Proepileptic phenotype of SV2A‐deficient mice is associated with reduced anticonvulsant efficacy of levetiracetam

Purpose:  Synaptic vesicle protein 2A (SV2A) constitutes a distinct binding site for an antiepileptic drug levetiracetam (Keppra). In the present study we characterized SV2A (+/−) heterozygous mice in several seizure models and tested if the anticonvulsant efficacy of levetiracetam is reduced in these mice.

[1]  K. Nocka,et al.  The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[2]  M. Barton,et al.  Pharmacological characterization of the 6 Hz psychomotor seizure model of partial epilepsy , 2001, Epilepsy Research.

[3]  E. Aronica,et al.  Decreased expression of synaptic vesicle protein 2A, the binding site for levetiracetam, during epileptogenesis and chronic epilepsy , 2009, Epilepsia.

[4]  J. Benson,et al.  Benzodiazepine actions mediated by specific γ-aminobutyric acidA receptor subtypes , 1999, Nature.

[5]  D. Margineanu,et al.  Effects of chronic treatment with levetiracetam on hippocampal field responses after pilocarpine-induced status epilepticus in rats , 2008, Brain Research Bulletin.

[6]  R. Palmiter,et al.  The anticonvulsant and proconvulsant effects of alpha2-adrenoreceptor agonists are mediated by distinct populations of alpha2A-adrenoreceptors. , 2004, Neuroscience.

[7]  W. Löscher,et al.  Profile of ucb L059, a novel anticonvulsant drug, in models of partial and generalized epilepsy in mice and rats. , 1993, European journal of pharmacology.

[8]  J. Benson,et al.  Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes. , 1999, Nature.

[9]  M. Cortez,et al.  Anticonvulsant properties of acetone, a brain ketone elevated by the ketogenic diet , 2003, Annals of neurology.

[10]  N. S. Austin,et al.  Synaptic Vesicle Protein 2 Enhances Release Probability at Quiescent Synapses , 2006, The Journal of Neuroscience.

[11]  R. Tallarida,et al.  Modulation of morphine antinociception by peripheral [Leu5]enkephalin: a synergistic interaction. , 1990, European journal of pharmacology.

[12]  R. Racine,et al.  Modification of seizure activity by electrical stimulation. II. Motor seizure. , 1972, Electroencephalography and clinical neurophysiology.

[13]  M. Gillard,et al.  Binding characteristics of [3H]ucb 30889 to levetiracetam binding sites in rat brain. , 2003, European journal of pharmacology.

[14]  R. Racine,et al.  Modification of seizure activity by electrical stimulation. 3. Mechanisms. , 1972, Electroencephalography and clinical neurophysiology.

[15]  M. Linial,et al.  Brain contains two forms of synaptic vesicle protein 2. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[16]  M. Rogawski,et al.  Allopregnanolone Analogs That Positively Modulate GABAA Receptors Protect against Partial Seizures Induced by 6‐Hz Electrical Stimulation in Mice , 2004, Epilepsia.

[17]  Wolfgang Löscher,et al.  Valproate: a reappraisal of its pharmacodynamic properties and mechanisms of action , 1999, Progress in Neurobiology.

[18]  R. Delorenzo,et al.  Levetiracetam Inhibits both ryanodine and IP3 receptor activated calcium induced calcium release in hippocampal neurons in culture , 2008, Neuroscience Letters.

[19]  J. Gobert,et al.  Evidence for a unique profile of levetiracetam in rodent models of seizures and epilepsy. , 1998, European journal of pharmacology.

[20]  D. Margineanu,et al.  Levetiracetam inhibits the high-voltage-activated Ca2+ current in pyramidal neurones of rat hippocampal slices , 2001, Neuroscience Letters.

[21]  R. Kaminski,et al.  SV2A protein is a broad-spectrum anticonvulsant target: Functional correlation between protein binding and seizure protection in models of both partial and generalized epilepsy , 2008, Neuropharmacology.

[22]  Y. Lamberty,et al.  Behavioural phenotyping reveals anxiety-like features of SV2A deficient mice , 2009, Behavioural Brain Research.

[23]  R. Palmiter,et al.  The anticonvulsant and proconvulsant effects of α2-adrenoreceptor agonists are mediated by distinct populations of α2a-adrenoreceptors , 2004, Neuroscience.

[24]  W. Löscher,et al.  Antiepileptogenic effects of the novel anticonvulsant levetiracetam (ucb L059) in the kindling model of temporal lobe epilepsy. , 1998, The Journal of pharmacology and experimental therapeutics.

[25]  R. Browning,et al.  Modification of electroshock and pentylenetetrazol seizure patterns in rats affer precollicular transections , 1986, Experimental Neurology.

[26]  Tao Xu,et al.  SV2 modulates the size of the readily releasable pool of secretory vesicles , 2001, Nature Cell Biology.

[27]  D. Margineanu,et al.  Reduction of voltage-operated potassium currents by levetiracetam: a novel antiepileptic mechanism of action? , 2003, Neuropharmacology.

[28]  R. Browning,et al.  Comparative fos immunoreactivity in the brain after forebrain, brainstem, or combined seizures induced by electroshock, pentylenetetrazol, focally induced and audiogenic seizures in rats , 2004, Neuroscience.

[29]  B. Rocha,et al.  Genetic deletion of the norepinephrine transporter decreases vulnerability to seizures , 2005, Neuroscience Letters.

[30]  T. Bolwig,et al.  Levetiracetam prevents changes in levels of brain-derived neurotrophic factor and neuropeptide Y mRNA and of Y1- and Y5-like receptors in the hippocampus of rats undergoing amygdala kindling: implications for antiepileptogenic and mood-stabilizing properties , 2004, Epilepsy & Behavior.

[31]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[32]  T. Sudhof,et al.  The synaptic vesicle cycle. , 2004, Annual review of neuroscience.

[33]  Brian D. Hale,et al.  Abnormal neurotransmission in mice lacking synaptic vesicle protein 2A (SV2A). , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[34]  Markus Missler,et al.  SV2A and SV2B Function as Redundant Ca2+ Regulators in Neurotransmitter Release , 1999, Neuron.

[35]  H. Klitgaard,et al.  Validation of corneally kindled mice: a sensitive screening model for partial epilepsy in man , 1998, Epilepsy Research.

[36]  D. Margineanu,et al.  Anti‐convulsive and anti‐epileptic properties of brivaracetam (ucb 34714), a high‐affinity ligand for the synaptic vesicle protein, SV2A , 2008, British journal of pharmacology.

[37]  M. Rogawski.  Brivaracetam: a rational drug discovery success story , 2008, British journal of pharmacology.

[38]  J. Hénichart,et al.  The novel antiepileptic drug levetiracetam (ucb L059) appears to act via a specific binding site in CNS membranes. , 1995, European journal of pharmacology.

[39]  H. Klitgaard,et al.  Levetiracetam: the first SV2A ligand for the treatment of epilepsy , 2007, Expert opinion on drug discovery.

[40]  R. Scheller,et al.  Differential expression of synaptic vesicle protein 2 (SV2) isoforms , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[41]  B Malgrange,et al.  The anti‐epileptic drug levetiracetam reverses the inhibition by negative allosteric modulators of neuronal GABA‐ and glycine‐gated currents , 2002, British journal of pharmacology.

[42]  E. Ben-Menachem,et al.  Levetiracetam reduces caffeine-induced Ca2+ transients and epileptiform potentials in hippocampal neurons , 2003, NeuroReport.