Effect of levetiracetam on molecular regulation of hippocampal glutamate and GABA transporters in rats with chronic seizures induced by amygdalar FeCl3 injection

Ueda, Yuto; Doi, Taku; Nagatomo, Keiko; Tokumaru, Jun; Takaki, Mayuko; Willmore, L. James

doi:10.1016/j.brainres.2007.03.021

Cited by 63 publications

(48 citation statements)

References 39 publications

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“…Interestingly, LEV reduces neurotransmitter release in a synaptic activity-dependent manner (50,51) and particularly in excitatory neurons with a sustained and high frequency of firing (51). In addition, LEV may promote glutamate uptake by increasing glutamate transporter expression (52). By modulating presynaptic release or glutamate uptake, LEV might prevent excessive glutamate accumulation at the synaptic cleft, preventing overstimulation of postsynaptic glutamate receptors.…”

Section: Discussionmentioning

confidence: 99%

Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model

Sanchez

Zhu

Verret

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

567

534

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In light of the rising prevalence of Alzheimer's disease (AD), new strategies to prevent, halt, and reverse this condition are needed urgently. Perturbations of brain network activity are observed in AD patients and in conditions that increase the risk of developing AD, suggesting that aberrant network activity might contribute to AD-related cognitive decline. Human amyloid precursor protein (hAPP) transgenic mice simulate key aspects of AD, including pathologically elevated levels of amyloid-β peptides in brain, aberrant neural network activity, remodeling of hippocampal circuits, synaptic deficits, and behavioral abnormalities. Whether these alterations are linked in a causal chain remains unknown. To explore whether hAPP/amyloid-β-induced aberrant network activity contributes to synaptic and cognitive deficits, we treated hAPP mice with different antiepileptic drugs. Among the drugs tested, only levetiracetam (LEV) effectively reduced abnormal spike activity detected by electroencephalography. Chronic treatment with LEV also reversed hippocampal remodeling, behavioral abnormalities, synaptic dysfunction, and deficits in learning and memory in hAPP mice. Our findings support the hypothesis that aberrant network activity contributes causally to synaptic and cognitive deficits in hAPP mice. LEV might also help ameliorate related abnormalities in people who have or are at risk for AD.epilepsy | plasticity | therapy | dementia | hyperexcitability

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Section: Discussionmentioning

confidence: 99%

Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model

Sanchez

Zhu

Verret

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

567

534

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“…In vivo experiments with iron-chloride (FeCl 3 )-induced epileptic rats demonstrated suppression of glutamatergic excitation and enhancement of GABAergic inhibition in the epileptic and nonepileptic rats as a result of upregulation of glutamate and GABA transporters and downregulation of the glutamate transporter regulating protein GTRAP3-18 [Ueda et al 2007]. In vitro experiments demonstrated a limited (520%) reduction of evoked excitatory postsynaptic potentials in striatal slices [Costa et al 2006] and a reversible reduction in AMPA-receptor currents in cortical neuron cultures of nonepileptic mice [Carunchio et al 2007].…”

Section: Mechanism Of Action Of Levetiracetammentioning

confidence: 99%

Review: New treatment options in status epilepticus: a critical review on intravenous levetiracetam

Trinka

Dobesberger

2009

Ther Adv Neurol Disord

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The effectiveness of levetiracetam (LEV) in the treatment of focal and generalised epilepsies is well established. LEV has a wide spectrum of action, good tolerability and a favourable pharmacokinetic profile. An injectable formulation has been released as an intravenous (IV) infusion in 2006 for patients with epilepsy when oral administration is temporarily not feasible. Bioequivalence to the oral preparation has been demonstrated with good tolerability and safety enabling a smooth transition from oral to parenteral formulation and vice versa. Although IV LEV is not licensed for treatment of status epilepticus (SE), open-label experience in retrospective case series is accumulating. Until now (August 2008) 156 patients who were treated with IV LEV for various forms of SE have been reported with an overall success rate of 65.4%. The most often used initial dose was 2000-3000 mg over 15 minutes. Adverse events were reported in 7.1%, and were mild and transient. Although IV LEV is an interesting alternative for the treatment of SE due to the lack of centrally depressive effects and low potential of drug interactions, one has to be aware of the nonrandomised retrospective study design, the heterogenous patient population and treatment protocols, and the publication bias inherent in these type of studies. Only a large randomised controlled trial with an adequate comparator will reveal the efficacy and effectiveness of this promising new IV formulation.

