PT  - JOURNAL ARTICLE
AU  - Patrick Miller-Rhodes
AU  - Cuicui Kong
AU  - Gurpreet S. Baht
AU  - Ramona M. Rodriguiz
AU  - William C. Wetsel
AU  - Harris A. Gelbard
AU  - Niccolò Terrando
TI  - The broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disorders
AID  - 10.1101/537472
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 537472
4099  - http://biorxiv.org/content/early/2019/03/18/537472.short
4100  - http://biorxiv.org/content/early/2019/03/18/537472.full
AB  - 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.BBBblood-brain barrieripintraperitonealLPSlipopolysaccharideMLK3mixed-lineage kinase 3PNDperioperative neurocognitive disordersTSWCthin-skull cortical window2P-LSMtwo-photon laser-scanning microscope