Guide Introduction to the Blood-Brain Barrier: Methodology, Biology and Pathology

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A brain abscess is a rare, life-threatening condition. Local sources may include infections of the ear, the oral cavity and teeth, the paranasal sinuses, or an epidural abscess. Remote sources may include infections in the lung, heart or kidney. A brain abscess may also be caused by head trauma or as a complication of surgery. In children cerebral abscesses are usually linked to congenital heart disease.

Epilepsy is a common neurological disease that is characterized by recurrent and sometimes untreatable seizures.

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Several clinical and experimental data have implicated the failure of blood—brain barrier function in triggering chronic or acute seizures. In addition, expression of drug resistance molecules and transporters at the BBB are a significant mechanism of resistance to commonly used anti-epileptic drugs. Multiple sclerosis MS is considered to be an auto-immune and neurodegenerative disorder in which the immune system attacks the myelin that protects and electrically insulates the neurons of the central and peripheral nervous systems.

Normally, a person's nervous system would be inaccessible to the white blood cells due to the blood—brain barrier. However, magnetic resonance imaging has shown that when a person is undergoing an MS "attack," the blood—brain barrier has broken down in a section of the brain or spinal cord, allowing white blood cells called T lymphocytes to cross over and attack the myelin. It has sometimes been suggested that, rather than being a disease of the immune system, MS is a disease of the blood—brain barrier.

There are currently active investigations into treatments for a compromised blood—brain barrier.

Blood brain barrier (BBB)

It is believed that oxidative stress plays an important role into the breakdown of the barrier. Anti-oxidants such as lipoic acid may be able to stabilize a weakening blood—brain barrier. Neuromyelitis optica , also known as Devic's disease, is similar to and is often confused with multiple sclerosis. Among other differences from MS, a different target of the autoimmune response has been identified. Patients with neuromyelitis optica have high levels of antibodies against a protein called aquaporin 4 a component of the astrocytic foot processes in the blood—brain barrier.

De Vivo disease also known as GLUT1 deficiency syndrome is a rare condition caused by inadequate transportation of the sugar glucose across the blood—brain barrier, resulting in developmental delays and other neurological problems. Alzheimer's disease may be caused or more likely, aggravated by a breakdown in the blood—brain barrier.

A review indicated that latent HIV can cross the blood—brain barrier inside circulating monocytes in the bloodstream " Trojan horse theory" within the first 14 days of infection. Activated macrophages release virions into the brain tissue proximate to brain microvessels. These viral particles likely attract the attention of sentinel brain microglia and perivascular macrophages initiating an inflammatory cascade that may cause a series of intracellular signaling in brain microvascular endothelial cells and damage the functional and structural integrity of the BBB.

During systemic inflammation , whether in the form of infection or sterile inflammation, the BBB may become leaky to blood-borne compounds. These changes may also affect the course of multiple sclerosis or Alzheimer's disease. Paul Ehrlich was a bacteriologist studying staining , a procedure that is used in many microscopy studies to make fine biological structures visible using chemical dyes. However, in a later experiment in , Edwin Goldmann one of Ehrlich's students injected the dye directly into the cerebrospinal fluids of animal brains.

Introduction to the blood-brain barrier methodology, biology and pathology

He found then the brains did become dyed, but the rest of the body did not, demonstrating the existence of a compartmentalization between the two. At that time, it was thought that the blood vessels themselves were responsible for the barrier, since no obvious membrane could be found. The concept of the blood—brain barrier then termed hematoencephalic barrier was proposed by a Berlin physician, Lewandowsky, in From Wikipedia, the free encyclopedia.

Semipermeable membrane that separates blood from the brain. See also: Neuroimmune system. Main article: Circumventricular organs. Main article: Nanoparticles for drug delivery to the brain. Cold Spring Harbor Perspectives in Biology. Neurobiology of Disease. Histology and Histopathology.

Journal of Cerebral Blood Flow and Metabolism. Epub 4 : — Current Neuropharmacology. Biology Open. Nature Reviews Neuroscience. Journal of Anatomy. Medical Neuroscience Preview. Hayes Barton Press. Retrieved — via Google Books. Journal of Neurochemistry. Journal of the College of Physicians and Surgeons Pakistan.

