Vagal nerve stimulation decreases blood-brain barrier disruption after traumatic brain injury

Lopez, Nicole; Krzyżaniak, Michael; Costantini, Todd W.; Putnam, James G.; Hageny, A.; Eliceiri, Brian P.; Coimbra, Raúl; Bansal, Vishal

doi:10.1097/ta.0b013e3182569875

Cited by 52 publications

(41 citation statements)

References 20 publications

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“…Additionally, stimulation of the parasympathetic sphenopalatine ganglion has been found to induce BBB opening resulting in an increase in delivery of chemotherapeutic agents (i.e., anti-HER2 monoclonal antibody, etoposide) to the brain (72). In contrast, in a rodent model of traumatic brain injury (TBI), vagal stimulation following TBI resulted in a decrease in BBB permeability to FITC-dextran as compared to animals with TBI alone (73). It is noteworthy that many factors that modulate neuronal growth, development, and repair also regulate endothelial cell function.…”

Section: Components Of the Nvumentioning

confidence: 98%

Transporters at CNS Barrier Sites: Obstacles or Opportunities for Drug Delivery?

Sanchez-Covarrubias¹,

Slosky²,

Thompson³

et al. 2014

CPD

200

137

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The blood-brain barrier (BBB) and blood-cerebrospinal fluid (BCSF) barriers are critical determinants of CNS homeostasis. Additionally, the BBB and BCSF barriers are formidable obstacles to effective CNS drug delivery. These brain barrier sites express putative influx and efflux transporters that precisely control permeation of circulating solutes including drugs. The study of transporters has enabled a shift away from “brute force” approaches to delivering drugs by physically circumventing brain barriers towards chemical approaches that can target specific compounds of the BBB and/or BCSF barrier. However, our understanding of transporters at the BBB and BCSF barriers has primarily focused on understanding efflux transporters that efficiently prevent drugs from attaining therapeutic concentrations in the CNS. Recently, through the characterization of multiple endogenously expressed uptake transporters, this paradigm has shifted to the study of brain transporter targets that can facilitate drug delivery (i.e., influx transporters). Additionally, signaling pathways and trafficking mechanisms have been identified for several endogenous BBB/BCSF transporters, thereby offering even more opportunities to understand how transporters can be exploited for optimization of CNS drug delivery. This review presents an overview of the BBB and BCSF barrier as well as the many families of transporters functionally expressed at these barrier sites. Furthermore, we present an overview of various strategies that have been designed and utilized to deliver therapeutic agents to the brain with a particular emphasis on those approaches that directly target endogenous BBB/BCSF barrier transporters.

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Section: Components Of the Nvumentioning

confidence: 98%

Transporters at CNS Barrier Sites: Obstacles or Opportunities for Drug Delivery?

Sanchez-Covarrubias¹,

Slosky²,

Thompson³

et al. 2014

CPD

200

137

View full text Add to dashboard Cite

show abstract

“…The Tracey laboratories, for example, established that efferent signaling of the vagus nerve acts exclusively via α7nAChR activation in the spleen to regulate systemic cytokine responses to infection in mice (15)(16)(17)(18)(19)(20). Similarly, Costantini and colleagues demonstrated the existence of a similar α7nAChR-dependent regulation of the local inflammatory response in tissues (21)(22)(23)(24)(25)(26)(27). With α7nAChR activation clearly essential to inflammation, not to mention vagus nerve responsiveness and leukocyte function (28,29), we reasoned that it was therefore critical to understand how a human-specific α7nAChR in human leukocytes might influence human leukocyte function, the regulation of its expression and the biological consequences of its expression.…”

Section: Introductionmentioning

confidence: 98%

A Human-Specific α7-Nicotinic Acetylcholine Receptor Gene in Human Leukocytes: Identification, Regulation and the Consequences of CHRFAM7A Expression

