Papers by Janice Gilsdorf
Journal of Neurotrauma, 2021
Glibenclamide is the sixth drug tested by the Operation Brain Trauma Therapy (OBTT) consortium ba... more Glibenclamide is the sixth drug tested by the Operation Brain Trauma Therapy (OBTT) consortium based on substantial preclinical evidence of benefit in traumatic brain injury (TBI). Adult Sprague Dawley rats underwent fluid percussion injury (FPI, n=45), controlled cortical impact (CCI, n=30), or penetrating ballistic-like brain injury (PBBI, n=36). Efficacy of glibenclamide treatment (10g/kg intraperitoneal loading dose at 10 min post-injury followed by a continuous 7d subcutaneous infusion [0.2g/h]) on motor, cognitive, neuropathological, and biomarker outcomes was assessed across models. Glibenclamide improved motor outcome vs vehicle in FPI (cylinder task, p<0.05) and CCI (beam balance p<0.05; beam walk p<0.05). In FPI, glibenclamide did not benefit any other outcome, while in CCI, it reduced 21d lesion volume vs vehicle (p<0.05). On Morris Water Maze testing in CCI, glibenclamide worsened performance on hidden platform latency testing vs sham (p<0.05), but not vs TBI vehicle. In PBBI, glibenclamide did not improve any outcome. Blood levels of glial fibrillary acidic protein and ubiquitin carboxyl terminal hydrolase-1 at 24h did not show significant treatment-induced changes. In summary, glibenclamide showed greatest benefit in CCI; with positive effects on motor and neuropathologic outcomes. It is the second highest scoring agent overall tested by OBTT, and the only drug to reduce lesion volume after CCI. Our findings suggest that leveraging the use of a TBI model-based phenotype to guide treatment (i.e., glibenclamide in contusion) might represent a strategic choice to accelerate drug development in clinical trials and, ultimately, achieve precision medicine in TBI.
Journal of Neurotrauma, 2021
Civilian traumatic brain injury (TBI) guidelines recommend resuscitation of hypotensive TBI patie... more Civilian traumatic brain injury (TBI) guidelines recommend resuscitation of hypotensive TBI patients with crystalloids. However, increasing evidence suggests that whole blood (WB) resuscitation may improve physiological and survival outcomes at lower resuscitation volumes, and potentially at a lower mean arterial blood pressure (MAP), than crystalloid after TBI and hemorrhagic shock (HS). The objective of this study was to assess whether WB resuscitation with two different MAP targets improved behavioral and histological outcomes compared with Lactated Ringers (LR)in a mouse model of TBI+HS. Anesthetized mice (n=40) underwent controlled cortical impact followed by HS (MAP=25-27mmHg; 25min), and were randomized to five groups for a 90min resuscitation: LR with MAP target of 70mmHg (LR70), LR60, WB70, WB60, and monitored sham. Mice received a 20mL/kg bolus of LR or autologous WB followed by LR boluses (10ml/kg) every 5min for MAP below target. Shed blood was reinfused after 90min. Morris Water Maze testing was performed on days 14-20 post-injury. Mice were euthanized (21d) to assess contusion and total brain volumes. Latency to find the hidden platform was greater vs. sham for LR60 (p<0.002) and WB70 (p<0.007) but not LR70 or WB60. WB resuscitation did not reduce contusion volume or brain tissue loss. WB targeting a MAP of 60mmHg did not compromise function vs a 70mmHg target after CCI+HS, but further reduced fluid requirements (p<0.03). Using LR, higher achieved MAP was associated with better behavioral performance (rho= -0.67, p=0.028). Use of WB may allow lower MAP targets without compromising functional outcome, which could facilitate pre-hospital TBI resuscitation.
