Experimental subarachnoid hemorrhage induces changes in the levels of hippocampal NMDA receptor subunit mRNA.
NMDA receptors may play a crucial role in nerve cell death following subarachnoid hemorrhage (SAH). Changes in NMDA receptor-mediated transmission appear before neuronal death in rodent models of transient ischemia, and NMDA receptor function is known to be dependent on subunit composition. Here, we have investigated whether mRNA expression of the NMDA receptor subunits is altered in the hippocampal formation 3-5 h following experimental SAH, and correlated these early alterations to subsequent delayed cell death. SAH was induced by intraluminal perforation of the internal carotid artery intracranially, and cerebral blood flow (CBF) was bilaterally monitored by laser-Doppler flowmetry. Early changes in NMDA receptor subunit mRNA and early nerve cell death were analyzed at 3-5 h after SAH, and delayed nerve cell death was analyzed at 2-7 days after SAH. Duration of ipsilateral CBF reduction below 30% of baseline (CBF30) was predictive of ipsilateral delayed nerve cell death in the CA1 2-7 days after SAH. At CBF30 > 9 min, we found downregulation of mRNA for NR2A, NR2B, and NR3B at 3-5 h after SAH, whereas the levels of NR1 mRNA were unaffected. The downregulation of NR2A and NR2B mRNA may result in a reduced NMDA receptor function. Such reduction may be sufficient to provide neuroprotection in the dentate gyrus, where no cell death appears, but insufficient to rescue neurons in the hippocampus proper following SAH.
Bendel
Olof
O
Section of Clinical CNS Research, Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden.
Prunell
Giselle
G
Stenqvist
Anna
A
Mathiesen
Tiit
T
Holmin
Staffan
S
Svendgaard
Niels-Aage
NA
Euler
Gabriel von
Gv
D000818:Animals; D016923:Cell Death / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002560:Cerebrovascular Circulation / Q000502:physiology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D021122:Protein Subunits / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D013345:Subarachnoid Hemorrhage / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D013997:Time Factors
C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; C501155:NR3B NMDA receptor; D021122:Protein Subunits; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid