| 1. |
- Aaro Jonsson, Catherine, et al.
(author)
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Cognitive Recovery and Development after Traumatic Brain Injury in Childhood : A Person-Oriented, Longitudinal Study
- 2013
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In: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 0897-7151 .- 1557-9042. ; 30:2, s. 76-83
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Journal article (peer-reviewed)abstract
- Influence of childhood traumatic brain injury (TBI) on cognitive recovery and subsequent development is poorly understood. In this longitudinal study we used cluster analysis to explore acute stage individual profiles of injury age and cognition in 118 children with traumatic brain injury. Repeated measures of cognitive function were conducted at 30 months, indicating recovery, and 10 years post-injury, indicating development. Nine clusters were identified. Recovery was evident in three clusters, two of them with low functioning profiles. Developmental gains occurred for three clusters and an acute profile of higher freedom from distractibility (FFD) and lower processing speed (PS) was related to positive differences. One cluster, average low functioning and especially low verbal comprehension, demonstrated a slower development than peers. This suggests that developmental change after TBI in childhood takes place on a continuum, with both chance of long-term catching up, and risk of poor development. An acute profile of higher FFD and lower PS seemed to reflect injury consequences and were followed by developmental gains. These results challenge previous findings, and warrant further investigation.
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| 2. |
- Abu Hamdeh, Sami, et al.
(author)
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Differential DNA methylation of the genes for amyloid precursor protein, tau, and neurofilaments in human traumatic brain injury
- 2021
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In: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 0897-7151 .- 1557-9042. ; 38:12, s. 1662-1669
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Journal article (peer-reviewed)abstract
- Traumatic brain injury (TBI) is an established risk factor for neurodegenerative disorders and dementias. Epigenetic modifications, such as DNA methylation, may alter the expression of genes without altering the DNA sequence in response to environmental factors. We hypothesized that DNA methylation changes may occur in the injured human brain and be implicated in the neurodegenerative aftermath of TBI. The DNA methylation status of genes related to neurodegeneration; for example, amyloid beta precursor protein (APP), microtubule associated protein tau (MAPT), neurofilament heavy (NEFH), neurofilament medium (NEFM), and neurofilament light (NEFL), was analyzed in fresh, surgically resected human brain tissue from 17 severe TBI patients and compared with brain biopsy samples from 19 patients with idiopathic normal pressure hydrocephalus (iNPH). We also performed an epigenome-wide association study (EWAS) comparing TBI patients with iNPH controls. Thirty-eight CpG sites in the APP, MAPT, NEFH, and NEFL genes were differentially methylated by TBI. Among the top 20 differentially methylated CpG sites, 11 were in the APP gene. In addition, the EWAS evaluating 828,888 CpG sites revealed 308 differentially methylated CpG sites in genes related to cellular/anatomical structure development, cell differentiation, and anatomical morphogenesis. These preliminary findings provide the first evidence of an altered DNA methylome in the injured human brain, and may have implications for the neurodegenerative disorders associated with TBI.
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| 3. |
- Abu Hamdeh, Sami, et al.
(author)
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Extended anatomical grading in diffuse axonal injury using MRI : Hemorrhagic lesions in the substantia nigra and mesencephalic tegmentum indicate poor long-term outcome
- 2017
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In: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 0897-7151 .- 1557-9042. ; 5:34, s. 341-352
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Journal article (peer-reviewed)abstract
- Clinical outcome after traumatic diffuse axonal injury (DAI) is difficult to predict. In this study, three magnetic resonance imaging (MRI) sequences were used to quantify the anatomical distribution of lesions, to grade DAI according to the Adams grading system, and to evaluate the value of lesion localization in combination with clinical prognostic factors to improve outcome prediction. Thirty patients (mean 31.2 years ±14.3 standard deviation) with severe DAI (Glasgow Motor Score [GMS] <6) examined with MRI within 1 week post-injury were included. Diffusion-weighted (DW), T2*-weighted gradient echo and susceptibility-weighted (SWI) sequences were used. Extended Glasgow outcome score was assessed after 6 months. Number of DW lesions in the thalamus, basal ganglia, and internal capsule and number of SWI lesions in the mesencephalon correlated significantly with outcome in univariate analysis. Age, GMS at admission, GMS at discharge, and low proportion of good monitoring time with cerebral perfusion pressure <60 mm Hg correlated significantly with outcome in univariate analysis. Multivariate analysis revealed an independent relation with poor outcome for age (p = 0.005) and lesions in the mesencephalic region corresponding to substantia nigra and tegmentum on SWI (p = 0.008). We conclude that higher age and lesions in substantia nigra and mesencephalic tegmentum indicate poor long-term outcome in DAI. We propose an extended MRI classification system based on four stages (stage I—hemispheric lesions, stage II—corpus callosum lesions, stage III—brainstem lesions, and stage IV—substantia nigra or mesencephalic tegmentum lesions); all are subdivided by age (≥/<30 years).
