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Ther Hypothermia Temp Manag. 2011 Nov;1(3):159-164.

Protracted Tyrosine Phosphorylation of the Glutamate Receptor Subunit NR2 in the Rat Hippocampus Following Transient Cerebral Ischemia is Prevented by Intra-Ischemic Hypothermia.

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  • 1Laboratory for Experimental Brain Research, The Wallenberg Neuroscience Center , Lund University Hospital, Lund, Sweden . ; Shock, Trauma and Anesthesiology Research Center, Department of Anesthesiology, University of Maryland School of Medicine , Baltimore, Maryland.

Abstract

Changes in the dynamic interactions of macromolecules in cell membranes appear to underlie the robust neuroprotective effect of hypothermia against selective neuronal degeneration in the CA1 region of the rat hippocampus after transient cerebral ischemia, but the detailed mechanisms are still elusive. Using the two-vessel occlusion model of transient normothermic cerebral ischemia of 15 min duration, we investigated the tyrosine phosphorylation of synaptic proteins in general and that of the NMDA receptor subunits in particular, at different times of recirculation. Specifically, the effect of intra-ischemic hypothermia (33°C), which provides neuroprotection to the CA1 region of the hippocampus, was studied. Phosphorylation of tyrosine residues on the NMDA receptor (NR) 2, but not of the NR1 or the AMPA receptor subunit 1 (GluR1) proteins, was markedly enhanced following cerebral ischemia. Protein tyrosine phosphorylation was persistently increased in the postsynaptic densities of the vulnerable CA1 region, but was transient in the CA3/dentate gyrus (DG) neurons where cell death was not evident. The phospho-tyrosine phosphatase activity decreased during reperfusion in the CA1 region but not in CA3/DG. Importantly, decreasing body temperature to 33°C during ischemia modified the dynamics of the protein tyrosine phosphorylation of NR2 in the CA1 region, which was transient and similar in time course to that seen in the CA3/DG region after normothermic ischemia. We conclude that the protracted tyrosine phosphorylation of the NR2 subunit in the hippocampus CA1 region following normothermic ischemia is attenuated by hypothermia and therefore constitutes an important target for hypothermic neuroprotection.

PMID:
23667772
PMCID:
PMC3621595
DOI:
10.1089/ther.2011.0013
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