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.

70 Reads
  • Source
    • "Neutrophils are the first line of defense against pathogens and microbes, and are the first cell type to enter sites of infection and injury (Mantovani et al., 2011; David et al., 2012b). They are attracted to the site of injury by chemokines, complement proteins and lipid mediators like leukotriene B 4 (LTB 4 ) (Serhan, 2010; Mantovani et al., 2011; Roth et al., 2014). Neutrophils can cause bystander damage to cells via release of proteases, reactive oxygen species, and proinflammatory cytokines. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Macrophages in the injured spinal cord arise from resident microglia and from infiltrating peripheral myeloid cells. Microglia respond within minutes after central nervous system (CNS) injury and along with other CNS cells signal the influx of their peripheral counterpart. Although some of the functions they carry out are similar, they appear to be specialized to perform particular roles after CNS injury. Microglia and macrophages are very plastic cells that can change their phenotype drastically in response to in vitro and in vivo conditions. They can change from pro-inflammatory, cytotoxic cells to anti-inflammatory, pro-repair phenotypes. The microenvironment of the injured CNS importantly influences macrophage plasticity. This review discusses the phagocytosis and cytokine mediated effects on macrophage plasticity in the context of spinal cord injury. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 09/2015; 307. DOI:10.1016/j.neuroscience.2015.08.064 · 3.36 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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 · 4.70 Impact Factor
  • Source
    • "The cause of chronic electrode degradation is thought to arise either from a neuroinflammatory response or from biomaterial failure [19–22]. Cortical vessels can undergo extensive re-modeling in response to injury, as demonstrated in studies of stroke and traumatic brain injury [23–25]. Change to the vascular around an implanted electrode has the potential to be an early indicator or biomarker of signal degradation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Speckle variance optical coherence angiography (OCA) was used to characterize the vascular tissue response from craniotomy, window implantation, and electrode insertion in mouse motor cortex. We observed initial vasodilation ~40% greater than original diameter 2-3 days post-surgery (dps). After 4 weeks, dilation subsided in large vessels (>50 µm diameter) but persisted in smaller vessels (25-50 µm diameter). Neovascularization began 8-12 dps and vessel migration continued throughout the study. Vasodilation and neovascularization were primarily associated with craniotomy and window implantation rather than electrode insertion. Initial evidence of capillary re-mapping in the region surrounding the implanted electrode was manifest in OCA image dissimilarity. Further investigation, including higher resolution imaging, is required to validate the finding. Spontaneous lesions also occurred in many electrode animals, though the inception point appeared random and not directly associated with electrode insertion. OCA allows high resolution, label-free in vivo visualization of neurovascular tissue, which may help determine any biological contribution to chronic electrode signal degradation. Vascular and flow-based biomarkers can aid development of novel neural prostheses.
    Biomedical Optics Express 08/2014; 5(8). DOI:10.1364/BOE.5.002823 · 3.65 Impact Factor
Show more