Inhibition of NR2B phosphorylation restores alterations in NMDA receptor expression and improves functional recovery following traumatic brain injury in mice.
Traumatic brain injury (TBI) triggers a massive glutamate efflux, hyperactivation of N-methyl-D-aspartate receptors (NMDARs) and neuronal cell death. Previously it was demonstrated that, 15 min following experimentally induced closed head injury (CHI), the density of activated NMDARs increases in the hippocampus, and decreases in the cortex at the impact site. Here we show that CHI-induced alterations in activated NMDARs correlate with changes in the expression levels of the major NMDARs subunits. In the hippocampus, the expression of NR1, NR2A, and NR2B subunits as well as the GluR1 subunit of the AMPA receptor (AMPAR) were increased, while in the cortex at the impact site, we found a decrease in the expression of these subunits. We demonstrate that CHI-induced increase in the expression of NMDAR subunits and GluR1 in the hippocampus, but not in the cortex, is associated with an increase in NR2B tyrosine phosphorylation. Furthermore, inhibition of NR2B-phosphorylation by the tyrosine kinase inhibitor PP2 restores the expression of this subunit to its normal levels. Finally, a single injection of PP2, prior to the induction of CHI, resulted in a significant improvement in long-term recovery of motor functions observed in CHI mice. These results provide a new mechanism by which acute trauma contributes to the development of secondary damage and functional deficits in the brain, and suggests a possible role for Src tyrosine kinase inhibitors as preoperative therapy for planned neurosurgical procedures.
Schumann
Johanna
J
Department of Pharmacology, School of Pharmacy, Hebrew University of Jerusalem, Jerusalem, Israel.
Alexandrovich
G Alexander
GA
Biegon
Anat
A
Yaka
Rami
R
D000818:Animals; D001930:Brain Injuries / Q000378:metabolism* / Q000503:physiopathology; D002540:Cerebral Cortex / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation; D011743:Pyrimidines / Q000494:pharmacology; D018091:Receptors, AMPA / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
C412373:AG 1879; D004791:Enzyme Inhibitors; C121001:NR2B NMDA receptor; D011743:Pyrimidines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D019061:src-Family Kinases