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| 7. |
- Al-Husseini, Ali, et al.
(author)
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Shorter Recovery Time in Concussed Elite Ice Hockey Players by Early Head-and-Neck Cooling: A Clinical Trial
- 2023
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In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 40:11-12, s. 1075-1085
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Journal article (peer-reviewed)abstract
- A sports-related concussion (SRC) is most commonly sustained in contact sports, and is defined as a mild traumatic brain injury. An exercise-induced elevation of core body temperature is associated with increased brain temperature that may accelerate secondary injury processes following SRC, and exacerbate the brain injury. In a recent pilot study, acute head-neck cooling of 29 concussed ice hockey players resulted in shorter time to return-to-play. Here, we extended the clinical trial to include players of 19 male elite Swedish ice hockey teams over five seasons (2016-2021). In the intervention teams, acute head-neck cooling was implemented using a head cap for ≥45 min in addition to the standard SRC management used in controls. The primary endpoint was time from SRC until return-to-play (RTP). Sixty-one SRCs were included in the intervention group and 71 SRCs in the control group. The number of previous SRCs was 2 (median and interquartile range [IQR]: 1.0-2.0) and 1 (IQR 1.0-2.0) in the intervention and control groups, respectively; p = 0.293. Median time to initiate head-neck cooling was 10 min (IQR 7-15; range 5-30 min) and median duration of cooling was 45 min (IQR 45-50; range 45-70 min). The median time to RTP was 9 days in the intervention group (IQR 7.0-13.5 days) and 13 days in the control group (IQR 9-30; p < 0.001). The proportion of players out from play for more than the expected recovery time of 14 days was 24.7% in the intervention group, and 43.7% in controls (p < 0.05). Study limitations include that: 1) allocation to cooling or control management was at the discretion of the medical staff of each team, decided prior to each season, and not by strict randomization; 2) no sham cap was used and evaluations could not be performed by blinded assessors; and 3) it could not be established with certainty that injury severity was similar between groups. While the results should thus be interpreted with caution, early head-neck cooling, with the aim of attenuating cerebral hyperthermia, may reduce post-SRC symptoms and lead to earlier return-to-play in elite ice hockey players.
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| 8. |
- Alam, Aftab, et al.
(author)
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Modeling the Inflammatory Response of Traumatic Brain Injury Using Human Induced Pluripotent Stem Cell Derived Microglia
- 2023
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In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 40:19-20, s. 2164-2173
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Journal article (peer-reviewed)abstract
- The neuroinflammatory response after traumatic brain injury (TBI) is implicated as a key mediator of secondary injury in both the acute and chronic periods after primary injury. Microglia are the key innate immune cell in the central nervous system, responding to injury with the release of cytokines and chemokines. In this context, we aimed to characterize the downstream cytokine response of human induced pluripotent stem cell (iPSC)-derived microglia when stimulated with five separate cytokines identified after human TBI. The iPSC-derived microglia were exposed to interleukin (IL)-1 & beta;, IL-4, IL-6, IL-10, and tumor necrosis factor (TNF) in the concentration ranges identified in clinical TBI studies. The downstream cytokine response was measured against a panel of 37 separate cytokines over a 72h time-course. The secretome revealed concentration-, time- and combined concentration and time-dependent downstream responses. TNF appeared to be the strongest inducer of downstream cytokine changes (51), followed by IL-1 & beta; (26) and IL-4 (19). IL-10 (11) and IL-6 (10) produced fewer responses. We also compare these responses with our previous studies of iPSC-derived neuronal and astrocyte cultures and the in vivo human TBI cytokine response. Notably, we found microglial culture to induce both a wider range of downstream cytokine responses and a greater fold change in concentration for those downstream responses, compared with astrocyte and neuronal cultures. In summary, we present a dataset for human microglial cytokine responses specific to the secretome found in the clinical context of TBI. This reductionist approach complements our previous datasets for astrocyte and neuronal responses and will provide a platform to enable future studies to unravel the complex neuroinflammatory network activated after TBI.
