J Neuroinflamm
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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. ⋯ 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.