Fluids Barriers CNS. Acta Neurobiologiae Experimentalis. Funke; Christine L. Case Microbiology: An Introduction. San Francisco: Benjamin Cummings. Infection and Immunity. Future Microbiol. M Progress in Brain Research. Download to read the full article text. Kennedy T. Drug Discovery Today 2: —, CrossRef Google Scholar. ADMET in silico modelling: towards prediction paradise? Nat Rev Drug Discov 2: —, Sucrose and inulin space measurements of cerebral cortex in four mammalian species.

Introduction to the Blood-Brain Barrier: Methodology, Biology and Pathology - Google книги

Am J Physiol Lond —, Google Scholar. Lower limits of cerebrovascular permeability to nonelectrolytes in the conscious rat. Crone C. Acta Physiol Scand —, Renkin EM. Transport of potassium from blood to tissue in isolated mammalian skeletal muscles. Methods for quantifying the transport of drugs across brain barrier systems. Pharmacol Ther —, Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data.

J Cereb Blood Flow Metab 3: 1—7, J Cereb Blood Flow Metab 3: 8—32, Smith QR. A review of blood-brain barrier transport techniques. Methods Mol Med —, PubMed Google Scholar. Distributed model for drug delivery to CSF and brain tissue. Tetsuya T, Ohtsuki S. Brain-to-blood transporters for endogenous substrates and xenobiotics at the blood-brain barrier: an overview of biology and methodology.

NeuroRx 2: 63—71, Galanthamine: pharmacokinetics, tissue distribution and cholinesterase inhibition in brain of mice. Neuropharmacology —, Oldendorf WH. Measurement of brain uptake of radiolabeled substances using a tritiated water internal standard. Brain Res —, Clearance of radiolabeled substances by brain after arterial injection using a diffusible internal standard. New York: Plenum Publishing Co. Cornford EM. The carotid artery single injection technique.

In: Introduction to the blood-brain barrier: methodology, biology and pathology Pardridge WM, ed , pp 11— Carotid artery injection technique: bounds for bolus mixing by plasma and by brain. J Cereb Blood Flow Metab 5: —, An in situ brain perfusion technique to study cerebrovascular transport in the rat. J Neurochem —, Development of an in situ mouse brain perfusion model and its application to mdr1a P-glycoprotein-deficient mice. J Cereb Blood Flow Metab —, In situ brain perfusion technique.

Capillary depletion method for quantification of blood-brain barrier transport of circulating peptides and plasma proteins. Pardridge WM. Receptor-mediated transcytosis of peptides. In: Brain drug targeting—the future of brain drug development. Blood-brain barrier transport and brain metabolism of adenosine and adenosine analogs. J Pharmacol Exp Ther 14—18, Blood-brain barrier transport of neuropeptides: analysis with a metabolically stable dermorphin analogue.

Kinetics of blood-brain transport of hexoses. Biochim Biophys Acta —, Smith QR, Takasato Y. Kinetics of amino acid transport at the blood-brain barrier studied using an in situ brain perfusion technique. Ann NY Acad Sci —, Blood-brain barrier carrier-mediated transport and brain metabolism of amino acids. Neurochem Res —, The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat.

Measurement of local cerebral blood flow with iodo [14C] antipyrine. Measurement of blood-brain and blood-tumor barrier permeabilities with [14C]-labeled tracers. Transient middle cerebral artery occlusion by intraluminal suture: I. Three-dimensional autoradiographic image-analysis of local cerebral glucose metabolism-blood flow interrelationships during ischemia and early recirculation.

Fenstermacher JD, Wei L. Measuring local cerebral capillary permeability-surface area products by quantitative autoradiography. In: Introduction to the blood-brain barrier: methodology, biology and pathology Pardridge WM, ed , pp — Brain microdialysis The microdialysis technique has gained increasing popularity over the last decade for studying drug distribution to the CNS.