Journal of Neurotrauma, 2021
Loss of plasmalemmal integrity may mediate cell death after traumatic brain injury (TBI). Prior s... more Loss of plasmalemmal integrity may mediate cell death after traumatic brain injury (TBI). Prior studies in controlled cortical impact (CCI) indicated that the membrane resealing agent Kollidon VA64 improved histopathological and functional outcomes. Kollidon VA64 was thus selected as the seventh therapy tested by the Operation Brain Trauma Therapy consortium, across three pre-clinical TBI rat models: parasagittal fluid percussion injury (FPI), CCI, and penetrating ballistic-like brain injury (PBBI). In each model, rats were randomized to one of four exposures (7-15/group): (1) sham; (2) TBI+vehicle; (3) TBI+Kollidon VA64 low-dose (0.4 g/kg) (4) TBI+Kollidon VA64 high-dose (0.8 g/kg). A single intravenous VA64 bolus was given 15-min post-injury. Behavioral, histopathological, and serum biomarker outcomes were assessed over 21d generating a 22-point scoring matrix per model. In FPI, low-dose VA64 produced zero points across behavior and histopathology. High-dose VA64 worsened motor performance vs. TBI-vehicle producing -2.5 points. In CCI, low-dose VA64 produced intermediate benefit on beam balance and MWM, generating +3.5 points, while high-dose showed no effects on behavior or histopathology. In PBBI, neither dose altered behavior or histopathology. Regarding biomarkers, significant increases in GFAP levels were seen in TBI vs. sham at 4h and 24h across models. Benefit of low-dose VA64 on GFAP was seen at 24h only in FPI. UCH-L1 was increased in TBI vs vehicle across models at 4h but not 24h-without treatment effects. Overall, low dose VA64 generated +4.5 points (+3.5 in CCI) while high dose generated -2.0 points. The modest/inconsistent benefit observed reduced enthusiasm to pursue further testing.
Shock, 2020
Pre-hospital resuscitation using whole blood (WB) is the standard of care for hemorrhagic shock (... more Pre-hospital resuscitation using whole blood (WB) is the standard of care for hemorrhagic shock (HS) but there is no consensus recommendation for resuscitation in the presence of traumatic brain injury (TBI) due to a lack of sufficient evidence. In order to evaluate the optimal resuscitation strategies for TBI+HS, Sprague-Dawley rats were randomized into four groups based on resuscitation fluid and pre-hospital mean arterial pressure (MAP) threshold (n = 9-10/group): Lactated Ringer's (LR) -60mmHg (LR60), LR-70mmHg (LR70), WB-60mmHg (WB60), WB-70mmHg (WB70). All groups received a frontal penetrating ballistic-like brain injury followed by a 35-minute period of HS. During the pre-hospital phase, rats received an initial bolus of resuscitation fluid (WB or LR) followed by LR as needed to maintain MAP above the designated threshold for 90 minutes. During the in-hospital phase, rats received definitive resuscitation with shed WB. Physiological parameters were recorded continuously a...
Frontiers in Neuroscience
Frontiers in Neurology
Leung et al. In summary, 4-h SBC delivered through extraluminal cooling of the common carotid art... more Leung et al. In summary, 4-h SBC delivered through extraluminal cooling of the common carotid arteries effectively ameliorated motor deficits induced by PBBI and polytrauma. Improving cognitive function or mitigating subacute neurodegeneration and neuroinflammation might require a different cooling regimen such as extended cooling, a slow rewarming period and a lower temperature.
Frontiers in Neurology
Trauma is among the leading causes of death in the United States. Technological advancements have... more Trauma is among the leading causes of death in the United States. Technological advancements have led to the development of resuscitative endovascular balloon occlusion of the aorta (REBOA) which offers a pre-hospital option to non-compressible hemorrhage control. Due to the prevalence of concomitant traumatic brain injury (TBI), an understanding of the effects of REBOA on cerebral physiology is critical. To further this understanding, we employed a rat model of penetrating ballistic-like brain injury (PBBI). PBBI produced an injury pattern within the right frontal cortex and striatum that replicates the pathology from a penetrating ballistic round. Aortic occlusion was initiated 30 min post-PBBI and maintained continuously (cAO) or intermittently (iAO) for 30 min. Continuous measurements of mean arterial pressure (MAP), intracranial pressure (ICP), cerebral blood flow (CBF), and brain tissue oxygen tension (PbtO 2 ) were recorded during, and for 60 min following occlusion. PBBI increased ICP and decreased CBF and PbtO 2 . The arterial balloon catheter effectively occluded the descending aorta which augmented MAP in the carotid artery. Despite this, CBF levels were not changed by aortic occlusion. iAO caused sustained adverse effects to ICP and PbtO 2 while cAO demonstrated no adverse effects on either. Temporary increases in PbtO 2 were observed during occlusion, along with restoration of sham levels of ICP for the remainder of the recordings. These results suggest that iAO may lead to prolonged cerebral hypertension following PBBI. Following cAO, ICP, and PbtO 2 levels were temporarily improved. This information warrants further investigation using TBI-polytrauma model and provides foundational knowledge surrounding the non-hemorrhage applications of REBOA including neurogenic shock and stroke.
