Abstract
In the 1990s there was intense interest in ionotropic glutamate receptors as therapeutic targets for diverse neurological disorders, including epilepsy. NMDA receptors were thought to play a key role in the generation of seizures, leading to clinical studies of NMDA receptor blocking drugs in epilepsy. Disappointing results dampened enthusiasm for ionotropic glutamate receptors as a therapeutic target. Eventually it became appreciated that another type of ionotropic glutamate receptor, the AMPA receptor, is actually the predominant mediator of excitatory neurotransmission in the central nervous system and moreover that AMPA receptors are critical to the generation and spread of epileptic activity. As drugs became available that selectively target AMPA receptors, it was possible to demonstrate that AMPA receptor antagonists have powerful antiseizure activity in in vitro and in vivo models. A decade later, promising clinical studies with AMPA receptor antagonists, including the potent noncompetitive antagonist perampanel, are once again focusing attention on AMPA receptors as a drug target for epilepsy therapy.
Highlights
In the 1990s there was intense interest in ionotropic glutamate receptors as therapeutic targets for diverse neurological disorders, including epilepsy
It became appreciated that another type of ionotropic glutamate receptor, the amino-3-hydroxyl-5-methyl-4isoxazole-propionic acid (AMPA) receptor, is the predominant mediator of excitatory neurotransmission in the central nervous system and that AMPA receptors are critical to the generation and spread of epileptic activity
AMPA receptors play a more central role than NMDA receptors in excitatory synaptic transmission, and AMPA receptor antagonists have a broader spectrum of activity than NMDA antagonists in in vitro and in vivo epilepsy models
Summary
In the 1990s there was intense interest in ionotropic glutamate receptors as therapeutic targets for diverse neurological disorders, including epilepsy. A decade later, promising clinical studies with AMPA receptor antagonists, including the potent noncompetitive antagonist perampanel, are once again focusing attention on AMPA receptors as a drug target for epilepsy therapy. Repetitive activation of AMPA receptors can cause sufficient depolarization to relieve the magnesium block, enabling a slower NMDA receptor mediated component of the response that is associated with calcium influx into the postsynaptic neuron.
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