Thursday, July 26, 2012

Different food experiences among population

Why we differ in taste perception


Humans use several kinds of information to decide what to eat, and the combination of experience and sensory evaluation helps us to choose whether to consume a particular food. If the sight, smell, and taste of the food are acceptable, and we see others enjoying it, we finish chewing and swallow it. Several senses combine to create the idea of food flavor in the brain. For example, a raw chili pepper has a crisp texture, an odor, a bitter and sour taste, and a chemesthetic ‘burn.’ Each of these sensory modalities is associated with a particular group of receptors: at least three subtypes of somatosensory receptors (touch, pain, and temperature), about 400 human odor receptors, which respond either singly or in combination at least five types of taste receptors [bitter, sour, sweet, salty, and umami (the savory experience associated with monosodium glutamate)], and several families of other receptors tuned to the irritating chemicals in foods, especially herbs and spices (for example, Eugenol found in cloves or Allicin found in garlic). The information from all these receptors are transmitted to the brain, where it is processed and integrated. Experience is a potent modifier of chemosensory perception, and persistent exposure to an odorant is enough to change sensitivity.

The combined senses of taste, smell and the common chemical sense merge to form what we call ‘flavor.’ People show marked differences in their ability to detect many flavors. Most of the genes identified to date encode receptors responsible for detecting tastes or odorants. Although the repertoire of receptors involved in taste perception is relatively small, with 25 bitter and only a few sweet and umami receptors, the number of odorant receptors is much larger, with about 400 functional receptors and another 600 potential odorant receptors predicted to be non-functional. Despite this, to date, there are only a few cases of odorant receptor variants that encode differences in the perception of odors: receptors for androstenone (musky), isovaleric acid (cheesy), cis-3-hexen-1-ol (grassy), and the urinary metabolites of asparagus. A genome-wide study also implicates genes other than olfactory receptors for some individual differences in perception. Although there are only a small number of examples reported to date, there may be many more genetic variants in odor and taste genes yet to be discovered.



Each person lives in a unique flavor world, and part of this difference lies in our genetic composition, especially within our sensory receptors. This idea is illustrated by bitter perception and bitter receptors. The bitter receptor family, TAS2, has approximately 25 receptors, found at three locations in the human genome. We say ‘approximately’ because bitter receptors have copy number variants, and it is currently unclear at what point a recently duplicated gene should be assigned a distinct name. This conundrum is more than a mere matter of record-keeping; the bitter receptor gene copy number is a source of biological variation and may affect perception, although this prospect has not yet been demonstrated empirically. 



The first demonstration that genetic variants contribute to person-to-person differences in human taste perception was for the bitter receptor TAS2R38. It has been known since 1931 that some people are insensitive to the bitter compound phenylthiocarbamide (PTC), a chemical that was synthesized by Arthur Fox for making dyes. While he was working in his laboratory, Fox accidentally tasted the compound and found it bland, yet when his benchmate also accidentally tasted the compound, he found it very bitter. This observation contributed to the formation of a hypothesis, now widely accepted, that there is a family of bitter receptors, at least one of which is sensitive to this compound, but that is inactive in some people. In 2003, this hypothesis was tested using genetic linkage analysis. Relatives such as parents and children were assessed for their ability to taste PTC and for their pattern of DNA sharing. The genomic region most often shared by relatives with similar tasting ability was near the TAS2R38 gene, but this evidence in itself was insufficient to conclude that the TAS2R38 gene was responsible for this sensory trait. Genes encoding bitter taste receptors are physically clustered on chromosomes, and nearby DNA regions tend to be inherited together, so it was not clear whether TAS2R38 or a neighboring receptor was the responsible gene. This issue was resolved later, when individual bitter receptors were introduced into cells without taste receptors. Only those cells that contained the TAS2R38 gene responded to PTC. Moreover, cells containing naturally occurring genetic variants of the TAS2R38 gene from people who could not taste PTC were also unresponsive to this bitter compound. Together, these data showed that TAS2R38 and its variants explained the inability of some people to taste PTC at concentrations at which it is readily detectable to others. The inability to taste PTC as bitter can be considered a categorical trait (either people can taste it or they cannot), and can also be considered a quantitative trait, that is, as a continuum, but with most people falling at either end.



