This Article Full Text Full Text (PDF) All Versions of this Article: 34/1/214    most recent 01.STR.0000048846.09677.62v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ginsberg, M. D. Search for Related Content PubMed PubMed Citation Articles by Ginsberg, M. D. Related Collections Animal models of human disease Gene expression Ischemic biology - basic studies Acute Cerebral Infarction Brain Circulation and Metabolism Neuroprotectors

(Stroke. 2003;34:214.)
© 2003 American Heart Association, Inc.

Comments, Opinions, and Reviews

Adventures in the Pathophysiology of Brain Ischemia: Penumbra, Gene Expression, Neuroprotection

The 2002 Thomas Willis Lecture

From the Cerebral Vascular Disease Research Center, Department of Neurology, University of Miami School of Medicine, Miami, Fla.

Correspondence to Myron D. Ginsberg, MD, Department of Neurology (D4-5), University of Miami School of Medicine, PO Box 016960, Miami, FL 33101. E-mail mdginsberg{at}stroke.med.miami.edu

Background— The pathophysiology of cerebral ischemia is well studied in small-animal models, which offer reproducibility and control of confounding variables—factors essential to hypothesis-testing. This presentation first highlights insights into the ischemic penumbra enabled by a multimodal experimental approach; second, discusses gene expression in ischemia; and third, confronts the challenges of neuroprotectant therapy.

Summary of Review— The ischemic penumbra: Transient (2-hour) middle cerebral artery suture-occlusion in anesthetized rats gives rise to highly consistent neurological and histopathological sequelae. Autoradiographic local cerebral blood flow (LCBF) studies at 2 hours of occlusion define the penumbra as a region of intermediate CBF depression (20% to 40% of control) surrounding the densely ischemic core (5% to 20% of control) and constituting one half of the entire lesion. Local glucose metabolic rate in the acute penumbra is not reduced despite the critical CBF reduction, so that the penumbral metabolism/blood flow ratio is markedly elevated. In contrast, following 1 hour of recirculation, glucose metabolism throughout the previously ischemic hemisphere has become markedly depressed, and the metabolism/flow ratio has pseudonormalized. By correlating these data with histopathology using multimodal image analysis, the probability of infarction is shown to be highly determined by the degree of antecedent CBF reduction. These animal data agree strikingly with published results in patients with acute stroke studied by positron emission tomography. This remarkable correspondence belies the assertion that data from lower species may not be relevant to human stroke. Gene expression: Perfusion gradients also determine differential patterns of gene expression in ischemia. This can be demonstrated by correlating in situ hybridization autoradiographs for gene expression with autoradiographic LCBF data and histological infarct maps derived from replicate series. In other studies, DNA microarray technology is used to screen for thousands of expressed genes. In the 2-hour middle cerebral artery occlusion model with 3-hour recirculation, we have identified 28 known ischemia-hypoxia response genes that are upregulated and 6 that are downregulated, together with 35 upregulated and 41 downregulated genes newly connected with ischemia. These findings underscore the enormous complexity of ischemic biology and suggest possible novel mechanisms for future exploration. Neuroprotection: A desirable neuroprotectant would, in theory, antagonize multiple injury mechanisms. We have explored 2 such therapies of particular promise. Mild brain hypothermia (32°C target temperature, for 5 hours) is highly neuroprotective even when initiated at the onset of recirculation. Another highly protective agent is human albumin, administered in doses of 1.25 to 2.5 g/kg—a therapy that reduces infarct volume in this ischemia model by 60% to 65%, markedly diminishes brain swelling, and has a therapeutic window extending to 4 hours.

Conclusion— The careful study of rodent ischemia models can yield valuable, clinically relevant insights into the pathophysiology of ischemic stroke.

Key Words: cerebral blood flow • gene expression • glucose utilization • neuroprotection • penumbra

This article has been cited by other articles:

				J. Bardutzky, Q. Shen, N. Henninger, S. Schwab, T. Q. Duong, and M. Fisher Characterizing Tissue Fate After Transient Cerebral Ischemia of Varying Duration Using Quantitative Diffusion and Perfusion Imaging Stroke, April 1, 2007; 38(4): 1336 - 1344. [Abstract] [Full Text] [PDF]

				F. Adhami, G. Liao, Y. M. Morozov, A. Schloemer, V. J. Schmithorst, J. N. Lorenz, R. S. Dunn, C. V. Vorhees, M. Wills-Karp, J. L. Degen, et al. Cerebral Ischemia-Hypoxia Induces Intravascular Coagulation and Autophagy Am. J. Pathol., August 1, 2006; 169(2): 566 - 583. [Abstract] [Full Text] [PDF]

				N. J. Spratt, U. Ackerman, H. J. Tochon-Danguy, G. A. Donnan, and D. W. Howells Characterization of Fluoromisonidazole Binding in Stroke Stroke, July 1, 2006; 37(7): 1862 - 1867. [Abstract] [Full Text] [PDF]

				J. Woitzik, P. G. Pena-Tapia, U. C. Schneider, P. Vajkoczy, and C. Thome Cortical Perfusion Measurement by Indocyanine-Green Videoangiography in Patients Undergoing Hemicraniectomy for Malignant Stroke Stroke, June 1, 2006; 37(6): 1549 - 1551. [Abstract] [Full Text] [PDF]

				T. Omura, Y. Tanaka, N. Miyata, C. Koizumi, T. Sakurai, M. Fukasawa, K. Hachiuma, T. Minagawa, T. Susumu, S. Yoshida, et al. Effect of a New Inhibitor of the Synthesis of 20-HETE on Cerebral Ischemia Reperfusion Injury Stroke, May 1, 2006; 37(5): 1307 - 1313. [Abstract] [Full Text] [PDF]

				M. Shamloo, L. Soriano, T. Wieloch, K. Nikolich, R. Urfer, and D. Oksenberg Death-associated Protein Kinase Is Activated by Dephosphorylation in Response to Cerebral Ischemia J. Biol. Chem., December 23, 2005; 280(51): 42290 - 42299. [Abstract] [Full Text] [PDF]

				J. Bardutzky, Q. Shen, N. Henninger, J. Bouley, T. Q. Duong, and M. Fisher Differences in Ischemic Lesion Evolution in Different Rat Strains Using Diffusion and Perfusion Imaging Stroke, September 1, 2005; 36(9): 2000 - 2005. [Abstract] [Full Text] [PDF]

				P. R. Weinstein, S. Hong, and F. R. Sharp Molecular Identification of the Ischemic Penumbra Stroke, November 1, 2004; 35(11_suppl_1): 2666 - 2670. [Abstract] [Full Text] [PDF]

				E. G. Hoeffner, I. Case, R. Jain, S. K. Gujar, G. V. Shah, J. P. Deveikis, R. C. Carlos, B. G. Thompson, M. R. Harrigan, and S. K. Mukherji Cerebral Perfusion CT: Technique and Clinical Applications Radiology, June 1, 2004; 231(3): 632 - 644. [Abstract] [Full Text] [PDF]

				E. T. Gum, R. A. Swanson, C. Alano, J. Liu, S. Hong, P. R. Weinstein, and S. S. Panter Human Serum Albumin and its N-Terminal Tetrapeptide (DAHK) Block Oxidant-Induced Neuronal Death Stroke, February 1, 2004; 35(2): 590 - 595. [Abstract] [Full Text] [PDF]

				S. Goto, K. Sampei, N. J. Alkayed, S. Dore, and R. C. Koehler Characterization of a new double-filament model of focal cerebral ischemia in heme oxygenase-2-deficient mice Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2003; 285(1): R222 - R230. [Abstract] [Full Text] [PDF]