Inhibition of calcium-permeable and calcium-impermeable AMPA receptors by perampanel in rat brain neurons.
Perampanel is an antiepileptic drug that is used to treat partial-onset seizures and generalized tonic-clonic seizures. It is a highly selective AMPA receptor allosteric antagonist. However, published data on perampanel activity vary in different studies. In the present work we studied the inhibition of native calcium-permeable and calcium-impermeable AMPA receptors in rat brain neurons by perampanel using whole-cell patch clamp technique. We found that inhibitory activity and kinetics of perampanel action do not differ between calcium-permeable AMPA receptors of rat giant striatum interneurons and calcium-impermeable receptors of hippocampal CA1 pyramidal neurons (the IC50value about 60nM). Also, perampanel caused the same inhibition of steady-state currents induced by kainate and glutamate. From the other side perampanel-induced inhibition was markedly reduced in the presence of cyclothiazide (IC50value increased to 1.2±0.2μM). We demonstrated that perampanel competes with GYKI-52466 for binding site.
I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, 194223, Torez pr. 44, Saint-Petersburg, Russia. Electronic address: Oleg_Barygin@mail.ru.
Oleg I
OI
Barygin
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology; D001581:Benzothiadiazines / Q000494:pharmacology; D001665:Binding Sites; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004347:Drug Interactions; D018698:Glutamic Acid / Q000494:pharmacology; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism; D007608:Kainic Acid / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009570:Nitriles; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology*; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000927:Anticonvulsants; D001581:Benzothiadiazines; D009570:Nitriles; D011728:Pyridones; D018091:Receptors, AMPA; C061950:GYKI 52466; D001569:Benzodiazepines; D018698:Glutamic Acid; C551441:perampanel; C004639:cyclothiazide; D007608:Kainic Acid; D002118:Calcium
AMPA receptors; Anticonvulsants; Inhibition; Mechanisms; Patch clamp; Perampanel