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| 9. |
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| 13. |
- Bentzer, Peter, et al.
(author)
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Infusion of prostacyclin following experimental brain injury in the rat reduces cortical lesion volume
- 2001
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In: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 1557-9042 .- 0897-7151. ; 18:3, s. 275-285
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Journal article (peer-reviewed)abstract
- Endothelial-derived prostacyclin is an important regulator of microvascular function, and its main actions are inhibition of platelet/leukocyte aggregation and adhesion, and vasodilation. Disturbances in endothelial integrity following traumatic brain injury (TBI) may result in insufficient prostacyclin production and participate in the pathophysiological sequelae of brain injury. The objective of this study was to evaluate the potential therapeutic effects of a low-dose prostacyclin infusion on cortical lesion volume, CA3 neuron survival and functional outcome following TBI in the rat. Anesthetized animals (sodium pentobarbital, 60 mg/kg, i.p.) were subjected to a lateral fluid percussion brain injury (2.5 atm) or sham injury. Following TBI, animals were randomized to receive a constant infusion of either prostacyclin (1 ng/kg x min(-1) i.v.) or vehicle over 48 h. All sham animals received vehicle (n = 6). Evaluation of neuromotor function, lesion volume, and CA3 neuronal loss was performed blindly. By 7 days postinjury, cortical lesion volume was significantly reduced by 43% in the prostacyclin-treated group as compared to the vehicle treated group (p < 0.01; n = 12 prostacyclin, n = 12 vehicle). No differences were observed in neuromotor function (48 h and 7 days following TBI), or in hippocampal cell loss (7 days following TBI) between the prostacyclin- and vehicle-treated groups. We conclude that prostacyclin in a low dose reduces loss of neocortical neurons following TBI and may be a potential clinical therapeutic agent to reduce neuronal cell death associated with brain trauma.
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| 14. |
- Bentzer, Peter, et al.
(author)
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Low-Dose Prostacyclin Improves Cortical Perfusion following Experimental Brain Injury in the Rat.
- 2003
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In: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 1557-9042 .- 0897-7151. ; 20:5, s. 447-461
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Journal article (peer-reviewed)abstract
- It was recently shown that prostacyclin at a low dose reduces cortical cell death following brain trauma in the rat. Conceivably, prostacyclin with its vasodilatory, anti-aggregatory, anti-adhesive and permeability-reducing properties improved a compromised perfusion caused by post-traumatic vasoconstriction, microthrombosis and increased microvascular permeability. The objective of the present study was therefore to investigate the hemodynamic effects of low-dose prostacyclin in the traumatized rat cortex. Following a fluid percussion brain injury or a sham procedure, animals were treated with a continuous intravenous infusion of prostacyclin of 1 or 2 ng x kg(-1) x min(-1), or vehicle. Blood flow ([(14)C]-iodoantipyrine), the permeability-surface area product (PS) for [(51)Cr]-EDTA, and brain water content were measured after 3 or 48 h of treatment. Blood flow values in the injured cortex were transiently reduced to 0.42 +/- 0.2 mL x min(-1) in the vehicle group 3 h following trauma from a corresponding value of about 1.6 mL x min(-1) in the sham group, with recovery of blood flow after 48 h. Prostacyclin treatment caused a dose-dependent increase in blood flow which reached statistical significance 48 h following trauma. Brain water content and PS increased in the injured cortex post trauma and the higher dose of prostacyclin increased these parameters further at 48 h compared to the vehicle group (p < 0.05). The latter effects of prostacyclin cannot be attributed to an increase in permeability, as prostacyclin did not influence PS or brain water content following sham trauma. In fact prostacyclin has been shown to have permeability-decreasing properties. We conclude that prostacyclin improves cortical perfusion following brain trauma. The simultaneous aggravation of brain edema can be explained by an increased surface area, perhaps in combination with increased capillary hydrostatic pressure.
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| 15. |
- Bernick, Charles, et al.