Limitations of CSF sampling Especially in human pharmacokinetic studies the measurement of CSF concentrations is often taken as a substitute for brain interstitial fluid concentrations. Endothelial cell culture models Much effort is dedicated to the development of brain microvessel endothelial cell BMEC culture systems, which could be used for quantitative permeability studies and as screen in drug discovery. Primary endothelial cell cultures Accepted criteria for monitoring the quality of monolayers in transport studies include transendothelial electrical resistance TEER and permeability to hydrophilic markers like 14 C-sucrose, which reflect the degree of tight junction formation.

Computational prediction of brain uptake The in silico models evolved from experimental work on the correlation between brain uptake and two principal molecular properties: lipophilicity and molecular weight. Kennedy T. Drug Discovery Today 2 : —, ADMET in silico modelling: towards prediction paradise?

References

Nat Rev Drug Discov 2 : —, Sucrose and inulin space measurements of cerebral cortex in four mammalian species. Am J Physiol Lond : —, Lower limits of cerebrovascular permeability to nonelectrolytes in the conscious rat. Crone C. Acta Physiol Scand 58 : —, Renkin EM. Transport of potassium from blood to tissue in isolated mammalian skeletal muscles.

Methods for quantifying the transport of drugs across brain barrier systems. Pharmacol Ther 14 : —, Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab 3 : 1—7, J Cereb Blood Flow Metab 3 : 8—32, Smith QR. A review of blood-brain barrier transport techniques. Methods Mol Med 89 : —, Distributed model for drug delivery to CSF and brain tissue.

Tetsuya T, Ohtsuki S. Brain-to-blood transporters for endogenous substrates and xenobiotics at the blood-brain barrier: an overview of biology and methodology. NeuroRx 2 : 63—71, Galanthamine: pharmacokinetics, tissue distribution and cholinesterase inhibition in brain of mice. Neuropharmacology 30 : —, Oldendorf WH. Measurement of brain uptake of radiolabeled substances using a tritiated water internal standard. Brain Res 24 : —, Clearance of radiolabeled substances by brain after arterial injection using a diffusible internal standard.

New York: Plenum Publishing Co. Cornford EM. The carotid artery single injection technique. In: Introduction to the blood-brain barrier: methodology, biology and pathology Pardridge WM, ed , pp 11— Carotid artery injection technique: bounds for bolus mixing by plasma and by brain.

J Cereb Blood Flow Metab 5 : —, An in situ brain perfusion technique to study cerebrovascular transport in the rat. J Neurochem 46 : —, Development of an in situ mouse brain perfusion model and its application to mdr1a P-glycoprotein-deficient mice.

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J Cereb Blood Flow Metab 20 : —, In situ brain perfusion technique. Capillary depletion method for quantification of blood-brain barrier transport of circulating peptides and plasma proteins. J Neurochem 54 : —, Pardridge WM. Receptor-mediated transcytosis of peptides. In: Brain drug targeting—the future of brain drug development. Blood-brain barrier transport and brain metabolism of adenosine and adenosine analogs.

J Pharmacol Exp Ther : 14—18, Blood-brain barrier transport of neuropeptides: analysis with a metabolically stable dermorphin analogue. Kinetics of blood-brain transport of hexoses. Biochim Biophys Acta : —, Smith QR, Takasato Y. Kinetics of amino acid transport at the blood-brain barrier studied using an in situ brain perfusion technique. Ann NY Acad Sci : —, Blood-brain barrier carrier-mediated transport and brain metabolism of amino acids. Neurochem Res 23 : —, The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat.

J Neurochem 28 : —, Measurement of local cerebral blood flow with iodo [14C] antipyrine.

Measurement of blood-brain and blood-tumor barrier permeabilities with [14C]-labeled tracers. Transient middle cerebral artery occlusion by intraluminal suture: I. Three-dimensional autoradiographic image-analysis of local cerebral glucose metabolism-blood flow interrelationships during ischemia and early recirculation. J Cereb Blood Flow Metab 17 : —, Fenstermacher JD, Wei L. Measuring local cerebral capillary permeability-surface area products by quantitative autoradiography.

