The effects of AMPA receptor antagonists in models of stroke and neurodegeneration.
Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists have been shown to have neuroprotective effects in stroke models and although clinical trials with some agents are still ongoing, published results have not been favourable. We therefore wished to compare the effects of GYKI 52466, GYKI 53405, EGIS-8332 and EGIS-10608, non-competitive AMPA receptor antagonists with homophthalazine chemical structures, in standard animal stroke models with effects in a neurodegenerative model--excitoxicity in newborn mice. All compounds inhibited the S-AMPA-induced spreading depression in the chicken retina, in vitro, and were potent anticonvulsants against maximal electroshock in mice, in vivo. The AMPA receptor antagonists prevented domoate-induced cell death of motoneurons, in vitro, and reduced infarct size in a dose-dependent manner in the permanent middle cerebral artery occlusion model in mice, in vivo. In newborn mice (P5, histopathology at P10), local injection of the AMPA receptor agonist S-bromo-willardiine at day 5 after birth induced cortical damage and white matter damage, which was reduced in a dose-dependent manner by the AMPA receptor antagonists. EGIS 10608 was a very powerful receptor antagonist of white matter damage. In contrast, GYKI 52466 did not antagonize cortical and white matter damage induced by ibotenic acid. These models allow quantification of the effects of AMPA receptor antagonists in vitro and in vivo.
Gressens
Pierre
P
INSERM U676 and Service de Neurologie Pédiatrique, Hôpital Robert-Debré, 48 Blvd Sérurier, 75019 Paris, France.
Spedding
Michael
M
Gigler
Gabor
G
Kertesz
Szabolcs
S
Villa
Pascal
P
Medja
Fadia
F
Williamson
Toni
T
Kapus
Gabor
G
Levay
Gyorgy
G
Szenasi
Gabor
G
Barkoczy
Jozsef
J
Harsing
Laszlo G
LG
D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002545:Brain Ischemia / Q000150:complications; D002470:Cell Survival / Q000187:drug effects; D002645:Chickens; D013181:Cortical Spreading Depression / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004597:Electroshock / Q000009:adverse effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D020244:Infarction, Middle Cerebral Artery / Q000209:etiology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects; D009410:Nerve Degeneration / Q000517:prevention & control*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D012160:Retina / Q000187:drug effects / Q000503:physiopathology; D012640:Seizures / Q000209:etiology / Q000517:prevention & control; D020521:Stroke / Q000517:prevention & control*
D000927:Anticonvulsants; C505035:EGIS-10608; C505036:EGIS-8332; D018691:Excitatory Amino Acid Antagonists; D011810:Quinoxalines; D018091:Receptors, AMPA; C061950:GYKI 52466; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D001569:Benzodiazepines; C085266:talampanel