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bioRxiv · 10.1101/537472

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

Miller-Rhodes, P.·Kong, C.·Baht, G. S.·Rodriguiz, R. M.·Wetsel, W. C.·Gelbard, H. A.·Terrando, N.
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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 of 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 dynamics and morphology. Orthopedic surgery induced widespread 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.

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Miller-Rhodes, P., Kong, C., Baht, G. S., Rodriguiz, R. M., Wetsel, W. C., Gelbard, H. A., Terrando, N.. 2019-02-01. The broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disorders. https://doi.org/10.1101/537472

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