Structural and biochemical abnormalities in the absence of acute deficits in mild primary blast-induced head trauma

Abstract

OBJECTIVE Blast-induced neurotrauma (BINT), if not fatal, is nonetheless potentially crippling. It can produce a wide array of acute symptoms in moderate-to-severe exposures, but mild BINT (mBINT) is characterized by the distinct absence of acute clinical abnormalities. The lack of observable indications for mBINT is particularly alarming, as these injuries have been linked to severe long-term psychiatric and degenerative neurological dysfunction. Although the long-term sequelae of BINT are extensively documented, the underlying mechanisms of injury remain poorly understood, impeding the development of diagnostic and treatment strategies. The primary goal of this research was to recapitulate primary mBINT in rodents in order to facilitate well-controlled, long-term investigations of blast-induced pathological neurological sequelae and identify potential mechanisms by which ongoing damage may occur postinjury. METHODS A validated, open-ended shock tube model was used to deliver blast overpressure (150 kPa) to anesthetized rats with body shielding and head fixation, simulating the protective effects of military-grade body armor and isolating a shock wave injury from confounding systemic injury responses, head acceleration, and other elements of explosive events. Evans Blue–labeled albumin was used to visualize blood-brain barrier (BBB) compromise at 4 hours postinjury. Iba1 staining was used to visualize activated microglia and infiltrating macrophages in areas of peak BBB compromise. Acrolein, a potent posttraumatic neurotoxin, was quantified in brain tissue by immunoblotting and in urine through liquid chromatography with tandem mass spectrometry at 1, 2, 3, and 5 days postinjury. Locomotor behavior, motor performance, and short-term memory were assessed with open field, rotarod, and novel object recognition (NOR) paradigms at 24 and 48 hours after the blast. RESULTS Average speed, maximum speed, and distance traveled in an open-field exploration paradigm did not show significant differences in performance between sham-injured and mBINT rats. Likewise, rats with mBINT did not exhibit deficits in maximum revolutions per minute or total run time in a rotarod paradigm. Short-term memory was also unaffected by mBINT in an NOR paradigm. Despite lacking observable motor or cognitive deficits in the acute term, blast-injured rats displayed brain acrolein levels that were significantly elevated for at least 5 days, and acrolein’s glutathione-reduced metabolite, 3-HPMA, was present in urine for 2 days after injury. Additionally, mBINT brain tissue demonstrated BBB damage 4 hours postinjury and colocalized neuroinflammatory changes 24 hours postinjury. CONCLUSIONS This model highlights mBINT’s potential for underlying detrimental physical and biochemical alterations despite the lack of apparent acute symptoms and, by recapitulating the human condition, represents an avenue for further examining the pathophysiology of mBINT. The sustained upregulation of acrolein for days after injury suggests that acrolein may be a...

Dimercaprol is an acrolein scavenger that mitigates acrolein‐mediated PC‐12 cells toxicity and reduces acrolein in rat following spinal cord injury

“…; Walls et al . ), but also degenerative diseases, such as multiple sclerosis and Alzheimer's disease (Calingasan et al . ; Leung et al .…”

“…Taken together, acrolein likely damages the lipid membrane through direct destruction of membrane-bound proteins, as well as through lipid peroxidation by ROS. It has been suggested that acrolein plays a pathological role in not only neuronal trauma, such as SCI and traumatic brain injury (Luo et al 2005b;Hamann et al 2008a;Walls et al 2016), but also degenerative diseases, such as multiple sclerosis and Alzheimer's disease (Calingasan et al 1999;Leung et al 2011), cancers (Cohen et al 1992;Feng et al 2006), and chemotherapy-induced neuropathy (Conklin 2004;Barrera 2012). Therefore, removing acrolein by acrolein scavengers Fig.…”

Mild traumatic brain injury-induced hippocampal gene expressions: The identification of target cellular processes for drug development

“…Additional forms of analysis could employ a multiple protein target analysis using a multiplex ELISA method or protein array chips (Buttram et al, 2007; Mukherjee et al, 2011; Gyorgy et al, 2010; Kovesdi et al, 2012). For a yet larger scale detection of proteins changed by TBI, one could employ a mass spectrometry analysis approach (Ding et al, 2015; Sheth et al, 2015; Walls et al, 2015). …”

Primary Blast Injury Depressed Hippocampal Long-Term Potentiation through Disruption of Synaptic Proteins

“…2 Although the physiological consequences of brain deformation; that is, tertiary injury, are well studied, 3,4 the pathobiology of TBI caused by primary blast, or shock-wave exposure, remains debated. 5 Animal studies that investigated the effects of primary blast injury have produced conflicting results for motor [6][7][8][9][10][11] and cognitive deficits. 8,9,12,13 One potential reason for these discrepancies is the lack of standardization in several critical factors in the bTBI injury models, such as verification of head immobilization, thoracic protection, blast exposure magnitude and duration, and subject orientation.…”