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