This article describes a technique in which X-ray transmission readings are taken through the head at a multitude of angles: from these data, absorption values of the material contained within the head are calculated on a computer and presented as a series of pictures of slices of the cranium. The system is approximately 100 times more sensitive than conventional X-ray systems to such an extent that variations in soft tissues of nearly similar density can be displayed.

/pdf/computerized-transverse-axial-scanning-tomography-part-i-13qymylxxq.pdf

Computerized transverse axial scanning (tomography): Part I. Description of system. 1973.

The blood-brain barrier (BBB) is the regulated interface between the peripheral circulation and the central nervous system (CNS). Although originally observed by Paul Ehrlich in 1885, the nature of the BBB was debated well into the 20th century. The anatomical substrate of the BBB is the cerebral microvascular endothelium, which, together with astrocytes, pericytes, neurons, and the extracellular matrix, constitute a "neurovascular unit" that is essential for the health and function of the CNS. Tight junctions (TJ) between endothelial cells of the BBB restrict paracellular diffusion of water-soluble substances from blood to brain. The TJ is an intricate complex of transmembrane (junctional adhesion molecule-1, occludin, and claudins) and cytoplasmic (zonula occludens-1 and -2, cingulin, AF-6, and 7H6) proteins linked to the actin cytoskeleton. The expression and subcellular localization of TJ proteins are modulated by several intrinsic signaling pathways, including those involving calcium, phosphorylation, and G-proteins. Disruption of BBB TJ by disease or drugs can lead to impaired BBB function and thus compromise the CNS. Therefore, understanding how BBB TJ might be affected by various factors holds significant promise for the prevention and treatment of neurological diseases.

The Blood-Brain Barrier/Neurovascular Unit in Health and Disease

The blood-brain barrier (BBB) is formed by the brain capillary endothelium and excludes from the brain ∼100% of large-molecule neurotherapeutics and more than 98% of all small-molecule drugs. Despite the importance of the BBB to the neurotherapeutics mission, the BBB receives insufficient attention in either academic neuroscience or industry programs. The combination of so little effort in developing solutions to the BBB problem, and the minimal BBB transport of the majority of all potential CNS drugs, leads predictably to the present situation in neurotherapeutics, which is that there are few effective treatments for the majority of CNS disorders. This situation can be reversed by an accelerated effort to develop a knowledge base in the fundamental transport properties of the BBB, and the molecular and cellular biology of the brain capillary endothelium. This provides the platform for CNS drug delivery programs, which should be developed in parallel with traditional CNS drug discovery efforts in the molecular neurosciences.

https://link.springer.com/content/pdf/10.1602%2Fneurorx.2.1.3.pdf

The Blood-Brain Barrier: Bottleneck in Brain Drug Development

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.

/pdf/the-blood-brain-barrier-3kc38byrcn.pdf

The Blood–Brain Barrier

The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within ...

The Microbiota-Gut-Brain Axis

N-Acetyl-L-Aspartic acid: A literature review of a compound prominent in 1H-NMR spectroscopic studies of brain

Volumes of mitochondria in capillary endothelial cells were determined stereologically from electron micrographs of rat cerebellum, cerebral cortex, spinal cord, cauda equina, choroid plexus, anterior pituitary, median eminence of the hypothalamus, renal proximal tubules, skin, cardiac and skeletal muscle, lung, and renal glomerulus. The capillaries of the first four of these tissue types exhibit blood-brain barrier (BBB) characteristics of permeability and capillary ultrastructure and were found to have mitochondrial contents amounting to 8 to 11% of the endothelial cytoplasmic volume. Tissues from non-BBB regions were determined to have mitochondrial volumes of 2 to 5% of their respective cytoplasmic volumes, with a variety of capillary ultrastructures. The apparent excess metabloic work capability of the BBB suggested by this greater number of mitochondria may be related to maintenance of ion differentials between blood plasma and brain extracellular fluid, to extrachoroidal cerebrospinal fluid formation, or to maintaining the unique structural characteristics of central nervous system capillaries.

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

Measurement of brain uptake of radiolabeled substances using a tritiated water internal standard

THE ENDOTHELIAL cells of cerebral capillaries, like epithelial cells, possess tight junctions between the plasmalemma of adjacent cells (BRIGHTMAN et al., 1970). As a consequence, the plasma membranes of brain endothelial cells form a continuous membranous barrier between blood and brain interstitium. Similar to other cell membrane systems, the flux of circulating substances through the blood-brain barrier (BBB) occurs, via either (i) lipid mediation, or (ii) carrier mediation (OLDENDORF, 1976). During the past decade with the introduction of newer techniques such as tissue sampling, single-injection methodology (OLDENDORF, 1970), much quantitative information has been obtained regarding the carrier-mediated transport of metabolic substrates through the BBB. Plasma concentrations, transport K,, and V,,, estimates for substrates transported by one of four independent carrier systems (hexose, neutral amino acid, basic amino acid and monocarboxylic acid) have been recently tabulated (PARDRIDGE et ul., 1975; OLDENWRF, 1976). In addition, four other independent carrier systems have recently been identified; these systems mediate the transport into brain of nucleosides, purines (CORNFORD & OLDENDORF, 1975), acidic amino acids (OLDENDORF & SZABO, 1976), and choline (OLDENDORF & BRAUN, 1976). The 8 independent transport systems are listed in Table 1 relative to the V,,, estimate for each system. If it is assumed that each carrier moves through the membrane at a comparable rate, then the Vma,,,provides a measure of the redundancy of the transport system within the BBB. Generally, as barrier transport capacity (V,,,) decreases, the transport affinity increases, as represented by decreasing K , (Table 1). The non-saturable component of BBB transport of metabolic substrates varies over a 30-fold range (Table 1) and probably reflects transport via either very low affinity, high capacity systems, or via free diffusion.

Transport of metabolic substrates through the blood-brain barrier.

SummaryLipid/water partition coefficients of 19 radiolabeled drugs were correlated with uptake by brain during a single microcirculatory passage following carotid arterial injection. Uptake was measured relative to a simultaneously injected diffusible reference. When the lipid/ water partition coefficient was greater than about 0.03 a substantial fraction of the drug penetrated the blood-brain barrier and for most drugs above this range, uptake was essentially complete. These data suggest there is probably little reason to greatly exceed this degree of lipid solubility when designing drugs for blood-brain barrier penetration and central nervous system effects.Valuable discussions with Dr. Arthur K. Cho and Dr. Jared M. Diamond are acknowledged. Helpful suggestions from Mrs. Stella Z. Oldendorf were received, and technical assistance was provided by Mrs. Shigeyo Hyman and Mr. Leon Braun. Support is also acknowledged from the NIH-NINDS Project Grant No. NS 8711 and the Veterans Administration.

William H. Oldendorf

Papers

N-Acetyl-L-Aspartic acid: A literature review of a compound prominent in 1H-NMR spectroscopic studies of brain

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

Measurement of brain uptake of radiolabeled substances using a tritiated water internal standard

Transport of metabolic substrates through the blood-brain barrier.

Lipid solubility and drug penetration of the blood brain barrier.