Sprague-Dawley rats were subjected to a moderate level (2.2 atm) of traumatic brain injury (TBI) using fluid percussion. Injured animals were allowed post-trauma survival periods of 5 min, 3 and 24 h. Regional glutamate receptor subtype binding was assessed with quantitative autoradiography in each group for N-methyl-D-aspartate (NMDA), quisqualate and kainate receptor subpopulations at approximately the -3.8 bregma level and compared to a sham control group. [3H]glutamate binding to the NMDA receptor was significantly (P less than 0.05) decreased at 3 h post-TBI in the hippocampal CA1 stratum radiatum, the molecular layers of the dentate gyri and the outer (layers 1-3) and inner (layers 5 and 6) overlying neocortex. NMDA receptor binding was significantly reduced in layers 5 and 6 of the neocortex at all post-trauma survival times but no further differences were seen in the hippocampi. No significant changes were observed with [3H]AMPA binding to quisqualate receptors and [3H]KA binding was significantly reduced only in layers 5 and 6 of the neocortex at 24 h after TBI. These data further confirm the pathological involvement of the NMDA receptor complex in brain regions selectively vulnerable to moderate levels of TBI in this model.
"While advances in an understanding of the functional alterations occurring in the CA1 and other brain regions improves patient care, no specific pharmacological therapy for TBI is currently available that would improve neurological, behavioral, and cognitive outcomes (Beauchamp et al., 2008). Indeed, treatments directed at AMPA receptors may be ineffective , as no significant differences in the binding of extracellular excitatory amino acids to AMPA receptors following brain injury have been observed (McIntosh, 1993; Miller et al., 1990). NMDA receptor antagonists may be effective within hours of a TBI to reduce overstimulation, but may be ineffective or counter-effective 7 days after TBI (Beauchamp et al., 2008). "
"Compared to other NMDAR subtypes, NR2B-containing receptors appear to contribute preferentially to pathological processes linked to over-excitation of glutamatergic pathways (Mony et al., 2009). Impairments of NMDA-mediated transmission have been associated with increased neuronal Ca 2+ influx (Faden et al., 1989; Miller et al., 1990). Following brain injury, prolonged elevations of intracellular Ca 2+ in neurons may initiate molecular mechanisms that cause cellular injury and death and result in epileptogenesis within surviving neurons (DeLorenzo et al., 2005). "
[Show abstract][Hide abstract] ABSTRACT: Traumatic brain injury (TBI) can result in the development of posttraumatic epilepsy (PTE). Recently, we reported differential alterations in tonic and phasic GABA(A) receptor (GABA(A)R) currents in hippocampal dentate granule cells 90 days after controlled cortical impact (CCI) (Mtchedlishvili et al., 2010). In the present study, we investigated long-term changes in the protein expression of GABA(A)R α1, α4, γ2, and δ subunits, NMDA (NR2B) and AMPA (GluR1) receptor subunits, and heat shock proteins (HSP70 and HSP90) in the hippocampus of Sprague-Dawley rats evaluated by Western blotting in controls, CCI-injured animals without PTE (CCI group), and CCI-injured animals with PTE (PTE group). No differences were found among all three groups for α1 and α4 subunits. Significant reduction of γ2 protein was observed in the PTE group compared to control. CCI caused a 194% and 127% increase of δ protein in the CCI group compared to control (p<0.0001), and PTE (p<0.0001) groups, respectively. NR2B protein was increased in CCI and PTE groups compared to control (p=0.0001, and p=0.011, respectively). GluR1 protein was significantly decreased in CCI and PTE groups compared to control (p=0.003, and p=0.001, respectively), and in the PTE group compared to the CCI group (p=0.036). HSP70 was increased in CCI and PTE groups compared to control (p=0.014, and p=0.005, respectively); no changes were found in HSP90 expression. These results provide for the first time evidence of long-term alterations of GABA(A) and glutamate receptor subunits and a HSP following CCI.
Epilepsy research 03/2011; 95(1-2):20-34. DOI:10.1016/j.eplepsyres.2011.02.008 · 2.02 Impact Factor
"The excess glutamate results in an increased influx of calcium into the cell, which is mainly mediated through a specific post-synaptic glutamate receptor ion channel, the N-methyl- D-aspartate receptor (NMDAR). Therefore, this receptor was thought to play a key role in the mechanism of secondary excitotoxic damage after TBI (Faden et al., 1989; Hayes et al., 1988; Miller et al., 1990), although this theory was not universally accepted (Obrenovitch and Urenjak, 1997; Obrenovitch et al., 2000). NMDARs are heteromeric assemblies of a core NR1 subunit with different modulatory NR2 (A-D) and less common NR3 (A&B) subunits (Sucher et al., 1996; Sun et al., 1998). "
[Show abstract][Hide abstract] ABSTRACT: 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.
Journal of Neurotrauma 09/2008; 25(8):945-57. DOI:10.1089/neu.2008.0521 · 3.71 Impact Factor
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