(author)
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Longitudinal performance of plasma neurofilament light and tau in professional fighters: The Professional Fighters Brain Health Study.
- 2018
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In: Journal of neurotrauma. - : Mary Ann Liebert Inc. - 1557-9042 .- 0897-7151. ; 35:20
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Journal article (peer-reviewed)abstract
- The objective of this study is to evaluate longitudinal change in plasma neurofilament light (NF-L) and tau levels in relationship to clinical and radiological measures in professional fighters. Participants (active and retired professional fighters and control group) underwent annual blood sampling, 3 Tesla MRI brain imaging, computerized cognitive testing, and assessment of exposure to head trauma. Plasma tau and NF-L concentrations were measured using Simoa assays. Multiple linear regression models were used to compare the difference across groups in regard to baseline measurements, while mixed linear models was used for the longitudinal data with multiple measurements for each participant. Plasma samples were available on 471 participants. Baseline NF-L measures differed across groups (F_3,393=6.99, p=0.0001), with the active boxers having the highest levels. Higher NF-L levels at baseline were correlated with lower baseline MRI regional volumes and lower cognitive scores. The number of sparring rounds completed by the active fighters was correlated with NF-L (95% CI 0.0116-0.4053, p=0.0381), but not tau, levels. Among 126 subjects having multiple yearly samples, there was a significant difference in average yearly percentage change in tau across groups (F_3,83=3.87, p=0.0121).). We conclude that plasma NF-L and tau behave differently in a group of active and retired fighters; NF-L better reflects acute exposure whereas the role of plasma tau levels in signifying chronic change in brain structure over time requires further study.
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| 16. |
- Bernini, A., et al.
(author)
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Cerebral Metabolic Dysfunction at the Acute Phase of Traumatic Brain Injury Correlates with Long-Term Tissue Loss
- 2023
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In: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 0897-7151 .- 1557-9042. ; 40:5-6, s. 472-481
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Journal article (peer-reviewed)abstract
- Following traumatic brain injury (TBI), cerebral metabolic dysfunction, characterized by an elevated cerebral microdialysis (CMD) lactate/pyruvate (LP) ratio, is associated with poor outcome. However, the exact pathophysiological mechanisms underlying this association are not entirely established. In this pre-planned analysis of the BIOmarkers of AXonal injury after Traumatic Brain Injury (BIO-AX-TBI) prospective study, we investigated any associations of LP ratio with brain structure volume change rates at 1 year. Fourteen subjects underwent acute-phase (0-96 h post-TBI) CMD monitoring and had longitudinal magnetic resonance imaging (MRI) quantification of brain volume loss between the subacute phase (14 days to 6 weeks) and 1 year after TBI, recalculated as an annual rate. On average, CMD showed an elevated (>25) LP ratio (31 [interquartile range (IQR) 24-34]), indicating acute cerebral metabolic dysfunction. Annualized whole brain and total gray matter (GM) volume change rates were abnormally reduced (-3.2% [-9.3 to -2.2] and -1.9% [-4.4 to 1.7], respectively). Reduced annualized total GM volume correlated significantly with elevated CMD LP ratio (Spearman's rho = -0.68, p-value = 0.01) and low CMD glucose (rho = 0.66, p-value = 0.01). After adjusting for age, admission Glasgow Coma Scale (GCS) score and CT Marshall score, CMD LP ratio remained strongly associated with 1-year total GM volume change rate (p < 0.001; multi-variable analysis). No relationship was found between WM volume changes and CMD metabolites. We demonstrate a strong association between acute post-traumatic cerebral metabolic dysfunction and 1-year gray matter atrophy, reinforcing the role of CMD LP ratio as an early biomarker of poor long-term recovery after TBI.
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| 17. |
- Bersch, Ines, et al.
