Glutamate Receptor Blockade Attenuates Glucose Hypermetabolism in Perihematomal Brain After Experimental Intracerebral Hemorrhage in Rat

Abstract

Background and Purpose-Intracerebral hemorrhage has no effective treatment. The delayed appearance of edema, apoptosis, and inflammation in perihematomal brain suggests that these events may be targets for therapeutic intervention. To develop successful treatments, we must learn more about the effects of hemorrhage on brain tissue. In this study, we investigated the acute metabolic effects of intrastriatal hemorrhage in rat brain. Methods-Lysed blood or saline (50 L each) was injected into the striatum of male Sprague-Dawley rats. The rats recovered for 1 to 72 hours before injection of [ 14 C]-2-deoxyglucose (intraperitoneally) 30 minutes before decapitation. Animals were pretreated with the N-methyl-D-aspartate (NMDA) and ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonists dizolcilpine maleate (MK-801; 1 mg/kg) or 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline (NBQX; 30 mg/kg), or saline vehicle. Additional animals received intrastriatal injections of glutamate (1.0 mmol/L), NMDA (1.0 mmol/L), or AMPA (0.1 mmol/L) in the place of blood. Semiquantitative autoradiographs from the brains were analyzed to determine the effects of hemorrhage on relative glucose metabolism. Results-We found an acute phase of increased [14 C]-2-deoxyglucose uptake in the perihematomal region that peaks 3 hours after lysed blood injection. Saline injections had no effect on striatal glucose utilization. The increased [14 C]-2-deoxyglucose uptake produced by the hemorrhages was blocked by pretreatment with MK-801 and NBQX. Glutamate injections alone had no effect on striatal metabolism, whereas NMDA and AMPA injections increased [ 14 C]-2-deoxyglucose uptake. Conclusions-The data imply that glutamate activation of NMDA or AMPA receptors increases glucose metabolism in perihematomal brain at early times after intracerebral hemorrhage. This may provide a possible target for the treatment of intracerebral hemorrhage.

Src kinase inhibition decreases thrombin-induced injury and cell cycle re-entry in striatal neurons

“…This protection is roughly equivalent to that produced by MK801. The findings are consistent with our previous report that the Src kinase inhibitor PP1 improves outcomes following whole blood injections, and the protection was similar to that afforded by MK801 (Ardizzone et al, 2004, Ardizzone et al, 2007.…”

Transient Focal Increase in Perihematomal Glucose Metabolism After Acute Human Intracerebral Hemorrhage

“…23,24 Blockade of posttraumatic and post-ICH hyperglycolysis in animal models by glutamate receptor antagonists is consistent with glutamate-mediated hyperglycolysis. 25,26 However, the time course of the increase in glutamate after ICH (peaking within hours) does not correspond well to the transient increase in FDG uptake we observed.…”

Src Kinase Inhibition Improves Acute Outcomes After Experimental Intracerebral Hemorrhage

“…47 Our previous study showed increased cerebral glucose utilization at 3 hours and 8 hours after ICH. 30 Blocking NMDA or AMPA glutamate receptors blocked increased glucose metabolism. 30 These data coupled with studies showing that pp60-Src (Src) potentiates the function of NMDA receptors through direct phosphorylation of the NR2A subunit, 13 anchoring NMDA receptors 48 and phosphorylation of the scaffolding protein PSD95 at the postsynaptic density of NMDA receptors, 49 suggest that blocking Src might block NMDA receptor activation and, in turn, block the ICHinduced increases of glucose metabolism in this study.…”

“…30 Blocking NMDA or AMPA glutamate receptors blocked increased glucose metabolism. 30 These data coupled with studies showing that pp60-Src (Src) potentiates the function of NMDA receptors through direct phosphorylation of the NR2A subunit, 13 anchoring NMDA receptors 48 and phosphorylation of the scaffolding protein PSD95 at the postsynaptic density of NMDA receptors, 49 suggest that blocking Src might block NMDA receptor activation and, in turn, block the ICHinduced increases of glucose metabolism in this study. 30 Alternatively, because Src phosphorylates many targets, Src might modulate glucose metabolism after ICH by phosphorylating other molecules, perhaps even on non-neuronal cells.…”