Postinjury treatments to make early tactical aeromedical evacuation practical for the brain after TBI

Abstract

BACKGROUND:Traumatic brain injury (TBI) is common in civilians and military personnel. No potential therapeutics have been evaluated to prevent secondary injury induced by the hypobaric hypoxia (HH) environment integral to postinjury aeromedical evacuation (AE).We examined the role of allopurinol, propranolol, adenosine/lidocaine/magnesium (ALM), or amitriptyline administration prior to simulated flight following murine TBI. METHODS:Mice underwent TBI and were given allopurinol, propranolol, amitriptyline, or ALM prior to simulated AE or normobaric normoxia (NN) control. Heart rate (HR), respiratory rate, and oxygen saturation (SpO 2 ) were recorded throughout simulated AE. Mice were sacrificed at 24 hours, 7 days, or 30 days. Serum and cerebral cytokines were assessed by enzyme-linked immunosorbent assay. Motor function testing was performed with Rotarod ambulation. Immunohistochemistry was conducted to examine phosphorylated tau (p-tau) accumulation in the hippocampus at 30 days. RESULTS:While all treatments improved oxygen saturation, propranolol, amitriptyline, and allopurinol improved AE-induced tachycardia. At 24 hours, both propranolol and amitriptyline reduced tumor necrosis factor alpha levels while allopurinol and ALM reduced tumor necrosis factor alpha levels only in NN mice. Propranolol, amitriptyline, and ALM demonstrated lower serum monocyte chemoattractant protein-1 7 days after AE. Both amitriptyline and allopurinol improved Rotarod times for AE mice while only allopurinol improved Rotarod times for NN mice. Propranolol was able to reduce p-tau accumulation under both HH and NN conditions while ALM only reduced p-tau in hypobaric hypoxic conditions. CONCLUSION:Propranolol lowered post-TBI HR with reduced proinflammatory effects, including p-tau reduction. Amitriptyline-induced lower post-TBI HR and improved functional outcomes without affecting inflammatory response. Allopurinol did not affect vital signs but improved late post-TBI systemic inflammation and functional outcomes. Adenosine/lidocaine/magnesium provided no short-term improvements but reduced p-tau accumulation at 30 days in the HH cohort. Allopurinol may be the best of the four treatments to help prevent short-term functional deficits while propranolol may address long-term effects.

Effects of antifibrinolytics on systemic and cerebral inflammation after traumatic brain injury

“…Mice underwent a controlled weight drop injury, as previously described, to induce a TBI of moderate severity, as defined by righting reflex response times 13–16 . In brief, mice were anesthetized with 2% inhaled isoflurane in 100% oxygen at 1 L/min for approximately 2 minutes.…”

“…Serum and cerebral tissue samples were analyzed by Multiplex enzyme-linked immunosorbent assay, including IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-6, IL-10, IL-12, IL-17, monocyte chemoattractant protein 1 (MCP-1), TNF-α, granulocyte-macrophage colony-stimulated factor (GM-CSF), macrophage inflammatory protein 1α (MIP-1α), and regulated upon activation, normal T cell expressed and presumably secreted (RANTES) (Quansys Biosciences, Logan, UT). These cytokine and chemokines were selected as a comprehensive postinjury inflammatory profile to demonstrate the systemic and cerebral inflammatory responses after TBI 16,17 . Serum neuron-specific enolase (NSE) was additionally analyzed by enzyme-linked immunosorbent assay as a systemic biomarker of acute cerebral injury (Abcam, Cambridge, MA).…”

“…Mice underwent a controlled weight drop injury, as previously described, to induce a TBI of moderate severity, as defined by righting reflex response times. [13][14][15][16] In brief, mice were anesthetized with 2% inhaled isoflurane in 100% oxygen at 1 L/min for approximately 2 minutes. After determining that an appropriate level of anesthesia was obtained, mice were placed in a prone position onto the TBI platform.…”

“…These cytokine and chemokines were selected as a comprehensive postinjury inflammatory profile to demonstrate the systemic and cerebral inflammatory responses after TBI. 16,17 Serum neuron-specific enolase (NSE) was additionally analyzed by enzyme-linked immunosorbent assay as a systemic biomarker of acute cerebral injury (Abcam, Cambridge, MA).…”

Defining Endotheliopathy in Murine Polytrauma Models

“…Mice were then placed in a prone position onto the TBI platform with head centered underneath a 400 g cylindrical rod of 1 cm diameter. The rod was dropped from 2.5 cm above the surface of the platform, to induce a global concussive blunt TBI (12,(15)(16)(17). All mice were monitored until determined to be appropriately recovered from both a neurologic and respiratory standpoint.…”