The blood-brain barrier: an engineering perspective

Wong, Andrew D.; Ye, Mao; Levy, Amanda F.; Rothstein, Jeffrey D.; Bergles, Dwight E.; Searson, Peter C.

doi:10.3389/fneng.2013.00007

Cited by 507 publications

(515 citation statements)

References 271 publications

(425 reference statements)

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“…32 Due to the limited volume and diffusion constraints of the ECS, the local neuronal K þ efflux (e.g., occurring during the repolarization phase of action potentials) is sufficient to significantly increase ½K þ o . While the basal ½K þ o concentration is ∼3 mM, 33 somewhat lower than the plasma concentration, ½K þ o may rise to 10 to 12 mM during sustained neuronal activity.…”

Section: Discussionmentioning

confidence: 99%

Imaging extracellular potassium dynamics in brain tissue using a potassium-sensitive nanosensor

2017

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Abstract. Neuronal activity results in the release of K þ into the extracellular space (ECS). Classically, measurements of extracellular K þ (½K þ o ) are carried out using K þ -sensitive microelectrodes, which provide a single point measurement with undefined spatial resolution. An imaging approach would enable the spatiotemporal mapping of ½K þ o . Here, we report on the design and characterization of a fluorescence imaging-based K þ -sensitive nanosensor for the ECS based on dendrimer nanotechnology. Spectral characterization, sensitivity, and selectivity of the nanosensor were assessed by spectrofluorimetry, as well as in both wide-field and two-photon microscopy settings, demonstrating the nanosensor efficacy over the physiologically relevant ion concentration range. Spatial and temporal kinetics of the nanosensor responses were assessed using a localized iontophoretic K þ application on a two-photon imaging setup. Using acute mouse brain slices, we demonstrate that the nanosensor is retained in the ECS for extended periods of time. In addition, we present a ratiometric version of the nanosensor, validate its sensitivity in brain tissue in response to elicited neuronal activity and correlate the responses to the extracellular field potential. Together, this study demonstrates the efficacy of the K þ -sensitive nanosensor approach and validates the possibility of creating multimodal nanosensors. © The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.

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Section: Discussionmentioning

confidence: 99%

Imaging extracellular potassium dynamics in brain tissue using a potassium-sensitive nanosensor

2017

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“…This is clearly one mechanism underpinning the adverse effect of neuroinflammation and oxidative stress on iron accumulation in the CNS. Several authors have also reported that upregulation of divalent metal transporter 1 (DMT1) on the surface of neurones and glial cells results from the release of TNF-α, IL-1β, IL-6 and NO by LPS-activated microglia [330][331][332]. Importantly, the release of PICs from activated microglia, most notably IL-6, also leads to increases of hepcidin and reduction of ferroportin in neurones, which supplies a mechanism allowing increasing Fig.…”

Section: Transcriptional Regulation Of Iron Homeostasismentioning

confidence: 99%

“…Once in the cytosol, Fe(II) can be utilised for various essential metabolic processes such as the synthesis of iron-sulphur proteins, or sequestrated by cytosolic ferritin and mitochondrial ferritin (FtMt), which offers protection against the advent of the Fenton reaction. Iron is removed from neurones by ferroportin, supported by the multi-coppercontaining ferroxidase caeruloplasmin and sAPP, which both act to stabilise ferroportin at the cell surface levels of neuronal iron accumulation over time in an environment of neuroinflammation [330,331,333].…”

Section: Transcriptional Regulation Of Iron Homeostasismentioning

confidence: 99%

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

et al. 2018

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The classical amyloid cascade model for Alzheimer's disease (AD) has been challenged by several findings. Here, an alternative molecular neurobiological model is proposed. It is shown that the presence of the APOE ε4 allele, altered miRNA expression and epigenetic dysregulation in the promoter region and exon 1 of TREM2, as well as ANK1 hypermethylation and altered levels of histone post-translational methylation leading to increased transcription of TNFA, could variously explain increased levels of peripheral and central inflammation found in AD. In particular, as a result of increased activity of triggering receptor expressed on myeloid cells 2 (TREM-2), the presence of the apolipoprotein E4 (ApoE4) isoform, and changes in ANK1 expression, with subsequent changes in miR-486 leading to altered levels of protein kinase B (Akt), mechanistic (previously mammalian) target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3), all of which play major roles in microglial activation, proliferation and survival, there is activation of microglia, leading to the subsequent (further) production of cytokines, chemokines, nitric oxide, prostaglandins, reactive oxygen species, inducible nitric oxide synthase and cyclooxygenase-2, and other mediators of inflammation and neurotoxicity. These changes are associated with the development of amyloid and tau pathology, mitochondrial dysfunction (including impaired activity of the electron transport chain, depleted basal mitochondrial potential and oxidative damage to key tricarboxylic acid enzymes), synaptic dysfunction, altered glycogen synthase kinase-3 (GSK-3) activity, mTOR activation, impairment of autophagy, compromised ubiquitin-proteasome system, iron dyshomeostasis, changes in APP translation, amyloid plaque formation, tau hyperphosphorylation and neurofibrillary tangle formation.

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“…The BBB is a specialized system of capillary endothelial cells which are partially covered by pericytes and basement membrane is almost fully surrounded by the end feet of astrocytes preventing approximately 98% of the small molecules and nearly 100% of large molecules from being transported into the brain [2,3]. The BBB strictly limits drug transport into the brain by serving as a physical, metabolic and immunological barrier.…”

Section: Introductionmentioning

confidence: 99%

Brain Targeting Potential of Intravenous Carbamazepine SNEDDS

Kumar¹,

Rambhau²

2017

J Mol Pharm Org Process Res

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Purpose: The objective of this study was to evaluate the ability of nano-droplets of Self Nano Emulsifying Drug Delivery System to diffuse into the brain tissue. Methods:The preconcentrate was prepared by dissolving oils, surfactants and cosolvents in 1:1 mixture of methanol and chloroform and flash evaporated at 50°C and was stored at room temperature until their use in subsequent studies. CSEDD with surfactant polysorbate-80 were radiolabelled with radioactive C18 triglyceride. The nanodroplets formed by CSEDD in 5% dextrose were subjected to evaluation in blood and brain. Results:The intravenous pharmacokinetics of carbamazepine in rats of CSEDD formulation generated high initial serum levels (5.25 mcg/ml) at 0.25 h when compared to C-Sol (3.91 mcg/ml) at 0.5 h. It was found that oil to surfactant ratio had an impact on the physical characteristics of the nano-emulsion formed. The brain levels of CBZ from optimized CSEDD were significantly high at all-time points when compared to plain solution. The initial levels of CBZ from CSEDD was 8.023 mcg/ml thereafter the levels were consistently high till 8 h and the initial levels of CBZ from plain solution was 3.62 mcg/ml followed by a gradual decline till 4 h evidently showing that the clearance of CBZ from CSEDD was reduced. The brain targeting index of CSEDD and solution were 3 and 2 respectively. The brain enhancement factor value was found to be 22.29 at 15 min revealing a very rapid penetration of CBZ into brain. Conclusions:This study proposes intravenous CSEDD as a new brain delivery system and highlights two requirements to design adequate delivery systems for long circulating properties of the carrier and appropriate surface characteristics to allow interactions with BBB endothelial cells.

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The blood-brain barrier: an engineering perspective

Cited by 507 publications

References 271 publications

Imaging extracellular potassium dynamics in brain tissue using a potassium-sensitive nanosensor

Imaging extracellular potassium dynamics in brain tissue using a potassium-sensitive nanosensor

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

Brain Targeting Potential of Intravenous Carbamazepine SNEDDS

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