Propranolol Reduces p-tau Accumulation and Improves Behavior Outcomes in a Polytrauma Murine Model

Abstract

IntroductionTraumatic brain injury (TBI) can lead to neurocognitive decline, in part due to phosphorylated tau (p-tau). Whether p-tau accumulation worsens in the setting of polytrauma remains unknown. Propranolol has shown clinical benefit in head injuries; however, the underlying mechanism is also unknown. We hypothesize that hemorrhagic shock would worsen p-tau accumulation but that propranolol would improve functional outcomes on behavioral studies. MethodsA murine polytrauma model was developed to examine the accumulation of p-tau and whether it can be mitigated by early administration of propranolol. TBI was induced using a weight-drop model and hemorrhagic shock was achieved via controlled hemorrhage for 1 h. Mice were given intraperitoneal propranolol 4 mg/kg or saline control. The animals underwent behavioral testing at 30 d postinjury and were sacrificed for cerebral histological analysis. These studies were completed in male and female mice. ResultsTBI alone led to increased p-tau generation compared to sham on both immunohistochemistry and immunofluorescence (P < 0.05). The addition of hemorrhage led to greater accumulation of p-tau in the hippocampus (P < 0.007). In male mice, p-tau accumulation decreased with propranolol administration for both polytrauma and TBI alone (P < 0.0001). Male mice treated with propranolol also outperformed saline-control mice on the hippocampal-dependent behavioral assessment (P = 0.0013). These results were not replicated in female mice; the addition of hemorrhage did not increase p-tau accumulation and propranolol did not demonstrate a therapeutic effect. ConclusionsPolytrauma including TBI generates high levels of hippocampal p-tau, but propranolol may help prevent this accumulation to improve both neuropathological and functional outcomes in males.