Kollidon VA64 Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy.

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 therefore 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).

Glibenclamide Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy.

Glibenclamide (GLY) is the sixth drug tested by the Operation Brain Trauma Therapy (OBTT) consortium based on substantial pre-clinical evidence of benefit in traumatic brain injury (TBI). Adult Sprague-Dawley rats underwent fluid percussion injury (FPI;  = 45), controlled cortical impact (CCI;  = 30), or penetrating ballistic-like brain injury (PBBI;  = 36). Efficacy of GLY treatment (10-μg/kg intraperitoneal loading dose at 10 min post-injury, followed by a continuous 7-day subcutaneous infusion [0.

Serum-Based Phospho-Neurofilament-Heavy Protein as Theranostic Biomarker in Three Models of Traumatic Brain Injury: An Operation Brain Trauma Therapy Study.

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 after traumatic brain injury (TBI). Thus, biomarkers capable of assessing TAI are much needed.

Brain injury results in lower levels of melatonin receptors subtypes MT1 and MT2.

Background: Traumatic brain injury (TBI) is a devastating and costly acquired condition that affects individuals of all ages, races, and geographies via a number of mechanisms. The effects of TBI on melatonin receptors remain unknown.

Purpose: The purpose of this study is to explore whether endogenous changes in two melatonin receptor subtypes (MT1 and MT2) occur after experimental TBI.

Effects of DHA on Hippocampal Autophagy and Lysosome Function After Traumatic Brain Injury.

Traumatic brain injury (TBI) triggers endoplasmic reticulum (ER) stress and impairs autophagic clearance of damaged organelles and toxic macromolecules. In this study, we investigated the effects of the post-TBI administration of docosahexaenoic acid (DHA) on improving hippocampal autophagy flux and cognitive functions of rats. TBI was induced by cortical contusion injury in Sprague-Dawley rats, which received DHA (16 mg/kg in DMSO, intraperitoneal administration) or vehicle DMSO (1 ml/kg) with an initial dose within 15 min after the injury, followed by a daily dose for 3 or 7 days.

Administration of DHA Reduces Endoplasmic Reticulum Stress-Associated Inflammation and Alters Microglial or Macrophage Activation in Traumatic Brain Injury.

We investigated the effects of the administration of docosahexaenoic acid (DHA) post-traumatic brain injury (TBI) on reducing neuroinflammation. TBI was induced by cortical contusion injury in Sprague Dawley rats. Either DHA (16 mg/kg in dimethyl sulfoxide) or vehicle dimethyl sulfoxide (1 ml/kg) was administered intraperitonially at 5 min after TBI, followed by a daily dose for 3 to 21 days.

Insight into Pre-Clinical Models of Traumatic Brain Injury Using Circulating Brain Damage Biomarkers: Operation Brain Trauma Therapy.

Operation Brain Trauma Therapy (OBTT) is a multicenter pre-clinical drug screening consortium testing promising therapies for traumatic brain injury (TBI) in three well-established models of TBI in rats--namely, parasagittal fluid percussion injury (FPI), controlled cortical impact (CCI), and penetrating ballistic-like brain injury (PBBI). This article presents unique characterization of these models using histological and behavioral outcomes and novel candidate biomarkers from the first three treatment trials of OBTT. Adult rats underwent CCI, FPI, or PBBI and were treated with vehicle (VEH).

Levetiracetam Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy.

Levetiracetam (LEV) is an antiepileptic agent targeting novel pathways. Coupled with a favorable safety profile and increasing empirical clinical use, it was the fifth drug tested by Operation Brain Trauma Therapy (OBTT). We assessed the efficacy of a single 15 min post-injury intravenous (IV) dose (54 or 170 mg/kg) on behavioral, histopathological, and biomarker outcomes after parasagittal fluid percussion brain injury (FPI), controlled cortical impact (CCI), and penetrating ballistic-like brain injury (PBBI) in rats.

