Notably, strategies aimed at depleting microglia before surgery abrogated neuroinflammation and subsequent cognitive decline in mice, but do not present realistic prophylactic treatment options for at-risk patients. Imaging of PBR28 in patients receiving abdominal surgery revealed a role for microglial activation in the development of cognitive impairment in these individuals. In this model, we and others have described a key role for surgery-induced neuroinflammation, including microgliosis, astrogliosis, inflammatory cell ingress, and hippocampal-dependent memory impairments. This model recapitulates features of clinical procedures such as a fracture repair or hip arthroplasty, which are often associated with neurological disorders in frail subjects. To clarify the pathophysiology of PNDs, we have developed an orthopedic surgery mouse model in which the left hindlimb is subjected to an open tibial fracture with intramedullary fixation under general anesthesia and analgesia. Currently, there are no approved disease-modifying therapeutic options to treat PNDs and the pathogenesis of these complex phenomena is not fully understood. PNDs have profound effects on our society and are estimated to incur tens of billions of dollars in health care costs annually. Following surgery (e.g., common orthopedic procedures), up to 50% of patients experience cognitive disturbances that can lead to serious complications, including poorer prognosis and a higher 1-year mortality rate in subjects with pre-existing neurodegeneration. Together, these findings provide compelling evidence for the advancement of URMC-099 as a therapeutic option for PND.ĭelirium and postoperative cognitive dysfunction, now collectively referred to as perioperative neurocognitive disorders (PND), have become the most common complications after routine surgical procedures, particularly in the elderly. These findings show that prophylactic URMC-099 treatment is sufficient to prevent surgery-induced microgliosis and cognitive impairment without affecting fracture healing. URMC-099 prophylaxis had no effect on the mobilization of the peripheral innate immune response and fracture healing. Both URMC-099 dosing paradigms prevented the neuroinflammatory sequelae that accompanied orthopedic surgery. Surgically treated mice exhibited impaired object place and identity discrimination in the “What-Where-When” and Memory Load Object Discrimination tasks. Orthopedic surgery induced BBB disruption and microglial activation, but had no effect on microglial process motility. Finally, long-term fracture healing was assessed in fracture callouses using micro-computerized tomography (microCT) and histomorphometry analyses. The acute peripheral immune response to surgery was assessed by cytokine/chemokine profiling and flow cytometry. Surgery-induced memory impairment was assessed using the “What-Where-When” and Memory Load Object Discrimination tasks. Two-photon scanning laser microscopy and CLARITY with light-sheet microscopy were used to define surgery-induced changes in microglial dynamics and morphology, respectively. 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. In this experiment, microgliosis was evaluated using unbiased stereology and blood-brain barrier (BBB) permeability was assessed using immunoglobulin G (IgG) immunostaining. 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. Orthopedic surgery was performed by fracturing the tibia of the left hindlimb with intramedullary fixation under general anesthesia and analgesia. Here, we test the hypothesis that URMC-099 can prevent surgery-induced neuroinflammation and cognitive impairment. 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. Importantly, there are no disease-modifying therapeutic options for PND. 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. Patients with pre-existing neurodegenerative disease commonly experience fractures that require orthopedic surgery.
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