Neuroprotective effects of the AMPA antagonist PNQX in oxygen-glucose deprivation in mouse hippocampal slice cultures and global cerebral ischemia in gerbils

• Published in: Brain research Vol. 1177; pp. 124 - 135
• Main Authors: Montero, Maria, Nielsen, Marianne, Rønn, Lars Christian B, Møller, Arne, Noraberg, Jens, Zimmer, Jens
• Format: Journal Article
• Language: English
• Published: London Elsevier B.V 26.10.2007; Amsterdam Elsevier; New York, NY
• Subjects: Animals; Biological and medical sciences; Body Temperature - drug effects; Body Temperature - physiology; Cell Death - drug effects; Coloring Agents; Dizocilpine Maleate - pharmacology; Excitatory Amino Acid Antagonists - pharmacology; Fluoresceins; Gerbillinae; Glucose - deficiency; Glutamate receptor antagonist; Hippocampus; Hippocampus - pathology; Hypoxia, Brain - drug therapy; Hypoxia, Brain - pathology; Ischemia; Ischemic Attack, Transient - drug therapy; Ischemic Attack, Transient - pathology; Medical sciences; Meriones unguiculatus; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins - biosynthesis; Nerve Degeneration - pathology; Neurology; Neuropharmacology; Neuroprotection; Neuroprotective agent; Neuroprotective Agents - pharmacology; Organ Culture Techniques; Organic Chemicals; Pharmacology. Drug treatments; Quinoxalines - pharmacology; Receptors, AMPA - antagonists & inhibitors; Tolonium Chloride; Vascular diseases and vascular malformations of the nervous system; PNQX; 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo( F)quinoxaline; AMPA; N-methyl- d-aspartate; HRP; 6-cyano-7-nitroquinoxaline-2,3-dione; PFA; half inhibitory concentration; CA1; Tris-buffered saline; CA3; Ischemia; FBS; horseradish peroxidase; paraformaldehyde; α-amino-3-hydroxy-5-methyl-4-isoazole-propionic acid; 2-VO; TBS; fascia dentata; i.p; fetal bovine serum; half exposure time; endonuclease G; glial fibrillary acidic protein; FD; microtubule-associated protein 2; Hippocampus; Neuroprotection; IC 50; RT; room temperature; EndoG; CNQX; oxygen-glucose deprivation; toluidine blue; Fluoro-Jade B; cornu amonis region 3; MAP2; propidium iodide; cornu amonis region 1; NMDA; FJ-B; 9-methyl-amino-6-nitro-hexahydro-benzo( F)quinoxalinedione; diaminobenzidine; ET 50; intraperitoneal; DAB; OGD; TB; Glutamate receptor antagonist; GFAP; PI; 2-vessel occlusion; NBQX; Deprivation; Rodentia; Central nervous system; Cardiovascular disease; Glutamate receptor; Glucose; Encephalon; Hippocampus,Glutamate receptor antagonist,Neuroprotection,Ischemia; Vertebrata; AMPA receptor; Mammalia; Mouse; Animal; Antagonist; Gerbil
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2007.08.038

Abstract PNQX (9-methyl-amino-6-nitro-hexahydro-benzo( F )quinoxalinedione) is a selective AMPA antagonist with demonstrated neuroprotective effects in focal ischemia in rats. Here we report corresponding effects in mouse hippocampal slice cultures subjected to oxygen and glucose deprivation (OGD) and in transient global cerebral ischemia in gerbils. For in vitro studies, hippocampal slice cultures derived from 7-day-old mice and grown for 14 days, were submersed in oxygen-glucose deprived medium for 30 min and exposed to PNQX for 24 h, starting together with OGD, immediately after OGD, or 2 h after OGD. For comparison, other cultures were exposed to the NMDA antagonist MK-801 using the same protocol. Both PNQX and MK-801 displayed significant neuroprotective effects in all hippocampal subfields when present during and after OGD. When added just after OGD, only PNQX retained some neuroprotective effect. When added 2 h after OGD neither PNQX nor MK-801 had an effect. Transient global cerebral ischemia was induced in Mongolian gerbils by occlusion of both common carotid arteries for 4.5 min, with PNQX (10 mg/kg) being injected i.p. 30, 60 and 90 min after the insult. Subsequent analysis of brain sections stained for the neurodegeneration marker Fluoro-Jade B and immunostained for the astroglial marker glial fibrillary acidic protein revealed a significant PNQX-induced decrease in neuronal cell death and astroglial activation. We conclude that, PNQX provided neuroprotection against both global cerebral ischemia in gerbils in vivo and oxygen-glucose deprivation in mouse hippocampal slice cultures.