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

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.

Progress report on new antiepileptic drugs: A summary of the Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV). II. Drugs in more advanced clinical development

“…Unlike levetiracetam and brivaracetam, which selectively bind to SV2A, padsevonil binds with high affinity to all three isoforms of the SV2 protein: SV2A (pKi 8.5), SV2B (pKi 7.9), and SV2C (pKi 8.5) . Some data indicate that SV2B and SV2C might play a role in the pathogenesis of epilepsy and other neurodegenerative diseases . The way padsevonil interacts with SV2A also differs from levetiracetam and brivaracetam.…”

Analgesic, antiallodynic, and anticonvulsant activity of novel hybrid molecules derived from N-benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide and 2-(2,5-dioxopyrrolidin-1-yl)butanamide in animal models of pain and epilepsy

“…It is worth mentioning that regardless of the mechanism of action, they all act to reduce hyperexcitability by either decreasing excitatory or enhancing inhibitory neurotransmission (Löscher et al 2016). Voltage-dependent sodium and calcium channels seem to play a crucial role in establishing and regulating the excitability of CNS nerves and are the most common targets among currently available anticonvulsant drugs, including phenytoin, carbamazepine, lamotrigine, oxcarbazepine, and lacosamide (Brodie et al 2011; Liu et al 2003; Mantegazza et al 2010).…”

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

“…28 Several lines of evidence indicate that SV2A is the primary site of antiepileptic (antiseizure) action for LEV. 29 LEV's antiepileptogenic effects are also likely to be mediated by this target, although other targets of LEV may contribute to the overall effect. Epileptogenesis is accelerated in kindling experiments with SV2A-deficient mice.…”

“…29,34 SV2A knockout animals develop severe epilepsy early in their ontogeny. 29 The question arises how SV2A deficit leads to epileptogenesis, as the protein is present in both excitatory and inhibitory neurons under physiological conditions. Single-cell recordings in primary neuronal cultures from SV2A knockout animals indicate decreases in both excitatory and inhibitory postsynaptic currents.…”