Seletracetam

Seletracetam is an antiepileptic agent that targets the presynaptic mechanisms of epilepsy. It interferes with synaptic vesicle exocytosis and neurotransmitter release by binding to synaptic vesicle protein 2A (SV2A) which is involved in synaptic vesicle docking and fusion. It is also a N-type calcium channel blocker that inhibits the abnormal neuronal discharge by inhibiting the calcium channel function and associated calcium currents. Seletracetam markedly reduces epileptiform markers of both hyper-excitability and hyper-synchronization in an in vitro slice model of epilepsy and potently suppresses seizures in in vivo epilepsy models mimicking both partial and generalized epilepsy.

Seletracetam binds to SV2A in a stereospecific and selective manner. SV2A is a membrane glycoprotein present in synaptic vesicles of neurons that plays a role as calcium regulators in neurotransmitter release and modulate synaptic networks. Seletracetam is thought to reduce excessive neuronal activity by modulating SV2A function and restoring the ability of a neuron to regulate its neurotransmitter release. Seizure generation induces a sustained membrane depolarization causing a prolonged firing of voltage-dependent calcium currents sufficient to induce a significant rise in calcium concentration. High voltage-activated calcium currents are inhibited by seletracetam by blocking N-type calcium channels in the pyramidal neurons. The drug reduces the degree of calcium influx and decreases the intraneuronal calcium concentration, blocking the abnormal fluctuations in membrane potential occurring during epileptic discharges.