In: Introduction to the blood-brain barrier: methodology, biology and pathology Pardridge WM, ed , pp — Measurement of blood-brain barrier permeability in humans with positron emission tomography. Kinetic modeling in positron emission tomography. Q J Nucl Med 46 : 70—85, PET studies on P-glycoprotein function in the blood-brain barrier: how it affects uptake and binding of drugs within the CNS. Curr Pharm Des 10 : —, Measurement of the blood-brain barrier permeability and leakage space using dynamic MR imaging.

Fundamental concepts. Magn Reson Med 17 : —, Magn Reson Med 50 : —, Artemov D. Molecular magnetic resonance imaging with targeted contrast agents.


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J Cell Biochem 90 : —, Deguchi Y, Morimoto K. Application of an in vivo brain microdialysis technique to studies of drug transport across the blood-brain barrier. Curr Drug Metab 2 : —, Methodological issues in microdialysis sampling for pharmacokinetic studies. Adv Drug Deliv Rev 45 : —, Intracerebral dialysis and the blood-brain barrier.

J Neurochem 64 : —, Steady-state theory for quantitative microdialysis of solutes and water in vivo and in vitro. Life Sci 46 : —, Application of microdialysis in pharmacokinetic studies. Pharm Res 14 : —, Hammarlund-Udenaes M. The use of microdialysis in CNS drug delivery studies. Pharmacokinetic perspectives and results with analgesics and antiepileptics. Drug equilibration across the blood-brain barrier—pharmacokinetic considerations based on the microdialysis method. Wang Y, Welty DF. The simultaneous estimation of the influx and efflux blood-brain barrier permeabilities of gabapentin using a microdialysis-pharmacokinetic approach.

Pharm Res 13 : —, Distribution of morphine 6-glucuronide and morphine across the blood-brain barrier in awake, freely moving rats investigated by in vivo microdialysis sampling. J Pharmacol Exp Ther : —, Blood-brain barrier permeability to morphineglucuronide is markedly reduced compared with morphine. Drug Metab Dispos 25 : —, Poor permeability of morphine 3-glucuronide and morphine 6-glucuronide through the blood-brain barrier in the rat.

Br J Pharmacol : —, KA inhibits rat brain acetylcholinesterase in vitro but not in vivo. Neurosci Lett : Changes in blood-brain barrier permeability associated with insertion of brain cannulas and microdialysis probes. Brain Res : —, Quantitative assessment of blood-brain barrier damage during microdialysis. Considerations in the use of cerebrospinal fluid pharmacokinetics to predict brain target concentrations in the clinical setting: implications of the barriers between blood and brain.

Blood–brain barrier

Clin Pharmacokinet 41 : —, Quantitative brain microdialysis study on the mechanism of quinolones distribution in the central nervous system. Kinetic evidence for active efflux transport across the blood-brain barrier of quinolone antibiotics. Joo F. The blood-brain barrier in vitro: the second decade.

Neurochem Int 23 : —, Isolated brain capillaries: and in vitro model of blood-barin barrier research. In: Introduction to the blood-brain barrier: methodology, biology and pathology Pardridge WM, ed , pp 49— Lasbennes F, Gayet J Capacity for energy metabolism in microvessels isolated from rat brain. Neurochem Res 9 : 1—10, Huwyler J, Pardridge WM. Examination of blood-brain barrier transferrin receptor by confocal fluorescent microscopy of unfixed isolated rat brain capillaries. J Neurochem 70 : —, Xenobiotic transport across isolated brain microvessels studied by confocal microscopy.

Mol Pharmacol 58 : —, Neutral amino acid transport by the blood-brain barrier. Membrane vesicle studies. J Biol Chem : —, Transport studies using membrane vesicles. Gumbleton M, Audus KL. Progress and limitations in the use of in vitro cell cultures to serve as a permeability screen for the blood-brain barrier. J Pharm Sci 90 : —, An overview of in vitro techniques for blood-brain barrier studies. Brain microvessel endothelia cell culture systems.

In: Introduction to the blood-brain barrier: methodology, biology and pathology Pardridge WM, ed , pp 86— The role of unstirred layers for water exchange across the blood-brain barrier. Microvasc Res 21 : —, Electrical resistance across the blood-brain barrier in anaesthetized rats: a developmental study. J Physiol Lond : 47—62, In vitro model for evaluating drug transport across the blood-brain barrier.