Synthesis of Findings, Current Investigations, and Future Directions: Operation Brain Trauma Therapy.

Operation Brain Trauma Therapy (OBTT) is a fully operational, rigorous, and productive multicenter, pre-clinical drug and circulating biomarker screening consortium for the field of traumatic brain injury (TBI). In this article, we synthesize the findings from the first five therapies tested by OBTT and discuss both the current work that is ongoing and potential future directions. Based on the results generated from the first five therapies tested within the exacting approach used by OBTT, four (nicotinamide, erythropoietin, cyclosporine A, and simvastatin) performed below or well below what was expected based on the published literature.

Cyclosporine Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy.

Operation Brain Trauma Therapy (OBTT) is a consortium of investigators using multiple pre-clinical models of traumatic brain injury (TBI) to bring acute therapies to clinical trials. To screen therapies, we used three rat models (parasagittal fluid percussion injury [FPI], controlled cortical impact [CCI], and penetrating ballistic-like brain injury [PBBI]). We report results of the third therapy (cyclosporin-A; cyclosporine; [CsA]) tested by OBTT.

Nicotinamide Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy.

Nicotinamide (vitamin B3) was the first drug selected for cross-model testing by the Operation Brain Trauma Therapy (OBTT) consortium based on a compelling record of positive results in pre-clinical models of traumatic brain injury (TBI). Adult male Sprague-Dawley rats were exposed to either moderate fluid percussion injury (FPI), controlled cortical impact injury (CCI), or penetrating ballistic-like brain injury (PBBI). Nicotinamide (50 or 500 mg/kg) was delivered intravenously at 15 min and 24 h after injury with subsequent behavioral, biomarker, and histopathological outcome assessments.

Erythropoietin Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy.

Experimental studies targeting traumatic brain injury (TBI) have reported that erythropoietin (EPO) is an endogenous neuroprotectant in multiple models. In addition to its neuroprotective effects, it has also been shown to enhance reparative processes including angiogenesis and neurogenesis. Based on compelling pre-clinical data, EPO was tested by the Operation Brain Trauma Therapy (OBTT) consortium to evaluate therapeutic potential in multiple TBI models along with biomarker assessments.

Simvastatin Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy.

Simvastatin, the fourth drug selected for testing by Operation Brain Trauma Therapy (OBTT), is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor used clinically to reduce serum cholesterol. In addition, simvastatin has demonstrated potent antineuroinflammatory and brain edema reducing effects and has shown promise in promoting functional recovery in pre-clinical models of traumatic brain injury (TBI). The purpose of this study was to assess the potential neuroprotective effects of oral administration of simvastatin on neurobehavioral, biomarker, and histopathological outcome measures compared across three pre-clinical TBI animal models.

Approach to Modeling, Therapy Evaluation, Drug Selection, and Biomarker Assessments for a Multicenter Pre-Clinical Drug Screening Consortium for Acute Therapies in Severe Traumatic Brain Injury: Operation Brain Trauma Therapy.

Traumatic brain injury (TBI) was the signature injury in both the Iraq and Afghan wars and the magnitude of its importance in the civilian setting is finally being recognized. Given the scope of the problem, new therapies are needed across the continuum of care. Few therapies have been shown to be successful.

Alterations in Cholinergic Pathways and Therapeutic Strategies Targeting Cholinergic System after Traumatic Brain Injury.

Traumatic brain injury (TBI) results in varying degrees of disability in a significant number of persons annually. The mechanisms of cognitive dysfunction after TBI have been explored in both animal models and human clinical studies for decades. Dopaminergic, serotonergic, and noradrenergic dysfunction has been described in many previous reports.

Neuroprotective effects of collagen matrix in rats after traumatic brain injury.

Purpose: In previous studies, collagen based matrices have been implanted into the site of lesion in different models of brain injury. We hypothesized that semisynthetic collagen matrix can have neuroprotective function in the setting of traumatic brain injury.

