Therapeutic time window of neuroprotection by non-competitive AMPA antagonists in transient and permanent focal cerebral ischemia in rats

• Published in: Brain research Vol. 1123; no. 1; pp. 60 - 67
• Main Authors: Matucz, Éva, Móricz, Krisztina, Gigler, Gábor, Benedek, Angéla, Barkóczy, József, Lévay, György, Hársing, László G., Szénási, Gábor
• Format: Journal Article
• Language: English
• Published: London Elsevier B.V 06.12.2006; Amsterdam Elsevier; New York, NY
• Subjects: AMPA antagonist; Animals; Benzodiazepines - administration & dosage; Biological and medical sciences; Brain Ischemia - etiology; Brain Ischemia - pathology; Brain Ischemia - prevention & control; Cerebral Cortex - blood supply; Cerebral Cortex - drug effects; Cerebral Cortex - pathology; Drug Administration Schedule; Infarction, Middle Cerebral Artery - complications; Infarction, Middle Cerebral Artery - pathology; Male; Medical sciences; Middle cerebral artery occlusion; Neostriatum - blood supply; Neostriatum - drug effects; Neostriatum - pathology; Neurology; Neuropharmacology; Neuroprotection; Neuroprotective agent; Neuroprotective Agents - administration & dosage; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Receptors, AMPA - antagonists & inhibitors; Therapeutic time window; Time Factors; Vascular diseases and vascular malformations of the nervous system; Neuroprotection; AMPA antagonist; Middle cerebral artery occlusion; Therapeutic time window; Rat; Rodentia; Central nervous system; Cardiovascular disease; Glutamate receptor; Encephalon; Vertebrata; AMPA receptor; Mammalia; Treatment; Ischemia; Animal; Antagonist
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2006.09.043

EGIS-8332 and GYKI 53405 are selective, non-competitive AMPA (2-amino-3[3-hydroxy-5-methyl-4-isoxazolyl] propionic acid) antagonists that effectively protected against tissue injury caused by global and focal cerebral ischemia in laboratory animals. This study evaluated the therapeutic time window of neuroprotection by EGIS-8332 and GYKI 53405 in permanent and transient middle cerebral artery occlusion (MCAO) in Sprague-Dawley rats. Infarct size was measured by TTC staining 48 h after permanent MCAO (electrocoagulation), and 24 h after reperfusion following a 1-h transient MCAO carried out using the intraluminal filament technique. Treatment with EGIS-8332 (10 mg/kg, i.p.) 60 or 120 min after permanent MCAO, decreased infarct size by 30% and 36%, respectively, and the effect of GYKI 53405 (10 mg/kg, i.p.) was similar (30% and 33%, respectively; p < 0.01 all). Neither compound was effective if administered 180 or 240 min after permanent MCAO. Both EGIS-8332 and GYKI 53405 (20 mg/kg, i.p.) reduced the core and total (core plus penumbra) volumes of tissue injury in the whole brain and the cerebral cortex when administered 120 or 180 min after transient MCAO. The compounds did not alter tissue damage in the striatum. No neuroprotective effect was obtained at 240 min after transient MCAO. In conclusion, the therapeutic time window of neuroprotection by EGIS-8332 and GYKI 53405 was 2 h in permanent and 3 h in transient focal cerebral ischemia in rats. The results suggest that treatment with non-competitive AMPA antagonists can only be expected to produce a neuroprotective action in humans if administered shortly after the appearance of stroke symptoms.