

J. epilepsy clin. neurophysiol.

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Lamotrigine (LTG) is a generally well-tolerated antiepileptic drug with broad-spectrum efficacy in several forms of partial and generalized epilepsy. Adverse effects of lamotrigine are usually associated with introduction and titration. This risk increases in children and in the co-medication with valproate. Herein, we report four patients with late adverse-effects, under the co-medication valproate and LTG, not related to drug introduction or titration. This study demonstrates that late side-effects without apparent etiology in children, adolescents and adults in chronic use of LTG, especially when associated to VPA, led to a diagnostic investigation, sometimes invasive. It must be emphasized that, due to the excellent seizure control, the authors opted for drug decrease instead of drug withdrawal, as previously done. Studies on late adverse effects are scarce, but physicians must be aware of these risks.Key words: lamotrigine, side-effects, epilepsy, anti-epileptic drugs. RESUMOEfeitos adversos tardios no uso de valproate e lamotrigina Lamotrigina (LTG) é uma droga antiepiléptica bem tolerada com eficácia em diferentes formas de epilepsia, parcial e generalizada. Os efeitos adversos da lamotrigina estão freqüentemente associados com a sua introdução e a sua titulação. Este risco encontra-se aumentado em crianças e quando a LTG é usada em associação com o valproato. Nós relatamos quatro pacientes que apresentaram efeitos adversos tardios com a co-administração de LTG e valproato, não relacionados à introdução ou o escalonamento das drogas antiepilépticas. Este estudo demonstra que efeitos adversos tardios sem etiologia aparente nas crianças, adolescentes e adultos em uso crônico de LTG, especialmente quando associados ao valproato, levou à investigação diagnóstica, por vezes invasiva. Os autores enfatizam que, devido ao bom controle de crises, os autores optaram pela redução da dose ao invés da suspensão da medicação, como previamente realizado. Embora os estudos sobre efeitos adversos tardios das drogas antiepilépticas sejam escassos, os clínicos devem estar cientes deste risco.Unitermos: lamotrigine, efeitos adversos, epilepsia, drogas antiepilépticas.

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Neurochemical and Behavioral Aspects of Lamotrigine

Cited by 137 publications

References 10 publications

Effects of Lamotrigine on Field Potentials and Long‐Term Potentiation in Guinea Pig Hippocampal Slices

Effects of Lamotrigine on Field Potentials and Long‐Term Potentiation in Guinea Pig Hippocampal Slices

Clinical Significance of Animal Seizure Models and Mechanism of Action Studies of Potential Antiepileptic Drugs

Late side-effects of valproate and lamotrigine

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