Journal of Neurotrauma
Polytrauma, with combined traumatic brain injury (TBI) and systemic damage are common among milit... more Polytrauma, with combined traumatic brain injury (TBI) and systemic damage are common among military and civilians. However, the pathophysiology of peripheral organs following polytrauma is poorly understood. Using a rat model of TBI combined with hypoxemia and hemorrhagic shock, we studied the status of peripheral redox systems, liver glycogen content, creatinine clearance, and systemic inflammation. Male Sprague-Dawley rats were subjected to hypoxemia and hemorrhagic shock insults (HH), penetrating ballistic-like brain injury (PBBI) alone, or PBBI followed by hypoxemia and hemorrhagic shock (PHH). Sham rats received craniotomy only. Biofluids and liver, kidney, and heart tissues were collected at 1 day, 2 days, 7 days, 14 days, and 28 days post-injury (DPI). Creatinine levels were measured in both serum and urine. Glutathione levels, glycogen content, and superoxide dismutase (SOD) and cytochrome C oxidase enzyme activities were quantified in the peripheral organs. Acute inflammation marker serum amyloid A-1 (SAA-1) level was quantified using western blot analysis. Urine to serum creatinine ratio in PHH group was significantly elevated on 7-28 DPI. Polytrauma induced a delayed disruption of the hepatic GSH/GSSG ratio, which resolved within 2 weeks post-injury. A modest decrease in kidney SOD activity was observed at 2 weeks after polytrauma. However, neither PBBI alone nor polytrauma changed the mitochondrial cytochrome C oxidase activity. Hepatic glycogen levels were reduced acutely following polytrauma. Acute inflammation marker SAA-1 showed a significant increase at early time-points following both systemic and brain injury. Overall, our findings demonstrate temporal cytological/tissue level damage to the peripheral organs due to combined PBBI and systemic injury.
PLOS ONE
Repeated exposure to blast overpressure remains a major cause of adverse health for military pers... more Repeated exposure to blast overpressure remains a major cause of adverse health for military personnel who, as a consequence, are at a higher risk for neurodegenerative disease and suicide. Acute, early tracking of blast related effects holds the promise of rapid health assessment prior to onset of chronic problems. Current techniques used to determine blastrelated effects rely upon reporting of symptomology similar to that of concussion and neurocognitive assessment relevant to operational decrement. Here, we describe the results of a cross sectional study with pared observations. The concentration of multiple TBI-related proteins was tested in serum collected within one hour of blast exposure as a quantitative and minimally invasive strategy to augment assessment of blast-exposure effects that are associated with concussion-like symptomology and reaction time decrements. We determined that median simple reaction time (SRT) was slowed in accordance with serum Nf-L, tau, Aβ-40, and Aβ-42 elevation after overpressure exposure. In contrast, median levels of serum GFAP decreased. Individual, inter-subject analysis revealed positive correlations between changes in Nf-L and GFAP, and in Aβ-40 compared to Aβ-42. The change in Nf-L was negatively associated with tau, Aβ-40, and Aβ-42. Participants reported experiencing headaches, dizziness and taking longer to think. Dizziness was associated with reaction time decrements, GFAP or NfL suppression, as well as Aβ peptide elevation. UCH-L1 elevation had a weak association with mTBI/concussion history. Multiplexed serum biomarker quantitation, coupled with reaction time assessment and symptomology determined before and after blast exposure, may serve as a platform for tracking adverse effects in the absence of a head wound or diagnosed concussion. We propose further evaluation of serum biomarkers, which are often associated with TBI, in the context of acute operational blast exposures.
