Abstract
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.
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References
Ardizzone TD, Lu A, Wagner KR, Tang Y, Ran R, Sharp FR (2004) Glutamate receptor blockade attenuates glucose hypermetabolism in perihematomal brain after experimental intracerebral hemorrhage in rat. Stroke 35: 2587–2591
Ardizzone TD, Zhan X, Ander BP, Sharp FR (2007) Src kinase inhibition improves acute outcomes after experimental intracerebral hemorrhage. Stroke 38: 1621–1625
Fukami Y, Nagao T, Iwasaki T, Sato K (2002) Inhibition and activation of c-Src: the head and tail of a coin. Pharmacol Ther 93: 263–270
Gingrich JR, Pelkey KA, Fam SR, Huang Y, Petralia RS, Wenthold RJ, Salter MW (2004) Unique domain anchoring of Src to synaptic NMDA receptors via the mitochondrial protein NADH dehydroge-nase subunit 2. Proc Natl Acad Sci USA 101: 6237–6242
Lennmyr F, Ericsson A, Gerwins P, Akterin S, Ahlström H, Terént A (2004) Src family kinase-inhibitor PP2 reduces focal ischemic brain injury. Acta Neurol Scand 110: 175–179
Liu Y, Zhang G, Gao C, Hou X (2001) NMDA receptor activation results in tyrosine phosphorylation of NMDA receptor subunit 2A(NR2A) and interaction of Pyk2 and Src with NR2A after transient cerebral ischemia and reperfusion. Brain Res 909: 51–58
Lu A, Tang Y, Ran R, Ardizzone TL, Wagner KR, Sharp FR (2006) Brain genomics of intracerebral hemorrhage. J Cereb Blood Flow Metab 26: 230–252
Manzerra P, Behrens MM, Canzoniero LM, Wang XQ, Heidinger V, Ichinose T, Yu SP, Choi DW (2001) Zinc induces a Src family kinase-mediated up-regulation of NMDA receptor activity and excitotoxicity. Proc Natl Acad Sci USA 98: 11055–11061
Matz PG, Weinstein PR, Sharp FR (1997) Heme oxygenase-1 and heat shock protein 70 induction in glia and neurons throughout rat brain after experimental intracerebral hemorrhage. Neurosurgery 40: 152–162
Miyazawa N, Mitsuka S, Asahara T, Uchida M, Fukamachi A, Fukasawa I, Sasaki H, Nukui H (1998) Clinical features of relative focal hyperfusion in patients with intracerebral hemorrhage detected by contrast-enhanced xenon CT. Am J Neuroradiol 19: 1741–1746
Ogasawara K, Koshu K, Yoshimoto T, Ogawa A (1999) Transient hyperemia immediately after rapid decompression of chronic sub-dural hematoma. Neurosurgery 45: 484–489
Qureshi AI, Wilson DA, Hanley DF, Traystman RJ (1999) No evidence for an ischemic penumbra in massive experimental intracerebral hemorrhage. Neurology 52: 266–272
Sharp FR, Massa SM, Swanson RA (1999) Heat-shock protein protection. Trends Neurosci 22: 97–99
Turner CP, Bergeron M, Matz P, Zegna A, Noble LJ, Panter SS, Sharp FR (1998) Heme oxygenase-1 is induced in glia throughout brain by subarachnoid hemoglobin. J Cereb Blood Flow Metab 18: 257–273
Turner CP, Panter SS, Sharp FR (1999) Anti-oxidants prevent focal rat brain injury as assessed by induction of heat shock proteins (HSP70, HO-1/HSP32, HSP47) following subarachnoid injections of lysed blood. Brain Res Mol Brain Res 65: 87–102
Wang H, Reiser G (2003) Thrombin signaling in the brain: the role of protease-activated receptors. Biol Chem 384: 193–202
Wang H, Reiser G (2003) The role of the Ca2b-sensitive tyro-sine kinase Pyk2 and Src in thrombin signalling in rat astrocytes. J Neurochem 84: 1349–1357
Wang SJ (2003) A role for Src kinase in the regulation of glutamate release from rat cerebrocortical nerve terminals. Neuroreport 14: 1519–1522
Xi G, Keep RF, Hoff JT (1998) Erythrocytes and delayed brain edema formation following intracerebral hemorrhage in rats. J Neurosurg 89: 991–996
Xi G, Keep RF, Hoff JT (2006) Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol 5: 53–63
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Sharp, F., Liu, DZ., Zhan, X., Ander, B.P. (2008). Intracerebral hemorrhage injury mechanisms: glutamate neurotoxicity, thrombin, and Src. In: Zhou, LF., et al. Cerebral Hemorrhage. Acta Neurochirurgica Supplementum, vol 105. Springer, Vienna. https://doi.org/10.1007/978-3-211-09469-3_9
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DOI: https://doi.org/10.1007/978-3-211-09469-3_9
Publisher Name: Springer, Vienna
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