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“…Examples of this group of substances are the xCT-inducing anticonvulsants levetiracetam and zonisamide, which were shown to also induce EAAT3 expression (270,272) and the EAAT2-inducing neuroprotective antibiotic ceftriaxone, which has been shown to attenuate damage in models of both acute and chronic neurodegenerative disorders [for review see (247)] and increases xCT expression in vitro (136) as well as in the brain in vivo (121).…”

Section: Synopsis and Future Directions For System X Cmentioning

confidence: 99%

The Cystine/Glutamate Antiporter System x_c⁻in Health and Disease: From Molecular Mechanisms to Novel Therapeutic Opportunities

Lewerenz

Hewett

Huang

et al. 2013

Antioxidants & Redox Signaling

787

655

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The antiporter system x c -imports the amino acid cystine, the oxidized form of cysteine, into cells with a 1:1 counter-transport of glutamate. It is composed of a light chain, xCT, and a heavy chain, 4F2 heavy chain (4F2hc), and, thus, belongs to the family of heterodimeric amino acid transporters. Cysteine is the rate-limiting substrate for the important antioxidant glutathione (GSH) and, along with cystine, it also forms a key redox couple on its own. Glutamate is a major neurotransmitter in the central nervous system (CNS). By phylogenetic analysis, we show that system x c -is a rather evolutionarily new amino acid transport system. In addition, we summarize the current knowledge regarding the molecular mechanisms that regulate system x c -, including the transcriptional regulation of the xCT light chain, posttranscriptional mechanisms, and pharmacological inhibitors of system x c -. Moreover, the roles of system x c -in regulating GSH levels, the redox state of the extracellular cystine/cysteine redox couple, and extracellular glutamate levels are discussed. In vitro, glutamate-mediated system x c -inhibition leads to neuronal cell death, a paradigm called oxidative glutamate toxicity, which has successfully been used to identify neuroprotective compounds. In vivo, xCT has a rather restricted expression pattern with the highest levels in the CNS and parts of the immune system. System x c -is also present in the eye. Moreover, an elevated expression of xCT has been reported in cancer. We highlight the diverse roles of system x c -in the regulation of the immune response, in various aspects of cancer and in the eye and the CNS. Antioxid. Redox Signal. 18, 522-555.

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Effect of levetiracetam on molecular regulation of hippocampal glutamate and GABA transporters in rats with chronic seizures induced by amygdalar FeCl3 injection

Cited by 63 publications

References 39 publications

Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model

Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model

Review: New treatment options in status epilepticus: a critical review on intravenous levetiracetam

The Cystine/Glutamate Antiporter System x_c⁻in Health and Disease: From Molecular Mechanisms to Novel Therapeutic Opportunities

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Effect of levetiracetam on molecular regulation of hippocampal glutamate and GABA transporters in rats with chronic seizures induced by amygdalar FeCl3 injection

Cited by 63 publications

References 39 publications

Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model

Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model

Review: New treatment options in status epilepticus: a critical review on intravenous levetiracetam

The Cystine/Glutamate Antiporter System xc−in Health and Disease: From Molecular Mechanisms to Novel Therapeutic Opportunities

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Product

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The Cystine/Glutamate Antiporter System x_c⁻in Health and Disease: From Molecular Mechanisms to Novel Therapeutic Opportunities