Lynch BA, Lambeng N, Nocka K, Kensel-Hammes P, Bajjalieh SM, Matagne

Lynch BA, Lambeng N, Nocka K, Kensel-Hammes P, Bajjalieh SM, Matagne A, Fuks B Proc Natl Acad Sci U S A 2004;101:9861C9866 [PMC free article] [PubMed] [Google Scholar] Here, we show that the synaptic vesicle protein SV2A is the brain binding site of levetiracetam (LEV), a new antiepileptic drug with a unique activity profile in animal models of seizure and epilepsy. to SV2A expressed in fibroblasts, indicating Bardoxolone methyl manufacturer that SV2A is sufficient for LEV binding. No binding was observed to the related isoforms SV2B and SV2C. Furthermore, there is a high degree of correlation between binding affinities of a series of LEV derivatives to SV2A in fibroblasts and to the LEV-binding site in brain. Finally, there is a strong correlation between the affinity of a compound for SV2A and its ability to protect against seizures in an audiogenic mouse animal model of epilepsy. These experimental results suggest that SV2A is the binding site of LEV in the brain and that LEV acts by modulating the function of SV2A, supporting previous indications that LEV possesses a mechanism of action distinct from that of other antiepileptic drugs. Further, these outcomes indicate that proteins involved with vesicle exocytosis, and SV2 specifically, are promising targets for the advancement of brand-new CNS medication therapies. COMMENTARY Identification of a synaptic vesicle proteins SV2A as a binding site for levetiracetam (LEV) and Bardoxolone methyl manufacturer the association of SV2A with antiepileptic efficacy support the speculation that LEV is exclusive among the presently marketed antiepileptic medications (AEDs). This watch was predicated on previously observations displaying that, unlike almost every other AEDs, LEV didn’t show any significant anticonvulsant efficacy in seizure versions classically utilized to display screen novel AEDs, which includes maximal electroshock or pentylenetetrazol-induced seizures (1). Furthermore, analysis on the mechanisms of actions of LEV didn’t reveal any similarities with those of regular AEDs, such as for example facilitation of -aminobutyric acid (GABA)-mediated neurotransmission, modulation of sodium stations, or modulation of Bardoxolone methyl manufacturer low-voltageCactivated calcium currents. Two research have provided proof that LEV, unlike any various other AED, may possess modulatory results on activity-dependent plasticity and its own behavioral consequences. Initial, L?sher and co-workers showed that administration of LEV during induction of kindling led to long-lasting decrease in afterdischarge length, even after discontinuation of treatment (2). Lately Sasa et al. investigated a stress of rats that develop spontaneous seizures as adults (3). They administered LEV over the future to these rats prior to the appearance of seizures. Despite the fact that seizures continuing to build up, a significant reduction in the regularity and length Bardoxolone methyl manufacturer of both tonic and absence seizures was observed weighed against untreated pets. These data claim that LEV includes a different spectrum of action, as compared with other AEDs, which could relate to its novel mechanism of action. Research on the LEV binding site began in the mid-1990s when Noyer and coworkers showed that LEV binds to synaptic plasma membranes of the rat hippocampus, cortex, cerebellum, and striatum in a reversible, saturable, and stereoselective manner (4). Further, only one binding site appeared for LEV. Other AEDs, including carbamazepine, phenytoin, valproate, phenobarbital, and clonazepam, had no affinity for the LEV binding site. Interestingly, ethosuximide, pentobarbital, and convulsant pentylenetetrazol competed with binding site at concentrations active in vivo. Eight years later Fuks and coworkers studied photoaffinity labeling Bardoxolone methyl manufacturer of LEV analogue by autoradiography and found that its distribution did not match with any of the classic receptors (5). The highest binding density was found in the dentate gyrus, superior colliculus, several thalamic nuclei, and molecular layer of the cerebellum. Subcellular analysis revealed that binding sites were located in synaptic vesicles. The present study of Lynch and collaborators shows that the binding site in synaptic vesicles is the SV2A protein and that binding to SV2A is usually both necessary and sufficient for its antiepileptic action. SV2A proteins are specific to neurons and endocrine cells. Three isoforms of this 90-kDa protein exist: SV2A, SV2B, and SV2C, of which, SV2A is the most widely distributed. Much of the Cd47 data regarding the function of this protein comes from studies using SV2A and SV2A/B knockout mice. Interestingly, these mice express spontaneous seizures and die within 3 weeks of birth. Crowder et al. demonstrated that SV2A gene disruption leads to decrease in the actions potentialCdependent discharge of GABA in the CA3 subfield of the hippocampus, whereas actions potentialCindependent neurotransmission continues to be regular (6). If, nevertheless, several actions potentials had been fired in succession in cultured hippocampal neurons from SV2A-deficient mice, a sustained upsurge in calcium-dependent synaptic transmitting occurred (7). Predicated on these observations, Janz and co-workers hypothesized that disruption of SV2A outcomes in calcium accumulation during repetitive actions potentials and qualified prospects to elevated neurotransmitter discharge and synaptic circuitry destabilization, that could describe the seizures in these pet. Alterations in synaptic transmitting happened without.

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