Published online before print September 18, 2008, doi: 10.1161/STROKEAHA.108.527309
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(Stroke. 2008;39:e179.)
© 2008 American Heart Association, Inc.
Letters to the Editor |
Response to Letter by Kelsen et al
Department of Neurology and Radiology, Massachusetts General Hospital, Boston, Massachusetts
Response:
We appreciate the comments by Dr Kelsen and colleagues regarding our recent article.1 Before addressing the specific comments in the letter, we would like to emphasize that by using our newly created Ngb transgenic (Ngb-Tg, nontissue specific) mouse, we studied the effects of Ngb overexpression in focal cerebral ischemia. So, this published study was not aimed to fundamentally define or interpret the role of endogenous Ngb. Instead, this was an "outcomes" study. Overexpression of Ngb resulted in a reduction of ischemic brain injury. Our results were broadly consistent with an earlier report from Dr Greenberg’s group,2 suggesting that Ngb overexpression is neuroprotective against transient focal cerebral ischemia, although the possible mechanism of neuroprotective action needs to be further characterized.
Dr Kelsen and colleagues have extensively studied Ngb expression in both normal rats as well as responses to cerebral ischemia,3–5 and we have tried our best to interpret our own data in light of these critically important previous findings. We agree that controversies in published data on Ngb expression patterns in response to ischemia/hypoxia are at least partially caused by the use of different antibodies and ribonucleotide probes.5–8 These caveats remain to be further untangled. Regarding the reduction of ischemic infarction, we used 2 types of focal cerebral ischemia models: an acute model following outcomes after 2-hour transient ischemia, and a long-term recovery model following outcomes after a 1-hour transient ischemia. In the 2-hour ischemia model, the subcortical area is the ischemic core, and the overlying cortex is generally considered to be the penumbra. However, in the 1-hour ischemia model, the entire ischemic area is much smaller and in our study, seemed to be restricted to the subcortex. Hence, in the first scenario, neuroprotection is expected to occur in cortex, whereas in the second scenario, it is possible that neuroprotection occurs in the ischemic subcortex itself. Furthermore, the 2 ischemic models involve different pathogenic and recovery processes after focal cerebral ischemia. Thus, it is possible that reduction of acute 24-hour infarction was not found in subcortex after 2-hour transient focal ischemia, but was found in subcortex on 14 days after 1-hour focal ischemia in Ngb Tg mice. We also agree that malondialdehyde (MDA) is not only a surrogate biomarker of reactive oxygen species, and can be confounded by infarct size. Accordingly, we stated in our Discussion section that for in vivo stroke models, it is difficult to unequivocally prove causality because reduced tissue damage may secondarily contribute to decreased oxidative stress and/or mitochondrial dysfunction.
Once again, we are very grateful to Dr Kelsen et al for their interest in our article. They have raised many important questions. We fully agree that further dissections of Ngb function in normal versus ischemic brain need to be performed before firm conclusions regarding mechanisms can be made.
Acknowledgments
Disclosures
None.
References
1. Wang X, Liu J, Zhu H, Tejima E, Tsuji K, Murata Y, Atochin DN, Huang PL, Zhang C, Lo EH. Effects of neuroglobin overexpression on acute brain injury and long-term outcomes after focal cerebral ischemia. Stroke. 2008; 39: 1869–1874.
2. Khan AA, Wang Y, Sun Y, Mao XO, Xie L, Miles E, Graboski J, Chen S, Ellerby LM, Jin K, Greenberg DA. Neuroglobin-overexpressing transgenic mice are resistant to cerebral and myocardial ischemia. Proc Natl Acad Sci U S A. 2006; 103: 17944–17948.
3. Hundahl CA, Kelsen J, Dewilde S, Hay-Schmidt A. Neuroglobin in the rat brain (II): co-localisation with neurotransmitters. Neuroendocrinology. 2008; Epub. PMID:18509243.
4. Hundahl CA, Allen GC, Nyengaard JR, Dewilde S, Carter BD, Kelsen J, Hay-Schmidt A. Neuroglobin in the rat brain: Localization. Neuroendocrinology. 2008; Epub. PMID:18451642.
5. Hundahl C, Kelsen J, Kjaer K, Ronn LC, Weber RE, Geuens E, Hay-Schmidt A, Nyengaard JR. Does neuroglobin protect neurons from ischemic insult? A quantitative investigation of neuroglobin expression following transient mcao in spontaneously hypertensive rats. Brain Res. 2006; 1085: 19–27.[CrossRef][Medline] [Order article via Infotrieve]
6. Reuss S, Saaler-Reinhardt S, Weich B, Wystub S, Reuss MH, Burmester T, Hankeln T. Expression analysis of neuroglobin mrna in rodent tissues. Neuroscience. 2002; 115: 645–656.[CrossRef][Medline] [Order article via Infotrieve]
7. Wystub S, Laufs T, Schmidt M, Burmester T, Maas U, Saaler-Reinhardt S, Hankeln T, Reuss S. Localization of neuroglobin protein in the mouse brain. Neurosci Lett. 2003; 346: 114–116.[CrossRef][Medline] [Order article via Infotrieve]
8. Sun Y, Jin K, Mao XO, Xie L, Peel A, Childs JT, Logvinova A, Wang X, Greenberg DA. Effect of aging on neuroglobin expression in rodent brain. Neurobiol Aging. 2005; 26: 275–278.[CrossRef][Medline] [Order article via Infotrieve]
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