Neurochemical studies with the novel anticonvulsant levetiracetam in mouse brain

Sills, Graeme J.; Leach, John Paul; Fraser, Caroline M.; Forrest, Gerard; Patsalos, Philip N.; Brodie, Martin J.

doi:10.1016/s0014-2999(97)00105-2

Cited by 69 publications

(44 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This in turn makes difficult dissecting specific AED actions on different signaling pathways. The effects of acute and chronic LEV application on neurochemical parameters in the mouse brain were examined after single or repeated intraperitoneal LEV injections [Sills et al 1997]. No effect of LEV on whole brain preparations was detected either on the overall GABA and glutamate concentrations or on the overall activities of GABA transaminase and GAD.…”

Section: Synaptic Transmission In-vivomentioning

confidence: 99%

Review: Is levetiracetam different from other antiepileptic drugs? Levetiracetam and its cellular mechanism of action in epilepsy revisited

Surges¹,

Volynski²,

Walker³

2008

Ther Adv Neurol Disord

114

View full text Add to dashboard Cite

Levetiracetam (LEV) is a new antiepileptic drug that is clinically effective in generalized and partial epilepsy syndromes as sole or add-on medication. Nevertheless, its underlying mechanism of action is poorly understood. It has a unique preclinical profile; unlike other antiepileptic drugs (AEDs), it modulates seizure-activity in animal models of chronic epilepsy with no effect in most animal models of acute seizures. Yet it is effective in acute in-vitro 'seizure' models. A possible explanation for these dichotomous findings is that LEV has different mechanisms of actions, whether given acutely or chronically and in 'epileptic' and control tissue. Here we review the general mechanism of action of AEDs, give an updated and critical overview about the experimental findings of LEV's cellular targets (in particular the synaptic vesicular protein SV2A) and ask whether LEV represents a new class of AED.

show abstract

Section: Synaptic Transmission In-vivomentioning

confidence: 99%

Review: Is levetiracetam different from other antiepileptic drugs? Levetiracetam and its cellular mechanism of action in epilepsy revisited

Surges¹,

Volynski²,

Walker³

2008

Ther Adv Neurol Disord

114

View full text Add to dashboard Cite

show abstract

“…Brain concentrations of TPM were determined in excess homogenates prepared during the analysis of GABA-T activity. Determination of protein concentrations, amino acid (GABA, glutamate, glutamine) concentrations, and the activities of the enzymes GABA-transaminase (GABA-T) and GAD were performed in accordance with the methods described previously by Sills et al (15). Brain concentrations of TPM were determined by fluorescence polarisation immunoassay by using an OXIS International Inc. Innofluor TPM assay system (Biostat Diagnostics, Stockport, U.K.) on an Abbott TDX instrument (Abbott Diagnostics, Maidenhead, U.K.).…”

Section: Neurochemical Assaysmentioning

confidence: 99%

Concentration—Effect Studies with Topiramate on Selected Enzymes and Intermediates of the GABA Shunt

et al. 2000

Self Cite

View full text Add to dashboard Cite

Summary:Purpose: Topirainate (TPM) is a new antiepileptic agent with a multifactorial mechanism of action. The drug potentiates responses to y-aminobutyric acid (GABA) at the GABA, receptor and has inhibitory effects on neuronal sodium channels, the AMPA/kainate subtype of glutamate receptor, and carbonic anhydrase. Recent evidence has, however, suggested that the drug also increases brain GABA concentrations in humans. These studies were designed to investigate the neurochemical basis of this observation.Methods: Adult male mice were randomised into two groups and administered TPM (0-1,000 mg/kg) intraperitoneally either as a single dose or daily for 8 days. At 4 h after the final dose, brain tissues were analysed for concentrations of GABA, glutamate, and glutamine and for the activities of GABAtmnsaminase and glutamic acid decarboxylase. TPM levels in brain also were determined.Results: Single-dose and repeated TPM treatments were without effect on all of the parameters investigated, although the drug was detectable in the brain at doses of 3 1 0 mg/kg.Conclusions: These results contradict the reported increase in brain GABA concentrations with TPM. More detailed studies are required to determine the basis of this clinical observation and the extent to which it contributes to the antiepileptic activity of the drug. Key Words: Topiramate-Glutamate-GABA-Antiepileptic drugs-Epilepsy .Topiramate (TPM) is a new antiepileptic agent, licensed across the globe for the treatment of refractory epilepsy (1). It is a sugar sulphamate compound that has demonstrated efficacy in a range of experimental seizure models (2). TPM is effective against tonic extension induced by maximal electroshock (3) and prevents the motor manifestations of amygdaloid kindling (4). It elevates pentylenetetrazol (PTZ) seizure threshold in mice (3, but is only weakly effective against PTZ-induced clonic convulsions (3). In addition, the drug has shown efficacy in a rat model of ischaemia-induced epilepsy (6) and against tonic-and absence-like seizures in spontaneously epileptic rats and sound-induced seizures in DBAl2 mice (7).The mechanisms by which TPM exerts these anticonvulsant effects have been the subject of extensive research. The drug has a recognised inhibitory action at voltage-dependent sodium channels (8-10) and the AMPA/kainate subtype of glutamate receptor (1 1). TPM has also been proposed to potentiate responses to y-ami-

