Hazel C. Jones

Electrical resistance across the blood-brain barrier in anaesthetized rats: a developmental study.

1. Ion permeability of the blood‐brain barrier was studied by in situ measurement of transendothelial electrical resistance in anaesthetized rats aged between 17 days gestation and 33 days after birth, and by electron microscopic examination of lanthanum permeability in fetal and neonatal rats aged up to 10 days old. 2. The blood‐brain barrier in 17‐ to 20‐day fetuses had a resistance of 310 omega cm2 but was impermeable to lanthanum, and therefore had properties intermediate between leaky and tight epithelia. 3. From 21 days gestation, the resistance was 1128 omega cm2, indicating a tight blood‐brain barrier and low ion permeability. There was little further change in barrier resistance after birth, and in 28‐ to 33‐day rats, when the brain barrier systems are mature in other ways, vessels had a mean resistance of 1462 omega cm2. 4. In the tight blood‐brain barrier, arterial vessels had a significantly higher resistance than venous vessels, 1490 and 918 omega cm2 respectively. In vessels less than 50 microns diameter and within the normal 60 min experimental period, there was no significant variation in vessel resistance. 5. Hyperosmotic shock caused a rapid decay in resistance (maximal within 5 min), and after disruption of the blood‐brain barrier, vessel resistance was 100‐300 omega cm2 in both arterial and venous vessels, and the effect was reversible. After the application of metabolic poisons (NaCN plus iodoacetate) and low temperature there was a similarly low electrical resistance. 6. It is concluded that the increase in electrical resistance at birth indicates a decrease in paracellular ion permeability at the blood‐brain barrier and is required for effective brain interstitial fluid ion regulation.

Effect of histamine and antagonists on electrical resistance across the blood-brain barrier in rat brain-surface microvessels

The effect of histamine on blood-brain barrier permeability was investigated using in situ measurement of transendothelial electrical resistance in brain-surface microvessels of anaesthetized rats. Mean resistance of vessels superfused with artificial cerebrospinal fluid was 1500 omega.cm2, indicating a tight barrier with low ion permeability. The addition of 10(-4) M histamine resulted in a 75% decrease in resistance, in both arterial and venous vessels, indicating a marked increase in barrier permeability. To determine the nature of the response to histamine, rats were given presurgical intraperitoneal injections of promethazine (H1 receptor antagonist), cimetidine (H2 receptor antagonist) or indomethacin (cyclo-oxygenase inhibitor), singularly and in combinations. Cimetidine completely blocked the histamine-mediated increase in barrier permeability whereas promethazine only had a small effect and indomethacin was ineffective. In addition, cimetidine treatment resulted in a 100% increase in basal resistance in both arterial and venous vessels, suggesting endogenous histamine was acting to increase blood-brain barrier permeability. It is concluded that histamine causes an increase in blood-brain barrier permeability which is mediated via endothelial H2 receptors, and that the electrical resistance in cimetidine-treated rats most closely represents the true permeability of the blood-brain barrier.

Chapter 19: The development of ion regulation at the blood-brain barrier

Publisher Summary Electrolytes play an essential part in neuronal activity and normal central nervous system (CNS) function is dependent on ion regulation in both the intra- and extracellular fluids of the brain. In particular, both K + and Ca 2+ are important ions for neuronal function. It has been known for a long time that changing electrolyte concentrations in the cerebrospinal fluid (CSF) has marked effects on nervous activity, whereas changing electrolyte concentrations in blood has minimal effects in brain. The blood–brain barrier (BBB), sited at the brain capillary endothelium, together with the blood–CSF barrier at the choroid plexus epithelium, controls transfer to the brain of substances in the systemic circulation as well as transfer in the reverse direction. Very early brain capillaries may be permeable to large molecules and even have fenestrations. By late gestation in the rat and mouse, however, the BBB is tight to proteins, although smaller molecules such as inulin and sucrose penetrate into brain and CSF more readily in both late fetal and neonatal rats.

Fluids and Barriers of the CNS: a new journal encompassing Cerebrospinal Fluid Research.

