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: 42.35). 01/2014; 505(7482):223-8. DOI: 10.1038/nature12808
Source: PubMed

ABSTRACT 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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    • "In this regard, astrocyte released molecules that act on endothelia to reduce blood–brain barrier permeability after CNS injury include Sonic hedge hog (Shh) (Alvarez et al., 2011, 2013) and retinoic acid (Mizee et al., 2014). In addition, an astrocyte/microglial axis also likely to involve astrocyte-derived ATP gradients seems play a role in the maintenance of the blood–brain barrier early after TBI (Roth et al., 2014). Thus, astrocytes are emerging as pivotal regulators of endothelial blood–brain barrier properties that can, via specific molecular mechanisms , act to open, maintain or restore barrier functions, and do so in a context dependent manner as regulated by specific signaling events. "
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    ABSTRACT: Astrocytes sense changes in neural activity and extracellular space composition. In response, they exert homeostatic mechanisms critical for maintaining neural circuit function, such as buffering neurotransmitters, modulating extracellular osmolarity and calibrating neurovascular coupling. In addition to upholding normal brain activities, astrocytes respond to diverse forms of brain injury with heterogeneous and progressive changes of gene expression, morphology, proliferative capacity and function that are collectively referred to as reactive astrogliosis. Traumatic brain injury (TBI) sets in motion complex events in which noxious mechanical forces cause tissue damage and disrupt central nervous system (CNS) homeostasis, which in turn trigger diverse multi-cellular responses that evolve over time and can lead either to neural repair or secondary cellular injury. In response to TBI, astrocytes in different cellular microenvironments tune their reactivity to varying degrees of axonal injury, vascular disruption, ischemia and inflammation. Here we review different forms of TBI-induced astrocyte reactivity and the functional consequences of these responses for TBI pathobiology. Evidence regarding astrocyte contribution to post-traumatic tissue repair and synaptic remodeling is examined, and the potential for targeting specific aspects of astrogliosis to ameliorate TBI sequelae is considered. Copyright © 2015. Published by Elsevier Inc.
    Experimental Neurology 03/2015; DOI:10.1016/j.expneurol.2015.03.020 · 4.62 Impact Factor
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    • "vide high quality angiograms and functional images. A critical physiological assessment of the thin skull window concerns the potential brain inflammation and neuronal cell death caused by compression of the meningeal space during surgery (Roth et al., 2014). We controlled the expression of Iba1 and glial fibrillary acidic protein (GFAP), which are upregulated in reactive macrophages/ microglia and astrocytes, respectively, during brain injury (Drew et al., 2010). "
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