How could perampanel, a potent AMPAergic antagonist, inhibit seizures but largely spare normal neurotransmission?

Perampanel is a widely prescribed anticonvulsant that shows a strong inhibitory effect on AMPA receptors (AMPAR), which are critical for mammalian neural transmission. It is unclear how normal neurological functions are largely preserved during perampanel therapy.

The glutamate-dependent mechanisms of action of perampanel on AMPAergic transmission were investigated from biophysical to network levels in neurons, brain slices and animals.

Perampanel, at therapeutic concentrations, dose-dependently slowed AMPAR activation to decrease and desynchronise early AMPAergic currents. The desynchronisation effect was much more manifest in high (~1 mM) than in low (~0.3 mM) glutamate, or with strong than weak stimulation of glutamatergic neurons. There could even be a synchronisation effect in cases of low glutamate or weak stimulation, constituting a novel 'use-dependent' dichotomised effect on AMPAergic transmission.

AMPAR activation constitutes two sequential processes, namely the association (glutamate binding) and the transformation (protein conformational change) steps. Perampanel slows transformation, resulting in glutamate-dependent bidirectional effects. In seizures and high ambient glutamate, the association steps are so fast that the transformation steps are relatively rate-limiting in AMPAR activation. However, a synchronisation effect of perampanel may emerge in low and variable glutamate (by shifting the rate-limiting role to the slowed and more uniform transformation steps). Perampanel can therefore selectively inhibit ictal discharges, but may also contribute to inadvertent seizure aggravation or psychiatric events with the potential synchronisation effect. The latter can be managed by deliberate and delicate up-or-down titration of the perampanel clinical dosage.