Reduction of cerebral infarct size by non-competitive AMPA antagonists in rats subjected to permanent and transient focal ischemia.
Antagonists of 2-amino-3(3-hydroxy-5-methyl-4-isoxazolyl) propionic acid (AMPA) receptors can considerably reduce brain damage after cerebral ischemia, but effectiveness of selective AMPA antagonists has been questioned recently. Therefore, we evaluated the antiischemic efficacy of [+/-]-7-acetyl-5-[4-aminophenyl]-7,8-dihydro-8-cyano-8-methyl-9H-1,3-dioxolo-[4,5-h]-2,3-benzodiazepine (EGIS-8332) and GYKI 53405, two selective, non-competitive AMPA antagonists in two rat models of focal cerebral ischemia. Permanent focal ischemia was produced by electrocoagulation of the middle cerebral artery (MCA). EGIS-8332 and GYKI 53405 were administered 30 min after MCA occlusion at doses of 1, 3 or 10 mg/kg i.p. In transient focal ischemia, MCA was occluded for 1 h and reperfused for 24 h using the intraluminal filament technique and the compounds were given at 3x10 mg/kg i.p. 60, 120 and 180 min following occlusion. In permanent focal ischemia, EGIS-8332 decreased the volume of cerebral infarction both at 10 mg/kg i.p. (36.4%, p<0.01) and at 3 mg/kg i.p. (26.4%, p<0.05) in a dose-dependent manner. GYKI 53405 produced a similar antiischemic effect at 10 mg/kg i.p. (36.4%, p<0.01), but it was ineffective at 3 mg/kg i.p. (6.5%, p=0.57). In transient focal ischemia, EGIS-8332 reduced the volume of necrotic brain tissue (38.7%, p<0.01) and GYKI 53405 was similarly effective (32.6%, p<0.05). Both compounds afforded neuroprotection in the cortical and subcortical regions of the MCA territory. Selective, non-competitive AMPA antagonists administered after the ischemic insult can produce effective neuroprotective action in experimental models of focal cerebral ischemia; therefore, these compounds may be useful as therapeutic agents for the treatment of stroke and neurodegenerative disorders.
Matucz
Eva
E
Pharmacology Laboratory I, Division of Preclinical Research, EGIS Pharmaceuticals Ltd., 1475 Budapest 10 P.O.B. 100, Budapest, Hungary.
Móricz
Krisztina
K
Gigler
Gábor
G
Simó
Annamária
A
Barkóczy
József
J
Lévay
György
G
Hársing
László G
LG
Szénási
Gábor
G
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA