Published online before print August 3, 2006, doi: 10.1161/01.STR.0000237188.17849.24
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(Stroke. 2006;37:2200.)
© 2006 American Heart Association, Inc.
Letters to the Editor |
Response to Letter by Tsuda
Institute for Biomedical Research (IIBB)-Spanish Research Council (CSIC), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Response:
We thank Dr Tsuda for his interest in our work and his comments. In our study1 we addressed the question of whether the aggravation of ischemic damage caused by hyperglycemia was fully attributable to increased plasma corticosteroids and/or to cellular inflammatory responses. In a rat model of transient focal brain ischemia, we found that there was an intrinsic hyperglycemic damage not attributable to those factors. We detected increased O-linked glycosylation in brain tissue after hyperglycemia, and we argued that this might contribute to exacerbate ischemic damage. This is not incompatible with an effect of glucose in enhancing Ca2+-mediated damage, as suggested by Dr Tsuda. Indeed, hyperglycemia impairs intracellular calcium recovery at early reperfusion after focal brain ischemia,2 and chelation of intracellular calcium is protective after hyperglycemic in vitro ischemia.3 Several lines of evidence support that O-glycosylation alters cardiomyocyte calcium cycling and contributes to cardiac dysfunction in diabetic/hyperglycemic rats,4 and inhibition of O-glycosylation improves calcium handling and it is beneficial in this condition.5 A similar process might take place in the ischemic brain, but it has not been proven so far. Dr Tsuda proposes that glutamate receptor–mediated calcium conductance might have a crucial role in hyperglycemia-induced neurotoxicity. Excessive glutamate release to the extracellular space raises the intracellular Ca2+ concentration and contributes to ischemic brain damage.6 Yet, intracellular Ca2+ also increases through glutamate-independent mechanisms, such as those mediated by acid-sensing ion channels,7 by calpain-dependent cleavage of the Na+/Ca2+ exchanger,8 and by a reactive oxygen/nitrogen species–activated transient receptor potential cation channel (TRPM7).9,10 Hyperglycemia enhances ischemia-induced glutamate release,11 worsens tissue acidosis,12 increases the activity of calpains,13 and augments the production of intracellular reactive oxygen species through NADPH oxidase and mitochondrial pathways.14 Therefore, it is feasible that the metabolic and molecular changes generated by high glucose can further promote the raise of intracellular Ca2+ induced by brain ischemia. Further studies are certainly needed to unravel whether high glucose aggravates calcium toxicity in brain ischemia by glutamate-dependent or independent mechanisms, whether this is the major cause of exacerbation of ischemic damage, and whether O-linked glycosylation is involved in the process.
Acknowledgments
Disclosure
None.
References
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7. Xiong ZG, Zhu XM, Chu XP, Minami M, Hey J, Wei WL, MacDonald JF, Wemmie JA, Price MP, Welsh MJ, Simon RP. Neuroprotection in ischemia: blocking calcium-permeable acid-sensing ion channels. Cell. 2004; 118: 687–698.[CrossRef][Medline] [Order article via Infotrieve]
8. Bano D, Young KW, Guerin CJ, Lefeuvre R, Rothwell NJ, Naldini L, Rizzuto R, Carafoli E, Nicotera P. Cleavage of the plasma membrane Na+/Ca2+ exchanger in excitotoxicity. Cell. 2005; 120: 275–285.[CrossRef][Medline] [Order article via Infotrieve]
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12. Chopp M, Frinak S, Walton DR, Smith MB, Welch KM. Intracellular acidosis during and after cerebral ischemia: in vivo nuclear magnetic resonance study of hyperglycemia in cats. Stroke. 1987; 18: 919–923.
13. Stalker TJ, Skvarka CB, Scalia R. A novel role for calpains in the endothelial dysfunction of hyperglycemia. FASEB J. 2003; 17: 1511–1513.
14. Susztak K, Raff AC, Schiffer M, Bottinger EP. Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes. 2006; 55: 225–233.
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