(author)
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Motor Point Topography of Fundamental Grip Actuators in Tetraplegia: Implications in Nerve Transfer Surgery
- 2020
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In: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 0897-7151 .- 1557-9042. ; 37:3, s. 441-447
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Journal article (peer-reviewed)abstract
- The differentiation between an upper motoneuron (UMN) lesion and lower motoneuron (LMN) lesion of forearm muscles in patients with tetraplegia is critical for the choice of treatment strategy. Specifically, the M. pronator teres (PT), M. flexor digitorum profundus III (FDPIII), and M. flexor pollicis longus (FPL) were studied since they represent key targets in nerve transfer surgery to restore grasp function. Forearm muscles of 24 patients with tetraplegia were tested bilaterally with electrical stimulation (ES) to determine whether UMN or LMN lesion was present. For detecting and testing the nerve stimulation points, a standardized mapping was developed and clinically applied. The relationship between the anatomical segmental spinal innervation and the innervation pattern tested by ES was determined. The data of 44 arms were analyzed. For PT, 19 arms showed an intact UMN, 18 arms an UMN lesion, and seven arms partial denervation. For FDPIII, three arms demonstrated an intact UMN, 26 arms an UMN lesion, 10 arms partial denervation, and five arms denervation. For FPL, two arms presented an intact UMN, 16 arms an UMN lesion, 12 arms partial denervation, and 14 arms denervation. A total of 20.1% ES tested muscles were partially denervated. In four patients, only one arm could be tested because of surgery-related limitations. According to the level of lesion and the segmental spinal innervation, most denervated muscles were present in the patient group C6 to C8. The ES, together with the developed mapping system, is reliable and can be recommended for standardized testing in surgery and rehabilitation. It offers the possibility to detect if and to what extent UMN and LMN lesions are present for the target muscles. It allows for refined pre-operative diagnostics and prognostics in spinal cord injury neurotization surgery.
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| 18. |
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| 19. |
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| 20. |
- Brophy, Gretchen M., et al.
(author)
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Biokinetic analysis of ubiquitin C-terminal hydrolase-L1 (UCH-L1) in severe traumatic brain injury patient biofluids
- 2011
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In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 28:6, s. 861-870
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Journal article (peer-reviewed)abstract
- Ubiquitin C-terminal hydrolase-L1 (UCH-L1) is a neuron-specific enzyme that has been identified as a potential biomarker of traumatic brain injury (TBI). The study objectives were to determine UCH-L1 exposure and kinetic metrics, determine correlations between biofluids, and assess outcome correlations in severe TBI patients. Data were analyzed from a prospective, multicenter study of severe TBI (Glasgow Coma Scale [GCS] score ≤ 8). Cerebrospinal fluid (CSF) and serum data from samples taken every 6 h after injury were analyzed by enzyme-linked immunosorbent assay (ELISA). UCH-L1 CSF and serum data from 59 patients were used to determine biofluid correlations. Serum samples from 86 patients and CSF from 59 patients were used to determine outcome correlations. Exposure and kinetic metrics were evaluated acutely and up to 7 days post-injury and compared to mortality at 3 months. There were significant correlations between UCH-L1 CSF and serum median concentrations (r(s)=0.59, p<0.001), AUC (r(s)=0.3, p=0.027), Tmax (r(s)=0.68, p<0.001), and MRT (r(s)=0.65, p<0.001). Outcome analysis showed significant increases in median serum AUC (2016 versus 265 ng/mL*min, p=0.006), and Cmax (2 versus 0.4 ng/mL, p=0.003), and a shorter Tmax (8 versus 19 h, p=0.04) in those who died versus those who survived, respectively. In the first 24 h after injury, there was a statistically significant acute increase in CSF and serum median Cmax((0-24h)) in those who died. This study shows a significant correlation between UCH-L1 CSF and serum median concentrations and biokinetics in severe TBI patients, and relationships with clinical outcome were detected.
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| 21. |
- Büki, Andras, 1966-, et al.
(author)
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BIOMARKERS OF TRAUMATIC BRAIN- AND SPINAL CORD INJURY
- 2022
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In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 39:15-16, s. A7-A7
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Journal article (other academic/artistic)abstract
- Biomarkers of traumatic brain injury have long been investigated, yet their application in real life clinical practice is less than widespread.Research efforts under the umbrella of InTBIR and specifically CENTER TBI provided novel results based on a bulk of data collected.The symposium aims to provide an update on contemporary knowledge on purported clinical application of core biomarkers while also sharing novel data on emerging markers and novel technologies and approaches that may further improve our diagnostic and prognostic capabilities in the treatment of traumatic brain injury.The session will provide a critical review and update on biomarkers of spinal cord injury.
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| 22. |
- Büki, Andras, 1966-, et al.
