Delayed treatments for stroke influence neuronal death in rat organotypic slice cultures subjected to oxygen glucose deprivation

A. A. Hall, C. C. Leonardo, L. A. Collier, D. D. Rowe, A. E. Willing, K. R. Pennypacker

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

A major limitation of current stroke therapies is the need to treat candidate patients within 3 h of stroke onset. Human umbilical cord blood cell (HUCBC) and the sigma receptor agonist 1,3, di-o-tolylguanidine (DTG) administration both caused significant reductions in brain damage in the rat middle cerebral artery occlusion model of stroke when administered at delayed timepoints. In vivo, these treatments suppress the infiltration of peripheral lymphocytes into the brain in addition to decreasing neurodegeneration. An ex vivo organotypic slice culture (OTC) model was utilized to characterize the efficacy of these treatments in mitigating neurodegeneration in ischemic brain tissue in the absence of the peripheral immune system. Slice cultures subjected to oxygen glucose deprivation (OGD) had significantly elevated levels of degenerating neurons and microglial nitric oxide production when compared to their normoxic counterparts. In cultures subjected to OGD, HUCBC but not DTG treatment reduced the number of degenerating neurons and the production of microglial derived nitric oxide back to levels detected in normoxic controls. These data show that HUCBC treatment can mediate direct neuroprotection and suppress innate inflammation in ischemic brain tissue in the absence of the peripheral immune system, whereas DTG requires peripheral effects to mediate neuroprotection. These experiments yield insight into the mechanisms by which these neuroprotective treatments function at delayed timepoints following stroke.

Original languageEnglish
Pages (from-to)470-477
Number of pages8
JournalNeuroscience
Volume164
Issue number2
DOIs
StatePublished - Dec 1 2009

Bibliographical note

Funding Information:
This work was supported by the National Institute of Neurological Disorders and Stroke (RO 1-NS052839-03 to K.R.P. and A.E.W.; 5R21NS060907 to K.R.P. and A.E.W.) and the American Heart Association (0715096B to A.A.H.). We would also like to acknowledge Karen Lai M.S. for her contributions with image analysis. AEW is an inventor on multiple cord blood patents. She consults to Saneron CCEL Therapeutics, Inc. which has licensed the cord blood technology from the University of South Florida.

Funding

This work was supported by the National Institute of Neurological Disorders and Stroke (RO 1-NS052839-03 to K.R.P. and A.E.W.; 5R21NS060907 to K.R.P. and A.E.W.) and the American Heart Association (0715096B to A.A.H.). We would also like to acknowledge Karen Lai M.S. for her contributions with image analysis. AEW is an inventor on multiple cord blood patents. She consults to Saneron CCEL Therapeutics, Inc. which has licensed the cord blood technology from the University of South Florida.

FundersFunder number
National Institute of Neurological Disorders and StrokeR01NS052839, 5R21NS060907
American Heart Association0715096B

    Keywords

    • human umbilical cord blood cells
    • inflammation
    • ischemia
    • neuroprotection
    • sigma receptors

    ASJC Scopus subject areas

    • General Neuroscience

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