Intraischemic but not postischemic hypothermia prevents non-selective hippocampal downregulation of AMPA and NMDA receptor gene expression after global ischemia.
Hypothermia may afford histological neuroprotection induced by ischemia by preventing aberrant Ca2+ influx through NMDA (N-methyl-D-aspartic acid) or Ca2+-permeable AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) receptors. Expression of hippocampal GluR1A, GluR2B, GluR3C and NMDAR1 (NR1) subunits was investigated by in situ hybridization at 1 and 7 days after 10-min transient global ischemia in the presence and absence of intraischemic or postischemic brain hypothermia (30 degrees C). At 1 day, normothermic ischemia markedly suppressed the expression of GluR1A, GluR2B, and GluR3C receptor mRNAs to a similar degree in the vulnerable CA1. Less vulnerable CA3a-c subregions were also acutely downregulated. NR1 mRNA expression was reduced in CA1 but to a lesser extent than AMPA mRNAs. At 7 days after normothermic ischemia, a time of marked CA1 cell loss, all three AMPA transcripts were nearly absent in CA1 while a percentage (33.9+/-7.2%) of NR1 mRNA remained. Intraischemic hypothermia fully blocked the damage and non-selective mRNA downregulations at 1 and 7 days. By contrast, postischemic hypothermia postponed neurodegeneration but only partially rescued the expression of AMPA and NR1 mRNAs at 7 days and not at 1 day after the insult. Therefore, hippocampal AMPA receptor mRNAs decline at a relatively similar rate after normothermic global ischemia and cellular neuroprotection by intraischemic hypothermia occurred independently of altered subunit composition of AMPA receptors. Since decreases persist within resistant neurons under the postischemic condition, AMPA receptor-mediated Ca2+ currents probably do not contribute to selective vulnerability.
Friedman
L K
LK
Department of Neuroscience, Seton Hall University/NJ Neuroscience Institute at JFK Medical Center, 400 South Orange Avenue, South Orange, NJ 07079, USA. lfriedma@aol.com
Ginsberg
M D
MD
Belayev
L
L
Busto
R
R
Alonso
O F
OF
Lin
B
B
Globus
M Y
MY
D000818:Animals; D015536:Down-Regulation / Q000235:genetics; D015870:Gene Expression / Q000502:physiology; D006624:Hippocampus / Q000098:blood supply / Q000503:physiopathology*; D007036:Hypothermia, Induced; D017403:In Situ Hybridization; D002546:Ischemic Attack, Transient / Q000503:physiopathology*; D008297:Male; D009410:Nerve Degeneration / Q000503:physiopathology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000235:genetics*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*
D012333:RNA, Messenger; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C409466:NR1 NMDA receptor; C104723:glutamate receptor ionotropic, AMPA 3; C104722:glutamate receptor ionotropic, AMPA 2