The large apparent work capability of the blood‐brain barrier: A study of the mitochondrial content of capillary endothelial cells in brain and other tissues of the rat

Oldendorf, William H.; Cornford, Marcia E.; Brown, W. J.

doi:10.1002/ana.410010502

Cited by 535 publications

(281 citation statements)

References 33 publications

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“…The second are highly specific nutrient transporters that facilitate the transport of specific nutrients across the BBB into the CNS, as well as removal of specific waste products from the CNS into the blood (Mittapalli et al 2010). CNS ECs contain higher amounts of mitochondria compared to other ECs (Oldendorf et al 1977), which is thought to be critical to generate ATP to drive the ion gradients critical for transport functions. CNS ECs also express an extremely low level of leukocyte adhesion molecules (LAMs), as compared with ECs in other tissues greatly limiting the amount of immune cells that enter the CNS (Henninger et al 1997;Aird 2007a;Daneman et al 2010a).…”

Section: Endothelial Cellsmentioning

confidence: 99%

The Blood–Brain Barrier

Daneman

Prat

2015

Cold Spring Harb Perspect Biol

2,387

1,829

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Blood vessels are critical to deliver oxygen and nutrients to all of the tissues and organs throughout the body. The blood vessels that vascularize the central nervous system (CNS) possess unique properties, termed the blood-brain barrier, which allow these vessels to tightly regulate the movement of ions, molecules, and cells between the blood and the brain. This precise control of CNS homeostasis allows for proper neuronal function and also protects the neural tissue from toxins and pathogens, and alterations of these barrier properties are an important component of pathology and progression of different neurological diseases. The physiological barrier is coordinated by a series of physical, transport, and metabolic properties possessed by the endothelial cells (ECs) that form the walls of the blood vessels, and these properties are regulated by interactions with different vascular, immune, and neural cells. Understanding how these different cell populations interact to regulate the barrier properties is essential for understanding how the brain functions during health and disease.

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Section: Endothelial Cellsmentioning

confidence: 99%

The Blood–Brain Barrier

Daneman

Prat

2015

Cold Spring Harb Perspect Biol

2,387

1,829

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“…Thus, the small size and highly lipophilic surface of T-NPs helped their distribution in the brain. Furthermore, high mitochondrial density in cerebral endothelial cells than in peripheral endothelia further assisted these T-NPs to accumulate in the brain efficiently (14,15). The distinctive properties of brain endothelium, high lipophilicity, and mitochondria-targeting properties of T-NPs provided selective targeting of these NPs to the brain.…”

Section: Significancementioning

confidence: 99%

Detouring of cisplatin to access mitochondrial genome for overcoming resistance

Marrache

Pathak

Dhar

2014

Proc. Natl. Acad. Sci. U.S.A.

218

209

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Chemoresistance of cisplatin therapy is related to extensive repair of cisplatin-modified DNA in the nucleus by the nucleotide excision repair (NER). Delivering cisplatin to the mitochondria to attack mitochondrial genome lacking NER machinery can lead to a rationally designed therapy for metastatic, chemoresistant cancers and might overcome the problems associated with conventional cisplatin treatment. An engineered hydrophobic mitochondria-targeted cisplatin prodrug, Platin-M, was constructed using a strainpromoted alkyne-azide cycloaddition chemistry. Efficient delivery of Platin-M using a biocompatible polymeric nanoparticle (NP) based on biodegradable poly(lactic-co-glycolic acid)-block-polyethyleneglycol functionalized with a terminal triphenylphosphonium cation, which has remarkable activity to target mitochondria of cells, resulted in controlled release of cisplatin from Platin-M locally inside the mitochondrial matrix to attack mtDNA and exhibited otherwise-resistant advanced cancer sensitive to cisplatin-based chemotherapy. Identification of an optimized targeted-NP formulation with brain-penetrating properties allowed for delivery of Platin-M inside the mitochondria of neuroblastoma cells resulting in ∼17 times more activity than cisplatin. The remarkable activity of Platin-M and its targeted-NP in cisplatin-resistant cells was correlated with the hyperpolarization of mitochondria in these cells and mitochondrial bioenergetics studies in the resistance cells further supported this hypothesis. This unique dual-targeting approach to controlled mitochondrial delivery of cisplatin in the form of a prodrug to attack the mitochondrial genome lacking NER machinery and in vivo distribution of the delivery vehicle in the brain suggested previously undescribed routes for cisplatinbased therapy.click chemistry | brain cancer | OXPHOS | pharmacokinetics T he cellular powerhouse, mitochondria, are implicated in the process of carcinogenesis because of their vital roles in energy production and apoptosis. Mitochondria are the key players in generating the cellular energy through oxidative phosphorylation (OXPHOS) that produces reactive oxygen species (ROS) as by-products. Mitochondrial DNA (mtDNA) plays significant roles in cell death and metastatic competence. The close proximity of mtDNA to the ROS production site makes this genome vulnerable to oxidative damage. Mitochondrial dysfunction and associated mtDNA depletion possibly reversibly control epigenetic changes in the nucleus that contributes to cancer development (1). Thus, targeting mtDNA could lead to novel and effective therapies for aggressive cancers. Cisplatin, a Food and Drug Administration-approved chemotherapeutic agent, is most extensively characterized as a DNA-damaging agent and the cytotoxicity of cisplatin is attributed to the ability to form interstrand and intrastrand nuclear DNA (nDNA) cross-links (2). The nucleotide excision repair (NER) pathway plays major roles in repairing cisplatin-nDNA adducts (3). Resistance to cisplatin can result fr...

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“…Consequently, the transport role of the BBB is highly energy dependent; as evidenced by the greater number and volume of mitochondria compared to that of endothelia in peripheral vasculature [3].…”

Section: Introductionmentioning

confidence: 99%

Bioenergetic disruption of human micro-vascular endothelial cells by antipsychotics

Elmorsy

Smith

2015

Biochemical and Biophysical Research Communications

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Antipsychotics (APs) are widely used medications, however these are not without side effects such as disruption of blood brain barrier function (BBB). To investigate this further we have studied the chronic effects of the typical APs, chlorpromazine (CPZ) and haloperidol (HAL) and the atypical APs, risperidone (RIS) and clozapine (CLZ), on the bioenergetics of human micro-vascular endothelial cells (HBVECs) of the BBB. Alamar blue (AB) and ATP assays showed that these APs impair bioenergenesis in HBVECs in a concentration and time dependent manner. However since these effects were incomplete they suggest a population of cell bioenergetically heterogeneous, an idea supported by the bistable nature by which APs affected the mitochondrial transmembrane potential. CPZ, HAL and CLZ inhibited the activity of mitochondrial complexes I and III.Our data demonstrates that at therapeutic concentrations, APs can impair the bioenergetic status of HBVECs, an action that help explains the adverse side effects of these drugs when used clinically.

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The large apparent work capability of the blood‐brain barrier: A study of the mitochondrial content of capillary endothelial cells in brain and other tissues of the rat

Cited by 535 publications

References 33 publications

The Blood–Brain Barrier

The Blood–Brain Barrier

Detouring of cisplatin to access mitochondrial genome for overcoming resistance

Bioenergetic disruption of human micro-vascular endothelial cells by antipsychotics

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