This article celebrates the re-launch of Cerebrospinal Fluid Research in its new format as Fluids and Barriers of the CNS. Editors-in Chief, Hazel Jones and Tetsuya Terasaki, anticipate that this expanded journal will provide a unique and specialist platform for the publication of research in cerebrospinal fluid and all brain barriers and fluid systems in both health and disease.

Current research into brain barriers and the delivery of therapeutics for neurological diseases: a report on CNS barrier congress London, UK, 2017

This is a report on the CNS barrier congress held in London, UK, March 22–23rd 2017 and sponsored by Kisaco Research Ltd. The two 1-day sessions were chaired by John Greenwood and Margareta Hammarlund-Udenaes, respectively, and each session ended with a discussion led by the chair. Speakers consisted of invited academic researchers studying the brain barriers in relation to neurological diseases and industry researchers studying new methods to deliver therapeutics to treat neurological diseases. We include here brief reports from the speakers.After publication of the article [1], it has been brought to our attention that there are some errors in the formatting of names in the final version of the article.

Advances in brain barriers and brain fluid research and news from Fluids and Barriers of the CNS

Research into brain barriers and brain fluids has been advancing rapidly in recent years. This editorial aims to highlight some of the advances that have improved our understanding of this complex subject. It also brings you news of developments for Fluids and Barriers of the CNS including a new affiliation between the journal and the International Society for Hydrocephalus and CSF disorders.

Progress in brain barriers and brain fluid research in 2017

The past year, 2017, has seen many important papers published in the fields covered by Fluids and Barriers of the CNS. This article from the Editors highlights some.

Brain barriers and brain fluid research in 2016: advances, challenges and controversies

This editorial highlights some of the advances that occurred in relation to brain barriers and brain fluid research in 2016. It also aims to raise some of the attendant controversies and challenges in such research.

News from the editors of Fluids and Barriers of the CNS.

This editorial announces a new affiliation between Fluids and Barriers of the CNS (FBCNS) and the International Brain Barriers Society (IBBS) with mutual benefits to the journal and to society members. This is a natural progression from the appointment of two new Co-Editors in Chief: Professor Lester Drewes and Professor Richard Keep in 2013. FBCNS provides a unique and specialist platform for the publication of research in the expanding fields of brain barriers and brain fluid systems in both health and disease.

