Synaptic Vesicle Glycoprotein 2A Ligands in the Treatment of Epilepsy and Beyond

Wolfgang Löscher, Michel Gillard, Zara A Sands, Rafal M Kaminski, Henrik Klitgaard, Wolfgang Löscher, Michel Gillard, Zara A Sands, Rafal M Kaminski, Henrik Klitgaard

Abstract

The synaptic vesicle glycoprotein SV2A belongs to the major facilitator superfamily (MFS) of transporters and is an integral constituent of synaptic vesicle membranes. SV2A has been demonstrated to be involved in vesicle trafficking and exocytosis, processes crucial for neurotransmission. The anti-seizure drug levetiracetam was the first ligand to target SV2A and displays a broad spectrum of anti-seizure activity in various preclinical models. Several lines of preclinical and clinical evidence, including genetics and protein expression changes, support an important role of SV2A in epilepsy pathophysiology. While the functional consequences of SV2A ligand binding are not fully elucidated, studies suggest that subsequent SV2A conformational changes may contribute to seizure protection. Conversely, the recently discovered negative SV2A modulators, such as UCB0255, counteract the anti-seizure effect of levetiracetam and display procognitive properties in preclinical models. More broadly, dysfunction of SV2A may also be involved in Alzheimer's disease and other types of cognitive impairment, suggesting potential novel therapies for levetiracetam and its congeners. Furthermore, emerging data indicate that there may be important roles for two other SV2 isoforms (SV2B and SV2C) in the pathogenesis of epilepsy, as well as other neurodegenerative diseases. Utilization of recently developed SV2A positron emission tomography ligands will strengthen and reinforce the pharmacological evidence that SV2A is a druggable target, and will provide a better understanding of its role in epilepsy and other neurological diseases, aiding in further defining the full therapeutic potential of SV2A modulation.

Conflict of interest statement

Compliance with Ethical Standards Funding Wolfgang Löscher’s initial animal studies on levetiracetam were supported by grants from UCB Pharma. No funding was obtained for preparing this current review. The open access payment for this article was funded by UCB Pharma. Conflict of interest Michel Gillard, Zara Sands, Rafal M. Kaminski, and Henrik Klitgaard are employees of UCB Pharma (Braine-l’Alleud, Belgium). Wolfgang Löscher has no conflicts of interest to declare.

