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Preconditioning in the Rhesus Macaque Induces a Proteomic Signature Following Cerebral Ischemia that Is Associated with Neuroprotection

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Abstract

Each year, thousands of patients are at risk of cerebral ischemic injury, due to iatrogenic responses to surgical procedures. Prophylactic treatment of these patients as standard care could minimize potential neurological complications. We have shown that protection of brain tissue, in a non-human primate model of cerebral ischemic injury, is possible through pharmacological preconditioning using the immune activator D192935. We postulate that preconditioning with D192935 results in neuroprotective reprogramming that is evident in the brain following experimentally induced cerebral ischemia. We performed quantitative proteomic analysis of cerebral spinal fluid (CSF) collected post-stroke from our previously published efficacy study to determine whether CSF protein profiles correlated with induced protection. Four groups of animals were examined: naïve animals (no treatment or stroke); animals treated with vehicle prior to stroke; D192935 treated and stroked animals, further delineated into two groups, ones that were protected (small infarcts) and those that were not protected (large infarcts). We found that distinct protein clusters defined the protected and non-protected animal groups, with a 16-member cluster of proteins induced exclusively in D192935 protected animals. Seventy percent of the proteins induced in the protected animals have functions that would enhance neuroprotection and tissue repair, including several members associated with M2 macrophages, a macrophage phenotype shown to contribute to neuroprotection and repair during ischemic injury. These studies highlight the translational importance of CSF biomarkers in defining mechanism and monitoring responses to treatment in development of stroke therapeutics.

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Acknowledgements

The proteomics work described herein was performed in the Environmental Molecular Sciences Laboratory, a U.S. Department of Energy (DOE) national scientific user facility located at PNNL in Richland, Washington. PNNL is a multi-program national laboratory operated by Battelle Memorial Institute for the DOE under Contract DE-AC05-76RL01830.

Funding

This work was supported by National Institutes of Health grants NS064953 (MSP, SGK), OD011092 (SGK), and P41GM103493 (RDS).

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Authors and Affiliations

  1. Department of Molecular Microbiology and Immunology, Oregon Health & Science University, 3181 Sam Jackson Park Road, Portland, OR, 97239, USA

    Susan L. Stevens, Frances Rena Bahjat, Christine Glynn & Mary P. Stenzel-Poore

  2. Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA

    Tao Liu, Vladislav A. Petyuk, Athena A. Schepmoes, Ryan L. Sontag, Marina A. Gritsenko, Chaochao Wu, Sheng Wang, Anil K. Shukla, Jon M. Jacobs, Richard D. Smith & Karin D. Rodland

  3. Houston Methodist Neurosurgery, Houston, TX, USA

    G. Alexander West

  4. Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR, USA

    Steven G. Kohama

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  1. Susan L. Stevens
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  2. Tao Liu
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Correspondence to Mary P. Stenzel-Poore.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.

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Stevens, S.L., Liu, T., Bahjat, F.R. et al. Preconditioning in the Rhesus Macaque Induces a Proteomic Signature Following Cerebral Ischemia that Is Associated with Neuroprotection. Transl. Stroke Res. 10, 440–448 (2019). https://doi.org/10.1007/s12975-018-0670-7

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