| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
From the Department of Pediatrics,* Division of Developmental Biology, the Department of Radiology, Imaging Research Center, and the Department of Pediatrics,|| Division of Immunobiology, Children’s Hospital Medical Center, Cincinnati, Ohio; the Physician Scientist Training Program and the Department of Molecular and Cellular Physiology,¶ University of Cincinnati College of Medicine, Cincinnati, Ohio; the Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut; the Howard Hughes Medical Institute and Program in Molecular Medicine,** University of Massachusetts Medical School, Worcester, Massachusetts; the Department of Bioregulation and Metabolism, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan; Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi, Japan; and M.I.N.D. Institute and Department of Neurology, University of California at Davis, Sacramento, California
Hypoxia is a critical factor for cell death or survival in ischemic stroke, but the pathological consequences of combined ischemia-hypoxia are not fully understood. Here we examine this issue using a modified Levine/Vannucci procedure in adult mice that consists of unilateral common carotid artery occlusion and hypoxia with tightly regulated body temperature. At the cellular level, ischemia-hypoxia produced proinflammatory cytokines and simultaneously activated both prosurvival (eg, synthesis of heat shock 70 protein, phosphorylation of ERK and AKT) and proapoptosis signaling pathways (eg, release of cytochrome c and AIF from mitochondria, cleavage of caspase-9 and -8). However, caspase-3 was not activated, and very few cells completed the apoptosis process. Instead, many damaged neurons showed features of autophagic/lysosomal cell death. At the tissue level, ischemia-hypoxia caused persistent cerebral perfusion deficits even after release of the carotid artery occlusion. These changes were associated with both platelet deposition and fibrin accumulation within the cerebral circulation and would be expected to contribute to infarction. Complementary studies in fibrinogen-deficient mice revealed that the absence of fibrin and/or secondary fibrin-mediated inflammatory processes significantly attenuated brain damage. Together, these results suggest that ischemia-hypoxia is a powerful stimulus for spontaneous coagulation leading to reperfusion deficits and autophagic/lysosomal cell death in brain.
This article has been cited by other articles:
 |
|
 |
|
  Y. Gao, W. Liang, X. Hu, W. Zhang, R. A. Stetler, P. Vosler, G. Cao, and J. Chen Neuroprotection Against Hypoxic-Ischemic Brain Injury by Inhibiting the Apoptotic Protease Activating Factor-1 Pathway Stroke, January 1, 2010; 41(1): 166 - 172. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Ginet, J. Puyal, P. G.H. Clarke, and A. C. Truttmann Enhancement of Autophagic Flux after Neonatal Cerebral Hypoxia-Ischemia and Its Region-Specific Relationship to Apoptotic Mechanisms Am. J. Pathol., November 1, 2009; 175(5): 1962 - 1974. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Xu, S. M. Liachenko, P. Tang, and P. H. Chan Faster Recovery of Cerebral Perfusion in SOD1-Overexpressed Rats After Cardiac Arrest and Resuscitation Stroke, July 1, 2009; 40(7): 2512 - 2518. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Meller The Role of the Ubiquitin Proteasome System in Ischemia and Ischemic Tolerance Neuroscientist, June 1, 2009; 15(3): 243 - 260. [Abstract] [PDF]
|
|
|
|
 |
|
 J. Marik, A. Ogasawara, B. Martin-McNulty, J. Ross, J. E. Flores, H. S. Gill, J. N. Tinianow, A. N. Vanderbilt, M. Nishimura, F. Peale, et al. PET of Glial Metabolism Using 2-18F-Fluoroacetate J. Nucl. Med., June 1, 2009; 50(6): 982 - 990. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Di Napoli and P. Singh Is Plasma Fibrinogen Useful in Evaluating Ischemic Stroke Patients?: Why, How, and When Stroke, May 1, 2009; 40(5): 1549 - 1552. [Full Text] [PDF]
|
|
|
|
 |
|
 J.-L. Chen, H. H. Lin, K.-J. Kim, A. Lin, H. J. Forman, and D. K. Ann Novel Roles for Protein Kinase C{delta}-dependent Signaling Pathways in Acute Hypoxic Stress-induced Autophagy J. Biol. Chem., December 5, 2008; 283(49): 34432 - 34444. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Wei Xu, Miou Zhou, and M. Baudry Neuroprotection by Cell Permeable TAT-mGluR1 Peptide in Ischemia: Synergy between Carrier and Cargo Sequences Neuroscientist, October 1, 2008; 14(5): 409 - 414. [Abstract] [PDF]
|
|
|
|
|
|
F. Adhami, D. Yu, W. Yin, A. Schloemer, K. A. Burns, G. Liao, J. L. Degen, J. Chen, and C.-Y. Kuan Deleterious Effects of Plasminogen Activators in Neonatal Cerebral Hypoxia-Ischemia Am. J. Pathol., June 1, 2008; 172(6): 1704 - 1716. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Harraz, T. M. Dawson, and V. L. Dawson Advances in Neuronal Cell Death 2007 Stroke, February 1, 2008; 39(2): 286 - 288. [Full Text] [PDF]
|
|
|
|
|
|
C. T. Chu Eaten Alive: Autophagy and Neuronal Cell Death after Hypoxia-Ischemia Am. J. Pathol., February 1, 2008; 172(2): 284 - 287. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Mizushima Autophagy: process and function Genes & Dev., November 15, 2007; 21(22): 2861 - 2873. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. A. Burns, A. E. Ayoub, J. J. Breunig, F. Adhami, W.-L. Weng, M. C. Colbert, P. Rakic, and C.-Y. Kuan Nestin-CreER Mice Reveal DNA Synthesis by Nonapoptotic Neurons following Cerebral Ischemia Hypoxia Cereb Cortex, November 1, 2007; 17(11): 2585 - 2592. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Schachtrup, P. Lu, L. L. Jones, J. K. Lee, J. Lu, B. D. Sachs, B. Zheng, and K. Akassoglou Fibrinogen inhibits neurite outgrowth via beta3 integrin-mediated phosphorylation of the EGF receptor PNAS, July 10, 2007; 104(28): 11814 - 11819. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