Figures

Fig. 1
Fig. 1
Mechanism of action of clinically approved anti-seizure drugs. Updated and modified from Löscher and Schmidt [151]. Drugs marked with asterisks indicate that these compounds act by multiple mechanims (not all mechanisms shown here). GABA-T GABA aminotransferase, GAT GABA transporter, SV2A synaptic vesicle protein 2A, GABA gamma-aminobutyric acid, NMDA N-methyl-D-aspartate, AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, KCNQ a family of voltage-gated potassium channels (also known as the Kv7 family)
Fig. 2
Fig. 2
Chemical structures of the racetams piracetam, levetiracetam, brivaracetam and seletracetam
Fig. 3
Fig. 3
Effect of LEV on the a MEST in non-kindled rats, and b threshold for secondarily generalized seizures in amygdala-kindled rats. c, d Effect of BRV and SEL on the GST in amygdala-kindled rats. Data are shown as means ± SEM of a 20 non-kindled and b–d 9 fully kindled rats in percentage seizure threshold increase above vehicle control seizure thresholds. Significant differences to control thresholds are indicated by an asterisk (p < 0.05). Note the marked difference in anti-seizure efficacy of LEV in a non-kindled vs. b kindled rats. All drugs also significantly increased the threshold for focal seizures (ADT) in kindled rats. The minimum doses significantly increasing ADT were 1.25 mg/kg (LEV), 0.68 mg/kg (BRV), and 0.0074 mg/kg (SEL). Data on MEST in non-kindled rats are taken from Löscher and Hönack [12], and data on kindled rats are from Potschka and Löscher (unpublished observations). LEV levetiracetam, MEST maximal electroshock seizure threshold, GST generalized seizure threshold, BRV brivaracetam, SEL seletracetam, SEM standard error of the mean, ADT after-discharge threshold, i.p. intraperitoneally
Fig. 4
Fig. 4
Correlation between the anti-seizure activity of a series of LEV analogs in different epilepsy models and their SV2A in vitro binding affinities. a Genetically sound-susceptible mice; b corneally kindled mice; c rats with spontaneous absence-like EEG seizures from the GAERS strain. SV2A binding affinities pIC50 (−logIC50) were measured in rat brain membranes with the use of [3H]ucb 30889. Protective potencies, based on dose-response studies, are shown as pED50 (−logED50). All correlations were statistically significant (p < 0.01). From Kaminski et al. [20]. LEV levetiracetam, EEG electroencephalogram, GAERS genetical absence epilepsy rats from Strasbourg, SV2A synaptic vesicle protein 2A. ED50median effective dose, IC50half maximal inhibitory concentration, pED50 logED50, pIC50 logIC50
Fig. 5
Fig. 5
Schematic representation of the dynamics of SVs at the presynaptic terminal, illustrating detailed mechanism of NT release and synaptic vesicle recycling. SVs are specialized spheroidal membrane structures that traffic along the axon to the presynaptic terminals, where they internalize and store NTs (blue dots). The SV membrane harbors proteins, some of them highly glycosylated (synapsin, synaptotagmin, SV2, and synaptophysin), whose precise sorting is required for an efficient neurotransmission. A magnified view of an SV (top left) shows the main identified vesicular proteins (except for the proton pump). Some SV proteins, such as synapsins or SV2s, come in multiple isoforms. Once SVs are loaded by NTs, a number of processes lead to excocytosis. (1) NT-loaded SVs dock to the presynaptic membrane by interaction of Rab3 with the RIM protein. Docking displays the SVs in close contact with the SNARE ternary complex (syntaxin 1, SNAP25, and VAMP) and SNARE effectors (MUNCs). (2) Preactivation (priming). In response to increased presynaptic concentrations of Ca2+, sensed by synaptophysin, proteins of the complex change conformation, inducing SVs to fuse with the plasma membrane and release their contents into the synaptic cleft. (3) Fusion/release. Subsequently, empty SVs undergo coating with clathrin polymers, and dynamin-driven scission from plasma membrane. (4) Coating/scission allows SV membrane proteins to be recycled. SV2s are thought to be involved in several of these processes, including calcium-dependent exocytosis, NT loading/retention in synaptic vesicles, and synaptic vesicle priming, as well as transport of vesicle constituents. Updated and modified from Rossetto et al. [23]. SVs synaptic vesicles, NT neurotransmitter, SV2 synaptic vesicle protein-2, Syt synaptotagmin, VAMP vesicle integral membrane protein, SNARE soluble N-ethylmaleimide-sensitive factor attachment protein receptor, RIM proteins a family of active zone proteins, SNAP25 synaptosomal-associated protein 25, MUNC mammalian uncoordinated proteins, ADP adenosine diphosphate, ATP adenosine triphosphate
Fig. 6
Fig. 6
Schematic representation of SV2A. a SV2A is comprised of 2 TM domains (each of which is comprised of 6 TM helices) and three extramembranous domains, namely the amino domain (blue); a long intervening loop spanning region between TM helices 6 and 7 (orange); and an extracellular domain between TM helices 7 and 8 (green). 2D protein topology figure generated using Protter [152]. Models of b inward-open (based on GlpT template) and c outward-open (based on FucP) conformations of the SV2A protein [86] aligned using the numbering system for proteins of the major facilitator superfamily [153]. TM transmembrane, 2D 2-dimensional, SV2A synaptic vesicle protein-2A, GlpT glycerol-3-phosphate transporter, FucP L-fucose-proton symporter
Fig. 7
Fig. 7
Characterization of a novel SV2A PET radiotracer [11C]UCB-J in humans. a Axial, coronal and sagittal brain MRI images in a healthy volunteer subject (top row); regional volume of distribution maps (VT) during test (middle row) and retest (bottom row) PET scanning with [11C]UCB-J in the same subject. b Axial and coronal brain MRI images in a patient with temporal lobe epilepsy (top row); standardized uptake value maps (SUV) of [11C]UCB-J in the same subject (bottom row). Arrows show unilateral mesial temporal sclerosis (MTS) seen on MRI (top row) and reduced radioligand binding in the corresponding areas of the right mesial temporal lobe of the same subject (bottom row). From Finnema et al. [55]. SV2A synaptic vesicle protein-2A, PET positron emission tomography, MRI magnetic resonance imaging, SUV standardized uptake value, MTS mesial temporal sclerosis, VT volume of distribution

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