The broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disorders
Abstract Background Patients with pre-existing neurodegenerative disease commonly experience fractures that require orthopedic surgery. Perioperative neurocognitive disorders (PND), including delirium and postoperative cognitive dysfunction, are serious complications that can result in increased 1-y...
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2019-10-01
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Online Access: | http://link.springer.com/article/10.1186/s12974-019-1582-5 |
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language |
English |
format |
Article |
sources |
DOAJ |
author |
Patrick Miller-Rhodes Cuicui Kong Gurpreet S. Baht Priyanka Saminathan Ramona M. Rodriguiz William C. Wetsel Harris A. Gelbard Niccolò Terrando |
spellingShingle |
Patrick Miller-Rhodes Cuicui Kong Gurpreet S. Baht Priyanka Saminathan Ramona M. Rodriguiz William C. Wetsel Harris A. Gelbard Niccolò Terrando The broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disorders Journal of Neuroinflammation Microglia Delirium Postoperative neurocognitive disorders Intravital microscopy Mixed-lineage kinase 3 |
author_facet |
Patrick Miller-Rhodes Cuicui Kong Gurpreet S. Baht Priyanka Saminathan Ramona M. Rodriguiz William C. Wetsel Harris A. Gelbard Niccolò Terrando |
author_sort |
Patrick Miller-Rhodes |
title |
The broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disorders |
title_short |
The broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disorders |
title_full |
The broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disorders |
title_fullStr |
The broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disorders |
title_full_unstemmed |
The broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disorders |
title_sort |
broad spectrum mixed-lineage kinase 3 inhibitor urmc-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disorders |
publisher |
BMC |
series |
Journal of Neuroinflammation |
issn |
1742-2094 |
publishDate |
2019-10-01 |
description |
Abstract Background Patients with pre-existing neurodegenerative disease commonly experience fractures that require orthopedic surgery. Perioperative neurocognitive disorders (PND), including delirium and postoperative cognitive dysfunction, are serious complications that can result in increased 1-year mortality when superimposed on dementia. Importantly, there are no disease-modifying therapeutic options for PND. Our lab developed the “broad spectrum” mixed-lineage kinase 3 inhibitor URMC-099 to inhibit pathological innate immune responses that underlie neuroinflammation-associated cognitive dysfunction. Here, we test the hypothesis that URMC-099 can prevent surgery-induced neuroinflammation and cognitive impairment. Methods Orthopedic surgery was performed by fracturing the tibia of the left hindlimb with intramedullary fixation under general anesthesia and analgesia. In a pilot experiment, 9-month-old mice were treated five times with URMC-099 (10 mg/kg, i.p.), spaced 12 h apart, with three doses prior to surgery and two doses following surgery. In this experiment, microgliosis was evaluated using unbiased stereology and blood-brain barrier (BBB) permeability was assessed using immunoglobulin G (IgG) immunostaining. In follow-up experiments, 3-month-old mice were treated only three times with URMC-099 (10 mg/kg, i.p.), spaced 12 h apart, prior to orthopedic surgery. Two-photon scanning laser microscopy and CLARITY with light-sheet microscopy were used to define surgery-induced changes in microglial dynamics and morphology, respectively. Surgery-induced memory impairment was assessed using the “What-Where-When” and Memory Load Object Discrimination tasks. The acute peripheral immune response to surgery was assessed by cytokine/chemokine profiling and flow cytometry. Finally, long-term fracture healing was assessed in fracture callouses using micro-computerized tomography (microCT) and histomorphometry analyses. Results Orthopedic surgery induced BBB disruption and microglial activation, but had no effect on microglial process motility. Surgically treated mice exhibited impaired object place and identity discrimination in the “What-Where-When” and Memory Load Object Discrimination tasks. Both URMC-099 dosing paradigms prevented the neuroinflammatory sequelae that accompanied orthopedic surgery. URMC-099 prophylaxis had no effect on the mobilization of the peripheral innate immune response and fracture healing. Conclusions These findings show that prophylactic URMC-099 treatment is sufficient to prevent surgery-induced microgliosis and cognitive impairment without affecting fracture healing. Together, these findings provide compelling evidence for the advancement of URMC-099 as a therapeutic option for PND. |