Costantini

Dang

Yurchyshyna

et al. 2015

Mol Med

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The human genome contains a variant form of the α7-nicotinic acetylcholine receptor (α7nAChR) gene that is uniquely human. This CHRFAM7A gene arose during human speciation and recent data suggests that its expression alters ligand tropism of the normally homopentameric human α7-AChR ligand-gated cell surface ion channel that is found on the surface of many different cell types. To understand its possible significance in regulating inflammation in humans, we investigated its expression in normal human leukocytes and leukocyte cell lines, compared CHRFAM7A expression to that of the CHRNA7 gene, mapped its promoter and characterized the effects of stable CHRFAM7A overexpression. We report here that CHRFAM7A is highly expressed in human leukocytes but that the levels of both CHRFAM7A and CHRNA7 mRNAs were independent and varied widely. To this end, mapping of the CHRFAM7A promoter in its 5′-untranslated region (UTR) identified a unique 1-kb sequence that independently regulates CHRFAM7A gene expression. Because overexpression of CHRFAM7A in THP1 cells altered the cell phenotype and modified the expression of genes associated with focal adhesion (for example, FAK, P13K, Akt, rho, GEF, Elk1, CycD), leukocyte transepithelial migration (Nox, ITG, MMPs, PKC) and cancer (kit, kitL, ras, cFos cyclinD1, Frizzled and GPCR), we conclude that CHRFAM7A is biologically active. Most surprisingly however, stable CHRFAM7A overexpression in THP1 cells upregulated CHRNA7, which, in turn, led to increased binding of the specific α7nAChR ligand, bungarotoxin, on the THP1 cell surface. Taken together, these data confirm the close association between CHRFAM7A and CHRNA7 expression, establish a biological consequence to CHRFAM7A expression in human leukocytes and support the possibility that this human-specific gene might contribute to, and/or gauge, a human-specific response to inflammation.

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“…In addition to promoting an anti-inflammatory cholinergic response, VNS also directly improves the integrity of the tight gap junction proteins that regulate intestinal permeability 207 . VNS has also been shown to decrease intestinal permeability and improve the integrity of the blood-brain barrier, both of which would be beneficial following TBI 208,209 .…”

Section: Vagus Nerve Stimulationmentioning

confidence: 99%

The bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease

Sundman

Chen

Subbian

et al. 2017

Brain, Behavior, and Immunity

145

103

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The bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease. AbstractAs head injuries and their sequelae have become an increasingly salient matter of public health, experts in the field have made great progress elucidating the biological processes occurring within the brain at the moment of injury and throughout the recovery thereafter. Given the extraordinary rate at which our collective knowledge of neurotrauma has grown, new insights may be revealed by examining the existing literature across disciplines with a new perspective. This article will aim to expand the scope of this rapidly evolving field of research beyond the confines of the central nervous system (CNS). Specifically, we will examine the extent to which the bidirectional influence of the gut-brain axis modulates the complex biological processes occurring at the time of traumatic brain injury (TBI) and over the days, months, and years that follow. In addition to local enteric signals originating in the gut, it is well accepted that gastrointestinal (GI) physiology is highly regulated by innervation from the CNS. Conversely, emerging data suggests that the function and health of the CNS is modulated by the interaction between 1) neurotransmitters, immune signaling, hormones, and neuropeptides produced in the gut, 2) the composition of the gut microbiota, and 3) integrity of the intestinal wall serving as a barrier to the external environment. Specific to TBI, existing pre-clinical data indicates that head injuries can cause structural and functional damage to the GI tract, but research directly investigating the neuronal consequences of this intestinal damage is lacking. Despite this void, the proposed mechanisms emanating from a damaged gut are closely implicated in the inflammatory processes known to promote neuropathology in the brain following TBI, which suggests the gut-brain axis may be a therapeutic target to reduce the risk of Chronic Traumatic Encephalopathy and other neurodegenerative diseases following TBI. To better appreciate how various peripheral influences are implicated in the health of the CNS following TBI, this paper will also review the secondary biological injury mechanisms and the dynamic pathophysiological response to neurotrauma. Together, this review article will attempt to connect the dots to reveal novel insights into the bidirectional influence of the gut-brain axis and propose a conceptual model relevant to the recovery from TBI and subsequent risk for future neurological conditions.

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Vagal nerve stimulation decreases blood-brain barrier disruption after traumatic brain injury

Abstract: VNS attenuates cerebral vascular permeability and decreases the up-regulation of AQP-4 after TBI. Future studies are needed to assess the mechanisms by which VNS maintains the BBB.

Cited by 52 publications

References 20 publications

Transporters at CNS Barrier Sites: Obstacles or Opportunities for Drug Delivery?

Transporters at CNS Barrier Sites: Obstacles or Opportunities for Drug Delivery?

A Human-Specific α7-Nicotinic Acetylcholine Receptor Gene in Human Leukocytes: Identification, Regulation and the Consequences of CHRFAM7A Expression

The bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease

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