Frontiers in Neurology
Close-head concussive injury, as one of the most common forms of traumatic brain injury (TBI), ha... more Close-head concussive injury, as one of the most common forms of traumatic brain injury (TBI), has been shown to induce cognitive deficits that are long lasting. A concussive impact model was previously established in our lab that produces clinically relevant signs of concussion and induced acute pathological changes in rats. To evaluate the long-term effects of repeated concussions in this model, we utilized a comprehensive Morris water maze (MWM) paradigm for cognitive assessments at 1 and 6 months following repeated concussive impacts in rats. As such, adult Sprague-Dawley rats received either anesthesia (sham) or repeated concussive impacts (4 consecutive impacts at 1 h interval). At 1 month post-injury, results of the spatial learning task showed that the average latencies to locate the hidden "escape" platform were significantly longer in the injured rats over the last 2 days of the MWM testing compared to sham controls (p < 0.05). In the memory retention task, rats subjected to repeated concussive impacts also spent significantly less time in the platform zone searching for the missing platform during the probe trial (p < 0.05). On the working memory task, the injured rats showed a trend toward worse performance, but this failed to reach statistical significance compared to sham controls (p = 0.07). At 6 months post-injury, no differences were detected between the injured group and sham controls in either the spatial learning or probe trials. However, rats with repeated concussive impacts exhibited significantly worsened working memory performance compared to sham controls (p < 0.05). In addition, histopathological assessments for axonal neurodegeneration using silver stain showed that repeated concussive impacts induced significantly more axonal degeneration in the corpus callosum compared to sham controls (p < 0.05) at 1 month post-injury, whereas such difference was not observed at 6 months post-injury. Overall, the results show that repeated concussive impacts in our model produced significant cognitive deficits in both spatial learning abilities and in working memory abilities in a time-dependent fashion that may be indicative of progressive pathology and warrant further investigation.
Military Medicine
This study assessed the effect of caffeine on neurobehavioral recovery in the WRAIR penetrating b... more This study assessed the effect of caffeine on neurobehavioral recovery in the WRAIR penetrating ballistic-like brain injury (PBBI) model. Unilateral frontal PBBI was produced in the right hemisphere of anesthetized rats at moderate (7%-PBBI) or severe (10%-PBBI) injury levels. Animals were randomly assigned to pretreatment groups: acute caffeine (25 mg/kg CAF gavage, 1 h prior to PBBI), or chronic caffeine (0.25 g/L CAF drinking water, 30 days prior to PBBI). Motor function was evaluated on the rotarod at fixed-speed increments of 10, 15, and 20 RPM. Cognitive performance was evaluated on the Morris water maze. Acute caffeine showed no significant treatment effect on motor or cognitive outcome. Acute caffeine exposure prior to 10%-PBBI resulted in a significantly higher thigmotaxic response compared to vehicle-PBBI groups, which may indicate caffeine exacerbates post-injury anxiety/attention decrements. Results of the chronic caffeine study revealed a significant improvement in moto...
Frontiers in Neurology
Microglial activation is a pathological hallmark of traumatic brain injury (TBI). Following brain... more Microglial activation is a pathological hallmark of traumatic brain injury (TBI). Following brain injury, activated microglia/macrophages adopt different phenotypes, generally categorized as M-1, or classically activated, and M-2, or alternatively activated. While the M-1, or pro-inflammatory phenotype is detrimental to recovery, M-2, or the anti-inflammatory phenotype, aids in brain repair. Recent findings also suggest the existence of mixed phenotype following brain injury, where activated microglia simultaneously express both M-1 and M-2 markers. The present study sought to determine microglial activation states at early time points (6-72 h) following single or repeated concussive injury in rats. Closed-head concussive injury was modeled in rats using projectile concussive impact injury, with either single or repeated impacts (4 impacts, 1 h apart). Brain samples were examined using immunohistochemical staining, inflammatory gene profiling and real-time polymerase chain reaction analyses to detect concussive injury induced changes in microglial activation and phenotype in cortex and hippocampal regions. Our findings demonstrate robust microglial activation following concussive brain injury. Moreover, we show that multiple concussions induced a unique rod-shaped microglial morphology that was also observed in other diffuse brain injury models. Histological studies revealed a predominance of MHC-II positive M-1 phenotype in the post-concussive microglial milieu following multiple impacts. Although there was simultaneous expression of M-1 and M-2 markers, gene expression results indicate a clear dominance in M-1 pro-inflammatory markers following both single and repeated concussions. While the increase in M-1 markers quickly resolved after a single concussion, they persisted following repeated concussions, indicating a pro-inflammatory environment induced by multiple concussions that may delay recovery and contribute to long-lasting consequences of concussion.
