Eliprodil, a non-competitive, NR2B-selective NMDA antagonist, protects pyramidal neurons in hippocampal slices from hypoxic/ischemic damage.
The N-methyl-D-aspartate (NMDA) subtype of glutamate receptor is one pathway through which excessive influx of calcium has been suggested to trigger ischemia-induced delayed neuronal death. NMDA receptors are heterooligomeric complexes comprised of both NR1 and NR2A-D subunits, in various combinations. NR2B-containing NMDA complexes exhibit larger, more prolonged conductances than those lacking this subunit. We tested the ability of the non-competitive, NR2B-selective NMDA antagonist eliprodil to (a) protect synaptic transmission in in vitro hippocampal slices from hypoxia, and (b) reduce ischemic delayed neuronal death in hippocampal organotypic slice cultures. Eliprodil markedly improved the recovery of Schaffer collateral-CA1 excitatory postsynaptic potentials following a 15 min hypoxic insult, with an EC50 of approximately 0.5 microM. In contrast to this functional protection, eliprodil did not reduce delayed death of CA1 pyramidal neurons in organotypic hippocampal slice cultures treated with severe hypoxia plus hypoglycemia, though it did potently protect CA3 pyramidal neurons in the same cultures. These data indicate that NMDA receptors containing NR2B subunits may play a role in long-term recovery of hippocampal synaptic function following ischemia/hypoxia. Furthermore, the selective protection of CA3, but not CA1, pyramidal neurons suggests that NR2B-containing NMDA receptors may preferentially contribute to an excitotoxic component of ischemia-induced delayed neuronal death.
Reyes
M
M
Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461-1602, USA.
Reyes
A
A
Opitz
T
T
Kapin
M A
MA
Stanton
P K
PK
D000818:Animals; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D000860:Hypoxia / Q000473:pathology*; D066298:In Vitro Techniques; D007511:Ischemia / Q000473:pathology*; D008297:Male; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D010880:Piperidines; D016202:N-Methylaspartate; C058083:eliprodil