Transcranial amelioration of inflammation and cell death after brain injury

National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nature (Impact Factor: 41.46). 01/2014; 505(7482):223-8. DOI: 10.1038/nature12808
Source: PubMed


Traumatic brain injury (TBI) is increasingly appreciated to be highly prevalent and deleterious to neurological function. At present, no effective treatment options are available, and little is known about the complex cellular response to TBI during its acute phase. To gain insights into TBI pathogenesis, we developed a novel murine closed-skull brain injury model that mirrors some pathological features associated with mild TBI in humans and used long-term intravital microscopy to study the dynamics of the injury response from its inception. Here we demonstrate that acute brain injury induces vascular damage, meningeal cell death, and the generation of reactive oxygen species (ROS) that ultimately breach the glial limitans and promote spread of the injury into the parenchyma. In response, the brain elicits a neuroprotective, purinergic-receptor-dependent inflammatory response characterized by meningeal neutrophil swarming and microglial reconstitution of the damaged glial limitans. We also show that the skull bone is permeable to small-molecular-weight compounds, and use this delivery route to modulate inflammation and therapeutically ameliorate brain injury through transcranial administration of the ROS scavenger, glutathione. Our results shed light on the acute cellular response to TBI and provide a means to locally deliver therapeutic compounds to the site of injury.

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    • "ving the role of purinergic signaling in neuroinflammation is that inflammatory responses exacerbate injury. However, the complex pathways leading to inflammasome activation are highly conserved, suggesting a strong adaptive value. It is likely, therefore, that reducing neuroinflammation associated with pathology is not necessarily always of value. Roth et al. (2014) investigated the role of purinergic signaling in neuroinflammatory responses following TBI and found that the P2X7-mediated inflammatory response contributes to better outcomes, with activated microglia protecting the parenchyma and myelomonocytic cells invading the damaged meninges. Both purinergic mechanisms and reactive oxygen specie"

    Full-text · Dataset · Feb 2016
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    • "Microglia are long-lived tissue macrophages that populate the brain early in post-natal development and that are early responders to brain injury, disease and dysfunction (Carson et al. 2007). Previous reports have shown that various models of mild traumatic brain injury induce visible indications of microglial activation at the peri-contusional lesion site such as soma volume enlargement and altered surveillance distance of microglial processes (Roth et al. 2014) as well as an up-regulation in the CX3CR1 1 week post-TBI (Rancan et al. 2004). In addition, recent studies demonstrate that a midline fluid percussion injury causing mild to moderate injury is accompanied by significant microglia activation as measured by changes in morphology, protein and mRNA 4–24 h post-injury (Fenn et al. 2014). "
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    ABSTRACT: Seventy-five percent of all traumatic brain injuries are mild and do not cause readily visible abnormalities on routine medical imaging making it difficult to predict which individuals will develop unwanted clinical sequelae. Microglia are brain-resident macrophages and early responders to brain insults. Their activation is associated with changes in morphology or expression of phenotypic markers including P2Y12 and major histocompatibility complex class II. Using a murine model of unrestrained mild closed head injury (mCHI), we used microglia as reporters of acute brain injury at sites of impact versus sites experiencing rotational stress 24 h post-mCHI. Consistent with mild injury, a modest 20% reduction in P2Y12 expression was detected by quantitative real-time PCR (qPCR) analysis but only in the impacted region of the cortex. Furthermore, neither an influx of blood-derived immune cells nor changes in microglial expression of CD45, TREM1, TREM2, major histocompatibility complex class II or CD40 were detected. Using magnetic resonance imaging (MRI), small reductions in T2 weighted values were observed but only near the area of impact and without overt tissue damage (blood deposition, edema). Microglial morphology was quantified without cryosectioning artifacts using ScaleA2 clarified brains from CX3CR1-green fluorescence protein (GFP) mice. The cortex rostral to the mCHI impact site receives greater rotational stress but neither MRI nor molecular markers of microglial activation showed significant changes from shams in this region. However, microglia in this rostral region did display signs of morphologic activation equivalent to that observed in severe CHI. Thus, mCHI-triggered rotational stress is sufficient to cause injuries undetectable by routine MRI that could result in altered microglial surveillance of brain homeostasis. Acute changes in microglial morphology reveal brain responses to unrestrained mild traumatic brain injury In areas subjected to rotational stress distant from impact site In the absence of detectable changes in standard molecular indicators of brain damage, inflammation or microglial activation. That might result in decreased surveillance of brain function and increased susceptibility to subsequent brain insults.
    Full-text · Article · Jan 2016 · Journal of Neurochemistry
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    • "Therefore improved understanding of the complex processes following TBI [3] is crucial for the development of an effective neuroprotective treatment. Although the key role of the systemic cellular immune response in patients following multiple trauma has been emphasized by several authors, there is only a limited number of studies analyzing the cellular response of the key inflammatory cells such as monocytes and granulocytes in the cerebrospinal fluid (CSF) of patients following TBI [4] [5] [6]. Monocytes are characterized by CD14, a 56 kDa cell membrane anchored protein [7] [8]. "
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    ABSTRACT: In traumatic brain injury (TBI) the analysis of neuroinflammatory mechanisms gained increasing interest. In this context certain immunocompetent cells might play an important role. Interestingly, in the actual literature there exist only a few studies focusing on the role of monocytes and granulocytes in TBI patients. In this regard it has recently reported that the choroid plexus represents an early, selective barrier for leukocytes after brain injury. Therefore the aim of this study was to evaluate the very early dynamics of CD14+ monocytes and CD15+ granulocyte in CSF of patients following severe TBI with regard to the integrity of the BBB. Cytometric flow analysis was performed to analyze the CD14+ monocyte and CD15+ granulocyte population in CSF of TBI patients. The ratio of CSF and serum albumin as a measure for the BBB’s integrity was assessed in parallel. CSF samples of patients receiving lumbar puncture for elective surgery were obtained as controls. Overall 15 patients following severe TBI were enrolled. 10 patients were examined as controls. In patients, the monocyte population as well as the granulocyte population was significantly increased within 72 hours after TBI. The BBB’s integrity did not have a significant influence on the cell count in the CSF.
    Full-text · Article · Nov 2015 · Mediators of Inflammation
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