Michael William Blackburn Bradbury 1930–2013

Mike Bradbury: Professor of Physiology, King’s College London 1977–1995, Emeritus 1995–2013. Mike Bradbury was born on the 2nd of July 1930 in Capetown South Africa. He attended Sherborne School in Dorset and in 1949 was awarded an Open Scholarship to Christ Church, Oxford. He obtained an honours degree in Physiology in 1952 having been awarded inter alia a Theodore Williams Scholarship in Human Anatomy. Mike completed his medical training at St. Bartholomew’s Hospital in Smithfield, City of London. He subsequently graduated BM, BCh from the University of Oxford in 1956. After graduating, he carried out research for the degree of DM in the laboratory of R.V. Coxon, Nuffield Department of Clinical Biochemistry and University Laboratory of Physiology, Oxford, and presented a thesis in 1962 entitled “Transfer and Distribution of Urea in the Body”. Part of this study was on the movement of urea into the brain [1]. This aspect of his early research was to dominate the rest of his scientific career and subsequent research into the regulation of the brain fluid environment and the transport of drugs, ions and other solutes across the brain microvasculature which forms the major component of the blood–brain barrier. After Oxford, Mike returned to London to a post of Research Assistant, supported by the Medical Research Council, in the Department of Physiology at University College, where he worked with, and was highly influenced by, Hugh Davson [2]. Hugh was a pioneering figure in blood–brain barrier and cerebrospinal fluid research. Together they used the technique of ventriculo-cisternal perfusion adapted from the original method of Pappenheimer et al.[3] to quantify the transport of various substances into and out of the cerebrospinal fluid. This method is still in use today. In 1965 he moved to Los Angeles, California, as Assistant Professor of Physiology University of California and Research Physiologist at Cedars-Sinai Medical Center, where he worked with Bill Oldendorf [4], a leader in the quantification of transport phenomena at the blood–brain barrier. Returning to the UK in 1968 he was appointed Senior Lecturer in Physiology, St Thomas’s Hospital Medical School, then Reader in Physiology, King’s College London in 1972, being made full Professor in 1977. During this period he made a continuous and vigourous contribution to Departmental and College life serving as Chairman of the Integration and Steering Committee developing a new undergraduate medical curriculum. His undergraduate lectures were always, lively, informative and entertaining. He was also active at the London University level serving both as Secretary and Chairman of the Board of Studies in Physiology, and also the Academic Advisory Boards of Science and Medicine. He became a member of the Physiological Society in 1964 and served on the Editorial Board of Journal of Physiology from 1981–1988. Throughout his career, Mike published widely on the blood–brain barrier and transport phenomena across the cerebral microvasculature and also on the control of the brain extracellular fluid and cerebrospinal fluid composition. A major opus was the publication of his monograph volume “The Concept of the Blood–brain Barrier” in 1979 which reviewed and updated the entire field: a rapidly expanding area of research at this time [5]. This book was generally known as “the blue book” by its many adherents and readers on account of its striking blue dust jacket and binding. Its presence was a must on the bookshelves of colleagues and research students. At King’s, he established a thriving group and a laboratory which attracted a large number of scientists, colleagues and research students. During Mike’s career many visiting scientists spent some sabbatical time in his lab and these collaborations were invariably productive and usually led to publications and to lasting interactions. Amongst the many visitors and collaborators were Barbora Stulkova [6], Norman Saunders [7]. Hans Bronsted [8], Jill Cremer [9], Joe Fenstermacher [10], Mike Carey [11], Helen Cserr [12], Gabe Pinter [13], Sue Lightmann [13], and Gary Rosenberg [14]. Mike developed a number of techniques to quantify transport at the blood–brain barrier. He wanted to determine accurately the transport of ions into the brain using a method to maintain constant blood levels by continuous intravenous infusion: a technically difficult task. During a visit by colleagues Cliff Patlak and Ron Blasberg, from the National Institutes of Health, Bethesda, Maryland, a lively discussion developed on whether it was possible to mathematically compensate for a decreasing concentration of solute in blood. The next week when Cliff and Ron were visiting the lab of Christian Crone in Copenhagen, Cliff presented the mathematical solution to the problem on a blackboard. In the audience in Copenhagen was Albert Gjedde who was the first person to apply the analytical technique to Positron Emission Tomography studies in animals and man [15]. Mike had provided the intellectual concept and stimulus and Cliff the mathematical skills. Thus the method of multi-time-point regression analysis was born. This approach still remains the basis of the most accurate and sensitive methods for measuring solute uptake by the brain and is acknowledged as being the “Gold Standard” for comparative studies of brain solute uptake. It is also still called the Patlak plot [16]. When Mike retired, a Festschrift was held in his honour at King’s attended by over one hundred of his colleagues and former students, a mark of his significant international reputation. The collected conference proceedings were published in a volume entitled “New Concepts of a Blood–brain Barrier” [17] in honour of his earlier volume and his numerous contributions to the field. Mike had a sharp and very enquiring mind which was very open to radical ideas. At one point, in spite of some personal scepticism, he was advising the Physics Department on whether it was possible for practitioners like Uri Geller to generate electromagnetic potentials which made his apparent feats possible and whether these could be measured, and was also investigating the possible mechanisms of acupuncture. In retirement, Mike used his Professor Emeritus status to the full: he was a regular visitor to the labs of colleagues for lively discussion and he was an invaluable mentor and critic to a host of research students. Mike’s characteristic and penetrating laugh always announced his presence. A retirement project was writing a volume on the colonization of North America. Sadly this project was not finished. Privately, Mike was a wonderful host to his friends and colleagues and also an enthusiastic yachtsman. His wife Anne survives him together with a daughter Joanna and two sons Nicholas and Timothy. Mike died peacefully on the 9th of February 2013 in Blandford, Dorset. Mike is remembered fondly by his numerous colleagues and collaborators and by generations of Medical and Science students. Figure 1 Michael William Blackburn Bradbury.