SV2A protein is a broad-spectrum anticonvulsant target: Functional correlation between protein binding and seizure protection in models of both partial and generalized epilepsy

Kamiński, Rafał M.; Matagne, Alain; Leclercq, Karine; Gillard, Michel; Maury, Philippe; Kenda, Benoît; Talaga, Patrice; Klitgaard, Henrik

doi:10.1016/j.neuropharm.2007.11.021

Cited by 149 publications

(91 citation statements)

References 32 publications

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“…SV2A is ubiquitously expressed in the brain [15], yet little is known regarding the effects of the interaction between SV2A and LEV. It appears that SV2A is involved in controlling exocytosis of neurotransmitter-containing vesicles [7], [39].…”

Section: Discussionmentioning

confidence: 99%

Levetiracetam Inhibits both ryanodine and IP3 receptor activated calcium induced calcium release in hippocampal neurons in culture

Nagarkatti

Deshpande

DeLorenzo

2008

Neuroscience Letters

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Epilepsy affects approximately 1% of the population worldwide, and there is a pressing need to develop new anti-epileptic drugs (AEDs) and understand their mechanisms of action. Levetiracetam (LEV) is a novel AED and despite its increasingly widespread clinical use, its mechanism of action is as yet undetermined. Intracellular calcium ([Ca 2+ ] i ) regulation by both inositol 1,4,5-triphosphate receptors (IP3R) and ryanodine receptors (RyR) has been implicated in epileptogenesis and the maintenance of epilepsy. To this end, we investigated the effect of LEV on RyR and IP3R activated calcium-induced calcium release (CICR) in hippocampal neuronal cultures. RyR-mediated CICR was stimulated using the well-characterized RyR activator, caffeine. Caffeine (10mM) caused a significant increase in [Ca 2+ ] i in hippocampal neurons. Treatment with LEV (33μM) prior to stimulation of RyR-mediated CICR by caffeine led to a 61% decrease in the caffeine induced peak height of [Ca 2+ ] i when compared to the control. Bradykinin stimulates IP3R-activated CICR-to test the effect of LEV on IP3R-mediated CICR, bradykinin (1μM) was used to stimulate cells pretreated with LEV (100μM). The data showed that LEV caused a 74% decrease in IP3R-mediated CICR compared to the control. In previous studies we have shown that altered Ca 2+ homeostatic mechanisms play a role in seizure activity and the development of spontaneous recurrent epileptiform discharges (SREDs). Elevations in [Ca 2+ ] i mediated by CICR systems have been associated with neurotoxicity, changes in neuronal plasticity, and the development of AE. Thus, the ability of LEV to modulate the two major CICR systems demonstrates an important molecular effect of this agent on a major second messenger system in neurons.

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Section: Discussionmentioning

confidence: 99%

Levetiracetam Inhibits both ryanodine and IP3 receptor activated calcium induced calcium release in hippocampal neurons in culture

Nagarkatti

Deshpande

DeLorenzo

2008

Neuroscience Letters

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“…Indeed, there is a strong correlation between ligand affi nity for SV2A and anticonvulsant potency in animal models of both partial and generalized epilepsy ( Fig. 35.1) [1,10].…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

“…SV2A has been implicated in the modulation of synaptic vesicle exocytosis and neurotransmitter release [7,8] and binding to this protein is considered to be the primary mechanism for brivaracetam's anticonvulsant activity [1,2,9,10]. Indeed, there is a strong correlation between ligand affi nity for SV2A and anticonvulsant potency in animal models of both partial and generalized epilepsy ( Fig.…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

“…A single-blind, placebo-controlled phase IIa study assessed the effect of single doses of brivaracetam (10,20,40, or 80 mg) on the photoparoxysmal electroencephalographic response in 19 patients with photosensitive epilepsy [29]. Each patient received a single dose of placebo (day −1) and a single dose of brivaracetam (day 1) in the morning, at least 30 min after a light breakfast.…”

Section: Proof-of-concept In Photosensitive Epilepsymentioning

confidence: 99%

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Brivaracetam

Rosenstiel

Perucca

2009

The Treatment of Epilepsy

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“…It has a favourable pharmacokinetic profile and can be effective for a wide range of focal and generalized seizures [1] . The exact mechanism of action is unknown but it involves binding to a presynaptic vesicle protein [2] . It has recently attained a monotherapy licence for partial-onset seizures in adults.…”

Section: Introductionmentioning

confidence: 99%

Intravenous Levetiracetam for Epileptic Seizure Emergencies in Older People

Beyenburg

Reuber²,

Maraite³

2008

Gerontology

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Purpose and Background: Clinical experience with intravenous levetiracetam (LEV IV) is still very limited, especially in elderly subjects. The primary objective of this retrospective observational study was to describe the efficacy and tolerability of LEV IV in older patients presenting with epileptic seizure emergencies. Methods: Medical records of 14 older people treated with LEV IV were analysed retrospectively. All patients suffered from series of complex partial seizures or convulsive or non-convulsive status epilepticus needing emergent intravenous (IV) antiepileptic drug (AED) treatment. Nine patients were taking AED therapy when LEV IV was administered. Results: Mean age was 73.9 years (range 61–97). Mean dosage was 1,643 mg/day (range 500–4,000). Seizure control could be achieved in 11/14 patients (78.6%). No significant adverse events were noted besides sedation. Conclusion: LEV IV was effective and well tolerated in these critically ill older patients. LEV IV seems to be a reasonable practical alternative in multimorbid older patients who need IV treatment with an AED.

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SV2A protein is a broad-spectrum anticonvulsant target: Functional correlation between protein binding and seizure protection in models of both partial and generalized epilepsy

Cited by 149 publications

References 32 publications

Levetiracetam Inhibits both ryanodine and IP3 receptor activated calcium induced calcium release in hippocampal neurons in culture

Levetiracetam Inhibits both ryanodine and IP3 receptor activated calcium induced calcium release in hippocampal neurons in culture

Brivaracetam

Intravenous Levetiracetam for Epileptic Seizure Emergencies in Older People

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