Methods: Rats were subjected to sham injury or controlled cortical impact.

Chronic Histopathological and Behavioral Outcomes of Experimental Traumatic Brain Injury in Adult Male Animals.

The purpose of this review is to survey the use of experimental animal models for studying the chronic histopathological and behavioral consequences of traumatic brain injury (TBI). The strategies employed to study the long-term consequences of TBI are described, along with a summary of the evidence available to date from common experimental TBI models: fluid percussion injury; controlled cortical impact; blast TBI; and closed-head injury. For each model, evidence is organized according to outcome.

Docosahexaenoic acid reduces ER stress and abnormal protein accumulation and improves neuronal function following traumatic brain injury.

In this study, we investigated the development of endoplasmic reticulum (ER) stress after traumatic brain injury (TBI) and the efficacy of post-TBI administration of docosahexaenoic acid (DHA) in reducing ER stress. TBI was induced by cortical contusion injury in Sprague-Dawley rats. Either DHA (16 mg/kg in DMSO) or vehicle DMSO (1 ml/kg) was administered intraperitoneally at 5 min after TBI, followed by a daily dose for 3-21 d.

Differential effect of traumatic brain injury on the nuclear factor of activated T Cells C3 and C4 isoforms in the rat hippocampus.

The interaction between the phosphatase calcineurin and transcription factor nuclear factor of activated T cells (NFAT) plays an important role numerous signaling and the regulatory events. Although NFAT is mostly known for its transcription function in the immune system, NFAT also has essential functions even in the central nervous system (CNS). The effects of traumatic brain injury (TBI) on NFAT are currently unknown.

The effect of environmental enrichment on substantia nigra gene expression after traumatic brain injury in rats.

Experimental investigations into the effects of traumatic brain injury (TBI) have demonstrated significant alterations in dopaminergic systems. Dopaminergic fibers originating within the substantia nigra and ventral tegmental area (VTA) are important for reward learning, addiction, movement, and behavior. However, little is known about the effect of TBI on substantia nigra and VTA function.

Effects of nicotine administration on striatal dopamine signaling after traumatic brain injury in rats.

Previous studies on the therapeutic potential of agents affecting the dopamine system in traumatic brain injury (TBI) suggest that dopamine dysregulation may have a major role in behavioral deficit after TBI. We have previously identified that TBI reduces striatal dopamine synthesis and release at 7 days post-injury. In order to reverse deficits in the activity of tyrosine hydroxylase and dopamine release following TBI, we administered nicotine by intraperitoneal injection into rats for 7 days.

Oral fish oil restores striatal dopamine release after traumatic brain injury.

Omega-3 fatty acid administration can affect the release of neurotransmitters and reduce inflammation and oxidative stress, but its use in traumatic brain injury (TBI) has not been described extensively. We investigated the effect of 7 day oral fish oil treatment in the recovery of potassium evoked dopamine release after TBI. Sham rats and TBI rats were given either olive oil or fish oil by oral gavage and were subject to cerebral microdialysis.

The dopamine and cAMP regulated phosphoprotein, 32 kDa (DARPP-32) signaling pathway: a novel therapeutic target in traumatic brain injury.

Traumatic brain injury (TBI) causes persistent neurologic deficits. Current therapies, predominantly focused upon cortical and hippocampal cellular survival, have limited benefit on cognitive outcomes. Striatal damage is associated with deficits in executive function, learning, and memory.

Traumatic brain injury reduces striatal tyrosine hydroxylase activity and potassium-evoked dopamine release in rats.

There is increasing evidence that traumatic brain injury (TBI) induces hypofunction of the striatal dopaminergic system, the mechanisms of which are unknown. In this study, we analyzed the activity of striatal tyrosine hydroxylase (TH) in rats at 1 day, 1 week, and 4 weeks after TBI using the controlled cortical impact model. There were no changes in the level of TH phosphorylated at serine 40 site (pser40TH) at 1 day or 4 weeks.