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The Journal of Neuroscience, June 6, 2007, 27(23):6320-6332; doi:10.1523/JNEUROSCI.0449-07.2007

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Neurobiology of Disease
Neuron-Specific Inactivation of the Hypoxia Inducible Factor 1 Increases Brain Injury in a Mouse Model of Transient Focal Cerebral Ischemia

Oxana Baranova,¹ Luis F. Miranda,¹ Paola Pichiule,³ Ioannis Dragatsis,⁴ Randall S. Johnson,⁵ and Juan C. Chavez^1,2

¹Burke Medical Research Institute, White Plains, New York 10605, ²Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, New York 10021, ³Department of Pediatrics, Morgan Stanley Children's Hospital, Columbia University, New York, New York 10032, ⁴Department of Physiology, The University of Tennessee, Health Science Center, Memphis, Tennessee 38163, and ⁵Molecular Biology Section, Division of Biology, University of California, San Diego, La Jolla, California 92093

Correspondence should be addressed to Dr. Juan C. Chavez, Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605. Email: jcc2005{at}med.cornell.edu, Email: jchavez{at}burke.org

In the present study, we show a biphasic activation of hypoxia inducible factor 1 (HIF-1) after stroke that lasts for up to 10 d, suggesting the involvement of the HIF pathway in several aspects of the pathophysiology of cerebral ischemia. We provide evidence that HIF-1-mediated responses have an overall beneficial role in the ischemic brain as indicated by increased tissue damage and reduced survival rate of mice with neuron-specific knockdown of HIF-1 that were subjected to transient focal cerebral ischemia. In addition, we demonstrated that drugs known to activate HIF-1 in cultured cells as well as in vivo had neuroprotective properties in this model of cerebral ischemia. This protective effect was significantly attenuated but not completely abolished in neuron-specific HIF-1-deficient mice, suggesting that alternative mechanisms of neuroprotection are also implicated. Last, our study showed that hypoxia-induced tolerance to ischemia was preserved in neuron-specific HIF-1-deficient mice, indicating that the neuroprotective effects of hypoxic preconditioning do not depend on neuronal HIF-1 activation.

Key words: stroke; hypoxia; preconditioning; gene expression; neuroprotection; HIF

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Received Jan. 31, 2007; revised April 16, 2007; accepted April 17, 2007.

Correspondence should be addressed to Dr. Juan C. Chavez, Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605. Email: jcc2005{at}med.cornell.edu, Email: jchavez{at}burke.org

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