Neuroprotective effects of the AMPA antagonist PNQX in oxygen-glucose deprivation in mouse hippocampal slice cultures and global cerebral ischemia in gerbils.
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.
Montero
Maria
M
Anatomy and Neurobiology, Institute of Medical Biology, University of Southern Denmark, Winslowparken 21st, DK-5000 Odense C, Denmark. mmontero@health.sdu.dk
Nielsen
Marianne
M
Rønn
Lars Christian B
LC
Møller
Arne
A
Noraberg
Jens
J
Zimmer
Jens
J
D000818:Animals; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D016923:Cell Death / Q000187:drug effects; D004396:Coloring Agents; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005452:Fluoresceins; D005849:Gerbillinae; D005947:Glucose / Q000172:deficiency*; D006624:Hippocampus / Q000473:pathology*; D002534:Hypoxia, Brain / Q000188:drug therapy* / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis; D009410:Nerve Degeneration / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009924:Organ Culture Techniques; D009930:Organic Chemicals; D011810:Quinoxalines / Q000494:pharmacology*; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D014048:Tolonium Chloride
D004396:Coloring Agents; D018691:Excitatory Amino Acid Antagonists; D005452:Fluoresceins; D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents; D009930:Organic Chemicals; C120005:PD 152247; D011810:Quinoxalines; D018091:Receptors, AMPA; C435731:fluoro jade; D014048:Tolonium Chloride; D016291:Dizocilpine Maleate; D005947:Glucose