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Author Notes:

Address correspondence: Manuel Yepes, Department of Neurology and Center for Neurodegenerative Disease, Whitehead Biomedical Research Building, 615 Michael Street, Suite 505J, Atlanta, Georgia 30322. Telephone: (404) 712 8358. Fax: (404) 727 3728. myepes@emory.edu

Fang Wu, Jialing Wu and Andrew Nicholson contributed equally to this work

The authors declare no competing financial interests.

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Research Funding:

This work was supported in part by National Institutes of Health Grants NS-062073 and VA MERIT award BX000474 (to M. Yepes) and National Natural Science Foundation of China 81173086 (to J. An).

Tissue-Type Plasminogen Activator Regulates the Neuronal Uptake of Glucose in the Ischemic Brain

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Journal Title:

Journal of Neuroscience Nursing

Volume:

Volume 32, Number 29

Publisher:

, Pages 9848-9858

Type of Work:

Article | Post-print: After Peer Review

Abstract:

The ability to sense and adapt to hypoxic conditions plays a pivotal role in neuronal survival. Hypoxia induces the release of tissue-type plasminogen activator (tPA) from cerebral cortical neurons. We found that the release of neuronal tPA or treatment with recombinant tPA (rtPA) promotes cell survival in cerebral cortical neurons previously exposed to hypoxic conditions in vitro or experimental cerebral ischemia in vivo. Our studies using liquid chromatography and tandem mass spectrometry revealed that tPA activates the mammalian target of rapamycin (mTOR) pathway which adapts cellular processes to the availability of energy and metabolic resources. We found that mTOR activation leads to accumulation of the hypoxia-inducible factor-1α (HIF-1α) and induction and recruitment to the cell membrane of the HIF-1α-regulated neuronal transporter of glucose GLUT3. Accordingly, in vivo positron emission tomography studies with 18-fluorodeoxyglucose in mice overexpressing tPA in neurons show that neuronal tPA induces the uptake of glucose in the ischemic brain and that this effect is associated with decrease in the volume of the ischemic lesion and improved neurological outcome following the induction of ischemic stroke. Our data indicate that tPA activates a cell signaling pathway that allows neurons to sense and adapt to oxygen and glucose deprivation.

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© 2012 the authors

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