Journal of neurotrauma, Jan 10, 2018
Glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase (UCH-L1), markers of gl... more Glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase (UCH-L1), markers of glial and neuronal cell body injury respectively, have been previously selected by the Operation Brain Trauma Therapy (OBTT) pre-clinical therapy and biomarker screening consortium as drug development tools. However, traumatic axonal injury (TAI) also represents a major consequence and determinant of adverse outcomes following traumatic brain injury (TBI). Thus, biomarkers capable of assessing TAI are much needed. Neurofilaments (NFs) are found exclusively in axons. Here, we evaluated phospho-neurofilament-H (pNF-H) protein as a possible new TAI marker in serum and cerebrospinal fluid (CSF) across three rat TBI models in studies carried out by the OBTT consortium, namely, controlled cortical impact (CCI), parasagittal fluid percussion (FPI) and penetrating ballistics-like brain injury (PBBI). We indeed found that CSF and serum pNF-H levels are robustly elevated by 24 h post injury in all t...
Journal of Trauma and Acute Care Surgery
Journal of neurotrauma, Jan 22, 2017
Closed-head concussive injury is one of the most common causes of traumatic brain injury (TBI). I... more Closed-head concussive injury is one of the most common causes of traumatic brain injury (TBI). Isolated concussions frequently produce acute neurological impairments; however, individuals typically recover spontaneously within a short time frame. In contrast, brain injuries resulting from multiple concussions can result in cumulative damage and elevated risk of developing chronic brain pathologies, including chronic traumatic encephalopathy (CTE). Increased attention has focused on identification of diagnostic markers that can prognostically serve as indices of brain health after injury, revealing the temporal profile of vulnerability to a second insult. Such markers may demarcate adequate recovery periods before concussed patients can return to required activities. We developed a non-invasive closed-head impact model which captures the hallmark symptoms of concussion in the absence of gross tissue damage. Animals were subjected to single or repeated concussive impact and examined ...
Journal of Neurotrauma, 2015
Simvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor commonly used to reduc... more Simvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor commonly used to reduce serum cholesterol. The beneficial effects of oral simvastatin have been reported in preclinical models of traumatic brain injury (TBI). The current study was designed to evaluate the potential beneficial effects of simvastatin in a model of severe, penetrating TBI using an intravenous (IV) route of administration. Rats were subjected to unilateral frontal penetrating ballistic-like brain injury (PBBI) and simvastatin was delivered intravenously at 30min and 6h post-injury and continued once daily for either 4 or 10 days post-PBBI. Motor function was assessed on the rotarod and cognitive performance was evaluated using the Morris water maze (MWM) task. Serum levels of inflammatory cytokines and the astrocytic biomarker, glial fibrillary acidic protein (GFAP), were quantified at 1h, 4h and 24h post-injury. Histopathological damage was assessed at the terminal endpoint. Rotarod testing revealed significant motor deficits in all injury groups but no significant simvastatin-induced therapeutic benefits. All PBBI-injured animals showed cognitive impairment on the MWM test; however, 10-day simvastatin treatment mitigated these effects. Animals showed significantly improved latency to platform and retention scores, whereas the 4-day treatment regimen failed to produce any significant improvements. Biomarker and cytokine analysis showed that IV simvastatin significantly reduced GFAP, IL-1a, and IL-17 serum levels by 4, 2.6, and 7 fold, respectively, at 4 h post-injury. Collectively, our results demonstrate that IV simvastatin provides significant protection against injury-induced cognitive dysfunction and reduces TBI-specific biomarker levels. Further research is warranted to identify the optimal dose and therapeutic window for IV delivery of simvastatin in models of severe TBI.
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Papers by Janice Gilsdorf