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The broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disorders

View ORCID ProfilePatrick Miller-Rhodes, Cuicui Kong, Gurpreet S. Baht, Ramona M. Rodriguiz, William C. Wetsel, View ORCID ProfileHarris A. Gelbard, View ORCID ProfileNiccolò Terrando
doi: https://doi.org/10.1101/537472
Patrick Miller-Rhodes
1Center for Neurotherapeutics Discovery, University of Rochester Medical Center, Rochester, NY 14642
2Department of Neuroscience, University of Rochester Medical Center, Rochester, NY 14642
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  • ORCID record for Patrick Miller-Rhodes
Cuicui Kong
3Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC, 27710, USA
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Gurpreet S. Baht
4Department of Orthopedic Surgery and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, 27710, USA
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Ramona M. Rodriguiz
5Department of Psychiatry and Behavioral Sciences, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, North Carolina 27710, USA
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William C. Wetsel
5Department of Psychiatry and Behavioral Sciences, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, North Carolina 27710, USA
6Departments of Neurobiology and Cell Biology, Duke University Medical Center, Durham, NC 27710 USA
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Harris A. Gelbard
1Center for Neurotherapeutics Discovery, University of Rochester Medical Center, Rochester, NY 14642
2Department of Neuroscience, University of Rochester Medical Center, Rochester, NY 14642
7Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642
8Departments of Pediatrics and Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642
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  • For correspondence: Harris_Gelbard@URMC.Rochester.edu niccolo.terrando@duke.edu
Niccolò Terrando
3Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC, 27710, USA
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  • For correspondence: Harris_Gelbard@URMC.Rochester.edu niccolo.terrando@duke.edu
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Abstract

Perioperative neurocognitive disorders (PND), including delirium and postoperative cognitive dysfunction, are serious complications that afflict up to 50% of surgical patients and for which there are no disease-modifying therapeutic options. Here, we test whether prophylactic treatment with the broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents surgery-induced neuroinflammation and cognitive impairment in a translational model orthopedic surgery-induced PND. We used a combination of two-photon scanning laser microscopy and CLARITY with light-sheet microscopy to define surgery-induced changes in microglial morphology and dynamics. Orthopedic surgery induced microglial activation in the hippocampus and cortex that accompanied impairments in episodic memory. URMC-099 prophylaxis prevented these neuropathological sequelae without impacting bone fracture healing. Together, these findings provide compelling evidence for the advancement of URMC-099 as a therapeutic option for PND.

Footnotes

  • Patrick_MillerRhodes{at}URMC.Rochester.edu, cuicui.kong{at}duke.edu, gurpreet.baht{at}duke.edu, rodri007{at}duke.edu, william.wetsel{at}duke.edu, Harris_Gelbard{at}URMC.Rochester.edu, niccolo.terrando{at}duke.edu

  • Abbreviations

    BBB
    blood-brain barrier
    ip
    intraperitoneal
    LPS
    lipopolysaccharide
    MLK3
    mixed-lineage kinase 3
    PND
    perioperative neurocognitive disorders
    TSWC
    thin-skull cortical window
    2P-LSM
    two-photon laser-scanning microscope
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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    Posted March 18, 2019.
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    The broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disorders
    Patrick Miller-Rhodes, Cuicui Kong, Gurpreet S. Baht, Ramona M. Rodriguiz, William C. Wetsel, Harris A. Gelbard, Niccolò Terrando
    bioRxiv 537472; doi: https://doi.org/10.1101/537472
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    The broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disorders
    Patrick Miller-Rhodes, Cuicui Kong, Gurpreet S. Baht, Ramona M. Rodriguiz, William C. Wetsel, Harris A. Gelbard, Niccolò Terrando
    bioRxiv 537472; doi: https://doi.org/10.1101/537472

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