Intracerebral hemorrhage injury mechanisms: glutamate neurotoxicity, thrombin, and Src.
The mechanisms accounting for variable increases in blood flow and seizures following intracerebral hemorrhage (ICH) are unknown. Local cerebral glucose utilization (LCGU) studies performed to address this issue demonstrate increased LCGU within hours around an ICH that is blocked by NMDA and AMPA glutamate receptor antagonists. Local injections of NMDA or AMPA increased LCGU whereas glutamate did not, suggesting an ICH effect on glutamate uptake or glutamate receptors. To address these possibilities, we performed genomic studies of brain following ICH. Among the many regulated genes, an Src family member, Lyn, increased expression over 20-fold. This was important, since Src is known to phosphorylate NMDA receptors and augment their function, and thrombin is known to activate PARs that activate Src. This prompted us to study the Src antagonist, PP2. PP2 decreased LCGU and cell death around ICH and improved behavioral function following ICH. This data leads us to suggest our hypothesis, that ICH, possibly via thrombin activation of protease-activated receptors, activates Src that phosphorylates NMDA receptors and other proteins that mediate injury after ICH.
Sharp
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Department of Neurology, MIND Institute, University of California at Davis Medical Center, Sacramento, CA 95817, USA. frank.sharp@ucdmc.ucdavis.edu
Liu
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DZ
Zhan
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Ander
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BP
D000818:Animals; D002543:Cerebral Hemorrhage / Q000150:complications / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D020258:Neurotoxicity Syndromes / Q000188:drug therapy / Q000209:etiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*
D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D019061:src-Family Kinases; D013917:Thrombin