Capillary Depletion Method for Quantification of Blood–Brain Barrier Transport of Circulating Peptides and Plasma Proteins

Triguero, Domingo; Buciak, Jody L.; Pardridge, William M.

doi:10.1111/j.1471-4159.1990.tb04886.x

Cited by 435 publications

(317 citation statements)

References 33 publications

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“…In additional samples, a capillary depletion protocol was carried out to remove endothelial cells from the brain samples (11). The cortex was harvested as described above and homogenized in 3 ml perchloric acid.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics of fructose-1,6-diphosphate after intraperitoneal and oral administration to adult rats

Stringer

2008

Pharmacological Research

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Exogenously administered fructose-1,6-diphosphate (FDP) has been studied for its ability to protect tissue during hypoxia or ischemia. Recently, a clear effect of FDP on the central nervous system has raised the question whether FDP can get into the brain. FDP levels were measured in blood, brain, liver, kidney, muscle and fat after intraperitoneal administration of a single 0.5g kg-1 dose of FDP to adult male Sprague-Dawley rats. A complete time course of the levels in blood and brain was determined. The levels of FDP in the blood and brain increase simultaneously, i.e. there is no lag in the increase in the brain. The levels of FDP fall to baseline in liver, kidney, muscle and fat by 12 hours, but remain elevated in blood and brain. However, levels in the blood at 12 hours are significantly decreased from the peak levels, while those in brain are not different from the peak levels, suggesting that the kinetics of FDP in blood and brain are quite different. Stripping the endothelial cells from the brain tissue sample did not change the levels of FDP indicating that FDP is not trapped in the capillary cells. Incubation of brain slices in a solution of FDP, followed by washing, raised tissue levels of FDP indicating that FDP is taken up into cells within the brain. Finally, the experiments demonstrate a significant increase in brain levels of FDP after oral administration. These data suggest that an oral formulation of FDP might be developed for treatment of neurological disease.

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Section: Methodsmentioning

confidence: 99%

Pharmacokinetics of fructose-1,6-diphosphate after intraperitoneal and oral administration to adult rats

Stringer

2008

Pharmacological Research

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“…Brain was removed from the skull, leptomeningeal vessels were carefully isolated, and brain cortical tissue was subjected to microvascular depletionby dextran density gradient centrifugation (Triguero et al, 1990) to determine the fraction of radiolabeled peptide tightly bound to the BBB (Zlokovic, 1995). Total and TCA-precipitable 125J radioactivities were analyzed in whole brain, microvascular, and capillary-depleted brain tissue homogenates.…”

Section: Intravenous Injection Experimentsmentioning

confidence: 99%

Cerebrovascular Accumulation and Increased Blood‐Brain Barrier Permeability to Circulating Alzheimer's Amyloid β Peptide in Aged Squirrel Monkey with Cerebral Amyloid Angiopathy

Mačkić¹,

Weiss²,

Miao³

et al. 1998

Journal of Neurochemistry

132

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Senescent squirrel monkey is a valuable model to study pathogenesis of cerebrovascular amyloid angiopathy (CAA). Cerebrovascular sequestration and bloodbrain barrier (BBB) permeability to 1251-amyloid~3(1 -40) synthetic peptide (sA/3 1_40) were studied in adult versus aged squirrel monkey 1 h after a single intravenous injection. In aged monkey, the half-time of elimination of sA/31_40, t~12, was prolonged by 0.6 h, the systemic clearance,~was reduced from 1.8 to 1.1 mI/mm/kg, and the mean residence time of intact peptide in the circulation was increased by 1 h (45%). In adult monkey, cerebrovascular sequestration of intact sA/31_40 was significant, and the BBB permeability was 18.6-fold higher than for inulin. In aged monkey, the sequestration of intact sA/3140 by cortical and leptomeningeal microvessels and the BBB permeability were increased by 5.9, 1.8-, and 2.1 -fold, respectively, in the presence of an unchanged barrier to inulin. In brain parenchyma of aged animals, 76.1% of circulating sA/31_40 remained intact versus 45.7% in adult. We conclude that multiple age-related systemic effects, i.e., reduced body elimination and systemic clearance of sA/3140, and reduced peripheral metabolism, may act in concert with BBB mechanisms, i.e., increased transendothelial transport and microvascular accumulation of blood-borne sAft~40, and reduced brain metabolism to enhance the development of CAA. Key Words: Alzheimer's amyloid /3-Cerebrovascular amybid angiopathy-Squirrel monkey-Cerebrovascular sequestration-Blood-brain barrier permeability-Aging.

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“…Capillary depletion, modified for mouse brain, was carried out according to the method of Pardridge adapted from (Triguero et al, 1990) to measure JAK4D levels in brain capillaries and parenchyma following peripheral administration.…”

Section: Brain Permeationmentioning

confidence: 99%

First-in-class thyrotropin-releasing hormone (TRH)-based compound binds to a pharmacologically distinct TRH receptor subtype in human brain and is effective in neurodegenerative models

Kelly¹,

Boyle²,

Cole³

et al. 2015

Neuropharmacology

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Hardiman, O., First-in-class thyrotropin-releasing hormone (TRH)-based compound binds to a pharmacologically distinct TRH receptor subtype in human brain and is effective in neurodegenerative models, Neuropharmacology (2014), doi: 10.1016/j.neuropharm.2014.09.024. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPTABSTRACT JAK4D, a first-in-class thyrotropin-releasing hormone (TRH)-based compound, is a prospective therapeutic candidate offering a multifaceted approach to treating neurodegeneration and other CNS conditions. The purpose of these studies was to determine the ability of JAK4D to bind to TRH receptors in human brain and to evaluate its neuropharmacological effects in neurodegenerative animal models. Additionally, JAK4D brain permeation was examined in mouse, and initial toxicology was assessed in vivo and in vitro. We report that JAK4D bound selectively with nanomolar affinity to native TRH receptors in human hippocampal tissue and showed for the first time that these receptors are pharmacologically distinct from TRH receptors in human pituitary, thus revealing a new TRH receptor subtype which represents a promising neurotherapeutic target in human brain. Systemic administration of JAK4D elicited statistically significant and clinically-relevant neuroprotective effects in three established neurodegenerative animal models: JAK4D reduced cognitive deficits when administered post-insult in a kainate (KA)-induced rat model of neurodegeneration; it protected against free radical release and neuronal damage evoked by intrastriatal microdialysis of KA in rat; and it reduced motor decline, weight loss, and lumbar spinal cord neuronal loss in G93A-SOD1 transgenic Amyotrophic Lateral Sclerosis mice. Ability to cross the blood-brain-barrier and a clean initial toxicology profile were also shown. In light of these findings, JAK4D is an important tool for investigating the hitherto-unidentified central TRH receptor subtype reported herein and an attractive therapeutic candidate for neurodegenerative disorders.

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Capillary Depletion Method for Quantification of Blood–Brain Barrier Transport of Circulating Peptides and Plasma Proteins

Cited by 435 publications

References 33 publications

Pharmacokinetics of fructose-1,6-diphosphate after intraperitoneal and oral administration to adult rats

Pharmacokinetics of fructose-1,6-diphosphate after intraperitoneal and oral administration to adult rats

Cerebrovascular Accumulation and Increased Blood‐Brain Barrier Permeability to Circulating Alzheimer's Amyloid β Peptide in Aged Squirrel Monkey with Cerebral Amyloid Angiopathy

First-in-class thyrotropin-releasing hormone (TRH)-based compound binds to a pharmacologically distinct TRH receptor subtype in human brain and is effective in neurodegenerative models

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