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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.

Publication ,  Journal Article
Miller-Rhodes, P; Kong, C; Baht, GS; Saminathan, P; Rodriguiz, RM; Wetsel, WC; Gelbard, HA; Terrando, N
Published in: J Neuroinflammation
October 28, 2019

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.

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Published In

J Neuroinflammation

DOI

EISSN

1742-2094

Publication Date

October 28, 2019

Volume

16

Issue

1

Start / End Page

193

Location

England

Related Subject Headings

  • Pyrroles
  • Pyridines
  • Perioperative Care
  • Neurology & Neurosurgery
  • Neurocognitive Disorders
  • Mitogen-Activated Protein Kinase Kinase Kinase 11
  • Microglia
  • Mice, Inbred C57BL
  • Mice
  • Male
 

Citation

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Miller-Rhodes, P., Kong, C., Baht, G. S., Saminathan, P., Rodriguiz, R. M., Wetsel, W. C., … Terrando, N. (2019). The broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disorders. J Neuroinflammation, 16(1), 193. https://doi.org/10.1186/s12974-019-1582-5
Miller-Rhodes, Patrick, Cuicui Kong, Gurpreet S. Baht, Priyanka Saminathan, Ramona M. Rodriguiz, William C. Wetsel, Harris A. Gelbard, and 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.J Neuroinflammation 16, no. 1 (October 28, 2019): 193. https://doi.org/10.1186/s12974-019-1582-5.
Miller-Rhodes P, Kong C, Baht GS, Saminathan P, Rodriguiz RM, Wetsel WC, et al. The broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disorders. J Neuroinflammation. 2019 Oct 28;16(1):193.
Miller-Rhodes, Patrick, et al. “The broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disorders.J Neuroinflammation, vol. 16, no. 1, Oct. 2019, p. 193. Pubmed, doi:10.1186/s12974-019-1582-5.
Miller-Rhodes P, Kong C, Baht GS, Saminathan P, Rodriguiz RM, Wetsel WC, Gelbard HA, Terrando N. The broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disorders. J Neuroinflammation. 2019 Oct 28;16(1):193.
Journal cover image

Published In

J Neuroinflammation

DOI

EISSN

1742-2094

Publication Date

October 28, 2019

Volume

16

Issue

1

Start / End Page

193

Location

England

Related Subject Headings

  • Pyrroles
  • Pyridines
  • Perioperative Care
  • Neurology & Neurosurgery
  • Neurocognitive Disorders
  • Mitogen-Activated Protein Kinase Kinase Kinase 11
  • Microglia
  • Mice, Inbred C57BL
  • Mice
  • Male