topic |
Microglia Delirium Postoperative neurocognitive disorders Intravital microscopy Mixed-lineage kinase 3 |
url |
http://link.springer.com/article/10.1186/s12974-019-1582-5 |
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doaj-f036a56458e24c7f9b6d0b9180f542012020-11-25T03:58:15ZengBMCJournal of Neuroinflammation1742-20942019-10-0116111510.1186/s12974-019-1582-5The broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disordersPatrick Miller-Rhodes0Cuicui Kong1Gurpreet S. Baht2Priyanka Saminathan3Ramona M. Rodriguiz4William C. Wetsel5Harris A. Gelbard6Niccolò Terrando7Center for Neurotherapeutics Discovery, University of Rochester Medical CenterCenter for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical CenterDepartment of Orthopedic Surgery and Duke Molecular Physiology Institute, Duke University Medical CenterDepartment of Microbiology and Immunology, University of Rochester Medical CenterDepartment of Psychiatry and Behavioral Sciences, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical CenterDepartment of Psychiatry and Behavioral Sciences, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical CenterCenter for Neurotherapeutics Discovery, University of Rochester Medical CenterCenter for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical CenterAbstract Background Patients with pre-existing neurodegenerative disease commonly experience fractures that require orthopedic surgery. Perioperative neurocognitive disorders (PND), including delirium and postoperative cognitive dysfunction, are serious complications that can result in increased 1-year mortality when superimposed on dementia. Importantly, there are no disease-modifying therapeutic options for PND. Our lab developed the “broad spectrum” mixed-lineage kinase 3 inhibitor URMC-099 to inhibit pathological innate immune responses that underlie neuroinflammation-associated cognitive dysfunction. Here, we test the hypothesis that URMC-099 can prevent surgery-induced neuroinflammation and cognitive impairment. Methods Orthopedic surgery was performed by fracturing the tibia of the left hindlimb with intramedullary fixation under general anesthesia and analgesia. In a pilot experiment, 9-month-old mice were treated five times with URMC-099 (10 mg/kg, i.p.), spaced 12 h apart, with three doses prior to surgery and two doses following surgery. In this experiment, microgliosis was evaluated using unbiased stereology and blood-brain barrier (BBB) permeability was assessed using immunoglobulin G (IgG) immunostaining. In follow-up experiments, 3-month-old mice were treated only three times with URMC-099 (10 mg/kg, i.p.), spaced 12 h apart, prior to orthopedic surgery. Two-photon scanning laser microscopy and CLARITY with light-sheet microscopy were used to define surgery-induced changes in microglial dynamics and morphology, respectively. Surgery-induced memory impairment was assessed using the “What-Where-When” and Memory Load Object Discrimination tasks. The acute peripheral immune response to surgery was assessed by cytokine/chemokine profiling and flow cytometry. Finally, long-term fracture healing was assessed in fracture callouses using micro-computerized tomography (microCT) and histomorphometry analyses. Results Orthopedic surgery induced BBB disruption and microglial activation, but had no effect on microglial process motility. Surgically treated mice exhibited impaired object place and identity discrimination in the “What-Where-When” and Memory Load Object Discrimination tasks. Both URMC-099 dosing paradigms prevented the neuroinflammatory sequelae that accompanied orthopedic surgery. URMC-099 prophylaxis had no effect on the mobilization of the peripheral innate immune response and fracture healing. Conclusions These findings show that prophylactic URMC-099 treatment is sufficient to prevent surgery-induced microgliosis and cognitive impairment without affecting fracture healing. Together, these findings provide compelling evidence for the advancement of URMC-099 as a therapeutic option for PND.http://link.springer.com/article/10.1186/s12974-019-1582-5MicrogliaDeliriumPostoperative neurocognitive disordersIntravital microscopyMixed-lineage kinase 3 |