(author)
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Postinjury cyclosporin a administration limits axonal damage and disconnection in traumatic brain injury
- 1999
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In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 16:6, s. 511-521
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Journal article (peer-reviewed)abstract
- Recent observations concerning presumed calcium-induced mitochondrial damage and focal intraaxonal proteolysis in the pathogenesis of traumatic axonal injury (TAI) have opened new perspectives for therapeutic intervention. Studies from our laboratory demonstrated that cyclosporin A (CsA), a potent inhibitor of Ca2+-induced mitochondrial damage, administered 30 min prior to traumatic brain injury preserved mitochondrial integrity in those axonal foci destined to undergo delayed disconnection. We attributed this neuroprotection to the inhibition by CsA of mitochondrial permeability transition (MPT). Additional experiments proved that CsA pretreatment also significantly reduced calcium-induced, calpain-mediated spectrin proteolysis (CMSP) and neurofilament compaction (NFC), pivotal events in the pathogenesis of axonal failure and disconnection. Given these provocative findings the goal of the current study was to evaluate the potential of CsA to inhibit calcium-induced axonal damage in a more clinically relevant postinjury treatment paradigm. To this end, cyclosporin A was administered intrathecally to Sprague Dawley rats 30 min following impact acceleration traumatic brain injury. The first group of animals were sacrificed 120 min postinjury and the density of CMSP and NFC immunoreactive damaged axonal segments of CsA-treated and vehicle-treated injured animals were quantitatively analyzed. A second group of CsA- versus vehicle-treated rats was sacrificed at 24 h postinjury to compare the density of damaged axons displaying beta amyloid precursor protein (APP) immunoreactivity, a signature protein of axonal perturbation and disconnection. Postinjury CsA administration resulted in a significant decrease (>60%) in CMSP/NFC immunoreactivity in corticospinal tracts and medial longitudinal fasciculi. A similar decrease was detected in the density of APP immunoreactive damaged axons, indicating an attenuation of axonal disconnection at 24 h postinjury in CsA-treated animals. These results once again suggest that the maintenance of the functional integrity of the mitochondria can prevent TAI, presumably via the preservation of the local energy homeostasis of the axon. Moreover and perhaps more importantly, these studies also demonstrate the efficacy of CsA administration when given in the early posttraumatic period. Collectively, our findings suggest that a therapeutic window exists for the use of drugs targeting mitochondria and energy regulation in traumatic brain injury.
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| 23. |
- Büki, Andras, 1966-, et al.
(author)
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Preinjury administration of the calpain inhibitor MDL-28170 attenuates traumatically induced axonal injury
- 2003
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In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 20:3, s. 261-268
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Journal article (peer-reviewed)abstract
- Traumatic brain injury (TBI) evokes diffuse (traumatic) axonal injury (TAI), which contributes to morbidity and mortality. Damaged axons display progressive alterations gradually evolving to axonal disconnection. In severe TAI, the tensile forces of injury lead to a focal influx of Ca2+, initiating a series of proteolytic processes wherein the cysteine proteases, calpain and caspase modify the axonal cytoskeleton, causing irreversible damage over time postinjury. Although several studies have demonstrated that the systemic administration of calpain inhibitors reduces the extent of ischemic and traumatic contusional injury a direct beneficial effect on TAI has not been established to date. The current study was initiated to address this issue in an impact acceleration rat-TBI model in order to provide further evidence on the contribution of calpain-mediated proteolytic processes in the pathogenesis of TAI, while further supporting the utility of calpain-inhibitors. A single tail vein bolus injection of 30 mg/kg MDL-28170 was administered to Wistar rats 30 min preinjury. After injury the rats were allowed to survive 120 min when they were perfused with aldehydes. Brains were processed for immunohistochemical localization of damaged axonal profiles displaying either amyloid precursor protein (APP)- or RMO-14-immunoreactivity (IR), both considered markers of specific features of TAI. Digital data acquisition and statistical analysis demonstrated that preinjury administration of MDL-28170 significantly reduced the mean number of damaged RMO-14- as well as APP-IR axonal profiles in the brainstem fiber tracts analyzed. These results further underscore the role of calpain-mediated proteolytic processes in the pathogenesis of DAI and support the potential use of cell permeable calpain-inhibitors as a rational therapeutic approach in TBI.
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