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

Susan L. Stevens, Tao Liu, Frances Bahjat, 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, G. Alexander West, Steven Kohama, Christine Glynn, Mary Stenzel-Poore

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
JournalTranslational Stroke Research
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Brain Ischemia
Macaca mulatta
Proteomics
Stroke
Wounds and Injuries
Proteins
Macrophages
Brain
Therapeutics
Neuroprotection
Primates
Biomarkers
Pharmacology
Phenotype

Keywords

  • Cerebral spinal fluid
  • Neuroprotection
  • Non-human primates
  • Proteomics
  • Stroke

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

Cite this

Preconditioning in the Rhesus Macaque Induces a Proteomic Signature Following Cerebral Ischemia that Is Associated with Neuroprotection. / Stevens, Susan L.; Liu, Tao; Bahjat, Frances; Petyuk, Vladislav A.; Schepmoes, Athena A.; Sontag, Ryan L.; Gritsenko, Marina A.; Wu, Chaochao; Wang, Sheng; Shukla, Anil K.; Jacobs, Jon M.; Smith, Richard D.; Rodland, Karin D.; Alexander West, G.; Kohama, Steven; Glynn, Christine; Stenzel-Poore, Mary.

In: Translational Stroke Research, 01.01.2018.

Research output: Contribution to journalArticle

Stevens, SL, Liu, T, Bahjat, F, Petyuk, VA, Schepmoes, AA, Sontag, RL, Gritsenko, MA, Wu, C, Wang, S, Shukla, AK, Jacobs, JM, Smith, RD, Rodland, KD, Alexander West, G, Kohama, S, Glynn, C & Stenzel-Poore, M 2018, 'Preconditioning in the Rhesus Macaque Induces a Proteomic Signature Following Cerebral Ischemia that Is Associated with Neuroprotection', Translational Stroke Research. https://doi.org/10.1007/s12975-018-0670-7
Stevens, Susan L. ; Liu, Tao ; Bahjat, Frances ; Petyuk, Vladislav A. ; Schepmoes, Athena A. ; Sontag, Ryan L. ; Gritsenko, Marina A. ; Wu, Chaochao ; Wang, Sheng ; Shukla, Anil K. ; Jacobs, Jon M. ; Smith, Richard D. ; Rodland, Karin D. ; Alexander West, G. ; Kohama, Steven ; Glynn, Christine ; Stenzel-Poore, Mary. / Preconditioning in the Rhesus Macaque Induces a Proteomic Signature Following Cerebral Ischemia that Is Associated with Neuroprotection. In: Translational Stroke Research. 2018.
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AU - Liu, Tao

AU - Bahjat, Frances

AU - Petyuk, Vladislav A.

AU - Schepmoes, Athena A.

AU - Sontag, Ryan L.

AU - Gritsenko, Marina A.

AU - Wu, Chaochao

AU - Wang, Sheng

AU - Shukla, Anil K.

AU - Jacobs, Jon M.

AU - Smith, Richard D.

AU - Rodland, Karin D.

AU - Alexander West, G.

AU - Kohama, Steven

AU - Glynn, Christine

AU - Stenzel-Poore, Mary

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N2 - 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.

AB - 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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