show abstract

“…The seizure protection aorded by LEV in audiogenic-susceptible mice was unaected by the benzodiazepine receptor antagonist umazenil (Klitgaard et al, 1998). Likewise, a lack of eect on GABA levels and the enzymatic activities of GABA transaminase and glutamic acid decarboxylase was reported from a neurochemical study on mouse brain (Sills et al, 1997) and LEV was without eect on GABA transport and metabolism in rat astrocyte cultures (Fraser et al, 1999). This contrasts with one report showing that systemic administration of high doses of LEV induces short-lasting alterations in GABA metabolism and turnover in some brain regions (LoÈ scher et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

The anti‐epileptic drug levetiracetam reverses the inhibition by negative allosteric modulators of neuronal GABA‐ and glycine‐gated currents

Rigo

Hans

Nguyen

et al. 2002

British J Pharmacology

306

181

View full text Add to dashboard Cite

1 In this study in vitro and in vivo approaches were combined in order to investigate if the antiepileptic mechanism(s) of action of levetiracetam (LEV; Keppra 1 ) may involve modulation of inhibitory neurotransmission. 2 GABA-and glycine-gated currents were studied in vitro using whole-cell patch-clamp techniques applied on cultured cerebellar granule, hippocampal and spinal neurons. Protection against clonic convulsions was assessed in vivo in sound-susceptible mice. The eect of LEV was compared with reference anti-epileptic drugs (AEDs): carbamazepine, phenytoin, valproate, clonazepam, phenobarbital and ethosuximide. 3 LEV contrasted the reference AEDs by an absence of any direct eect on glycine-gated currents. At high concentrations, beyond therapeutic relevance, it induced a small reduction in the peak amplitude and a prolongation of the decay phase of GABA-gated currents. A similar action on GABA-elicited currents was observed with the reference AEDs, except ethosuximide. 4 These minor direct eects contrasted with a potent ability of LEV (EC 50 =1 ± 10 mM) to reverse the inhibitory eects of the negative allosteric modulators zinc and b-carbolines on both GABA A and glycine receptor-mediated responses. . In contrast, the benzodiazepine receptor antagonist¯umazenil (up to 10 mg kg 71) was without any eect on the protection aorded by LEV. 7 The results of the present study suggest that a novel ability to oppose the action of negative modulators on the two main inhibitory ionotropic receptors may be of relevance for the antiepileptic mechanism(s) of action of LEV.

show abstract

Neurochemical studies with the novel anticonvulsant levetiracetam in mouse brain

Cited by 69 publications

References 16 publications

Review: Is levetiracetam different from other antiepileptic drugs? Levetiracetam and its cellular mechanism of action in epilepsy revisited

Review: Is levetiracetam different from other antiepileptic drugs? Levetiracetam and its cellular mechanism of action in epilepsy revisited

Concentration—Effect Studies with Topiramate on Selected Enzymes and Intermediates of the GABA Shunt

The anti‐epileptic drug levetiracetam reverses the inhibition by negative allosteric modulators of neuronal GABA‐ and glycine‐gated currents

Contact Info

Product

Resources

About