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Cerebrovascular dysfunction following traumatic brain injury (TBI) is a well-characterized phenomenon. Given the therapeutic potential of xenon, we aimed to study its effects after localized delivery to the brain using microbubbles. We designed xenon-containing microbubbles stabilized by dibehenoylphosphatidylcholine (DBPC) and polyethylene glycol (PEG) attached to saturated phospholipid (DPSE-PEG5000). Using a pig model of TBI, these microbubbles were intravenously injected, and ultrasound was used to release xenon at the level of the carotid artery. The control group received perfluorobutane containing microbubbles. Diffusion tensor imaging (DTI) showed areas of higher fractional anisotropy for pigs receiving xenon microbubbles compared to the control group at 1 day after injury. Radial diffusivity analysis showed that this effect was mainly the result of acute edema. Pigs were euthanized at 5 days, and the brain tissues of xenon-treated animals showed reduction of perivascular inflammation and blood–brain barrier disruption. Endothelial cell culture experiments showed that glutamate reduces tight junction protein zona occludens-1 (ZO-1), but treatment with xenon microbubbles attenuates this effect. Xenon treatment protects cerebrovasculature and reduces astroglial reactivity after TBI. Further, these data support the future use of localized delivery of various therapeutic agents for brain injury using microbubbles in order to limit systemic side effects and reduce costs. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) causes significant white matter injury, which has been characterized by various rodent and human clinical studies. The exact time course of imaging changes in a pediatric brain after TBI and its relation to biomarkers of injury and cellular function, however, is unknown. To study the changes in major white matter structures using a valid model of TBI that is comparable to a human pediatric brain in terms of size and anatomical features, we utilized a four-week-old pediatric porcine model of injury with controlled cortical impact (CCI). Using diffusion tensor imaging differential tractography, we show progressive anisotropy changes at major white matter tracts such as the corona radiata and inferior fronto-occipital fasciculus between day 1 and day 30 after injury. Moreover, correlational tractography shows a large part of bilateral corona radiata having positive correlation with the markers of cellular respiration. In contrast, bilateral corona radiata has a negative correlation with the plasma biomarkers of injury such as neurofilament light or glial fibrillary acidic protein. These are expected correlational findings given that higher integrity of white matter would be expected to correlate with lower injury biomarkers. We then studied the magnetic resonance spectroscopy findings and report decrease in a N-acetylaspartate/creatinine (NAA/Cr) ratio at the pericontusional cortex, subcortical white matter, corona radiata, thalamus, genu, and splenium of corpus callosum at 30 days indicating injury. There was also an increase in choline/creatinine ratio in these regions indicating rapid membrane turnover. Given the need for a pediatric TBI model that is comparable to human pediatric TBI, these data support the use of a pediatric pig model with CCI in future investigations of therapeutic agents. This model will allow future TBI researchers to rapidly translate our pre-clinical study findings into clinical trials for pediatric TBI. [ABSTRACT FROM AUTHOR]

To establish the clinical relevance of porcine model of traumatic brain injury (TBI) using the plasma biomarkers of injury with diffusion tensor imaging (DTI) over 30 days, we performed a randomized, blinded, pre-clinical trial using Yorkshire pigs weighing 7-10 kg. Twelve pigs were subjected to Sham injury (n = 5) by skin incision or TBI (n = 7) by controlled cortical impact. Blood samples were collected before the injury, then at approximately 5-day intervals until 30 days. Both groups also had DTI at 24 h and at 30 days after injury. Plasma samples were isolated and single molecule array (Simoa) was performed for glial fibrillary acidic protein (GFAP) and neurofilament light (NFL) levels. Afterwards, brain tissue samples were stained for β-APP. DTI showed fractional anisotropy (FA) decrease in the right corona radiata (ipsilateral to injury), contralateral corona radiata, and anterior corpus callosum at 1 day. At 30 days, ipsilateral corona radiata showed decreased FA. Pigs with TBI also had increase in GFAP and NFL at 1-5 days after injury. Significant difference between Sham and TBI animals continued up to 20 days. Linear regression showed significant negative correlation between ipsilateral corona radiata FA and both NFL and GFAP levels at 1 day. To further validate the degree of axonal injury found in DTI, β-APP immunohistochemistry was performed on a perilesional tissue as well as corona radiata bilaterally. Variable degree of staining was found in ipsilateral corona radiata. Porcine model of TBI replicates the acute increase in plasma biomarkers seen in clinical TBI. Further, long term white matter injury is confirmed in the areas such as the splenium and corona radiata. However, future study stratifying severe and mild TBI, as well as comparison with other subtypes of TBI such as diffuse axonal injury, may be warranted. [ABSTRACT FROM AUTHOR]

Despite multiple prior pharmacological trials in traumatic brain injury (TBI), the search for an effective, safe, and practical treatment of these patients remains ongoing. Given the ease of delivery and rapid absorption into the systemic circulation, inhalational gases that have neuroprotective properties will be an invaluable resource in the clinical management of TBI patients. In this review, we perform a systematic review of both pre-clinical and clinical reports describing inhalational gas therapy in the setting of TBI. Hyperbaric oxygen, which has been investigated for many years, and some of the newest developments are reviewed. Also, promising new therapies such as hydrogen gas, hydrogen sulfide gas, and nitric oxide are discussed. Moreover, novel therapies such as xenon and argon gases and delivery methods using microbubbles are explored. [ABSTRACT FROM AUTHOR]

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. In addition, cholinergic dysfunction has also been a familiar topic among TBI researchers for many years. Although pharmacological agents that modulate cholinergic neurotransmission have been used with varying degrees of success in previous studies, improving their function and maximizing cognitive recovery is an ongoing process. In this article, we review the previous findings on the biological mechanism of cholinergic dysfunction after TBI. In addition, we describe studies that use both older agents and newly developed agents as candidates for targeting cholinergic neurotransmission in future studies. [ABSTRACT FROM AUTHOR]

AbstractExperimental 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. Environmental enrichment (EE) has been shown to improve functional outcome after TBI, and a number of studies suggest that it may exert some benefits via dopaminergic signaling. To better understand the role of dopamine in chronic TBI pathophysiology and the effect of EE, we examined the mRNA expression profile within the substantia nigra and VTA at 4 weeks post-injury. Specifically, three comparisons were made: 1) TBI versus sham, 2) sham+EE versus sham+standard (STD) housing, and 3) TBI+EE versus TBI+STD. There were differential expressions of 25, 4, and 40 genes in these comparisons, respectively. Chronic alterations in genes post-injury within the substantia nigra and VTA included genes important for cellular membrane homeostasis and transcription. EE-induced gene alterations after TBI included genes important for signal transduction, in particular calcium signaling pathways, membrane homeostasis, and metabolism. Elucidation of these alterations in gene expression within the substantia nigra and VTA provides new insights into chronic changes in dopamine signaling post-TBI, and the potential role of EE in TBI rehabilitation. [ABSTRACT FROM AUTHOR]