Although the genetics of taste perception has been dominated by the study of PTC and its effects, evidence is gradually accumulating that the ability (or inability) to perceive other bitter tastes is heritable. For example, identical twins, who have identical genetics, are more similar in their perception of bitter compounds (other than PTC) than are fraternal twins, who are no more similar genetically than siblings. A variant in a cluster of bitter receptors on chromosome 12 is associated with quinine perception, and the bitterness of some high-intensity sweeteners is associated with alleles within a cluster of bitter receptors on chromosome 12. These observations suggest that individual differences in bitter perception may be common, and related to genotype.


Bitterness is a part of human life in two ways, in food and in medicine. In general, humans tend to avoid bitter foods; in a study by Mattes, nearly half of people surveyed ate no bitter foods at all. When these subjects were asked to consume a bitter solution, they diluted it with water until the bitterness could no longer be detected. Other common methods to reduce bitterness include cooking, or the addition of salt or flavors, but bitterness is not an inevitable part of life for everyone. To illustrate this point, when we asked 8 people to rate 23 vegetables for bitterness intensity, we found that some people were insensitive to even the most bitter vegetables. Of course,    people who are sensitive to the bitterness of a particular vegetable or other food can avoid eating it.


Beyond the receptor
Most of the known gene variations relating to perceptual differences in taste and smell are specific to a single receptor. It may be that receptor variation affects only the perception of its ligand or it may have broader effects due to brain rewiring (in response to missing input) or to the clustering of receptor variants (LD). Thus, more characterization of human perceptual differences in conjunction with genotype studies is needed. The reduced ability to detect a single compound (such as PTC) might be associated with a reduced ability to detect structurally unrelated bitter compounds or even other taste qualities. 



Food-tasting business (Getting paid to eat)

The only thing that matters here is the food. Behind a door marked "Sensory Staff Only," a dozen or so professional tasters spend their days testing ingredients that end up in thousands of products around the world. They sniff, taste, feel and spit. All day long. 
Painstakingly trained, these tasters can describe the difference between a "vine-y green" and a "fresh-cut grassy green," a roasted peanut note from an over-roasted one. They are 'sensory specialists" — and an increasingly mechanized, sophisticated and complex food industry rests on their taste buds. "You get paid to eat stuff," said Chaquita Johnson-Moore, a chef-turned-sensory panelist, during a recent break from a session tasting a nutritional drink. "People can't believe there are people who do this."

Ref:





One-size-fits-all drug targets harmful brain inflammation in many diseases

A "one-size-fits-all" new class of drugs that targets a particular type of brain inflammation is showing early promise for the treatment of Alzheimer's disease, Parkinson's disease, multiple sclerosis and traumatic brain injury. 
A pre-clinical study due to be published this week in the Journal of Neuroscience shows one of the drugs stopped mice bred to have Alzheimer's from developing the full-blown disease. Northwestern has recently been issued patents to cover this new drug class and has licensed the commercial development to a biotech company that has recently completed the first human Phase 1 clinical trial for the drug.   
The drugs in this class target a particular type of brain inflammation, which is a common denominator in these neurological diseases and in traumatic brain injury and stroke. This brain inflammation, also called neuroinflammation, is increasingly believed to play a major role in the progressive damage characteristic of these chronic diseases and brain injuries. By addressing brain inflammation, the new class of drugs -- represented by MW151 and MW189 -- offers an entirely different therapeutic approach to Alzheimer’s than current ones being tested to prevent the development of beta amyloid plaques in the brain. The plaques are an indicator of the disease but not a proven cause.
MW151 and MW189 work by preventing the damaging overproduction of brain proteins called proinflammatory cytokines. Scientists now believe overproduction of these proteins contributes to the development of many degenerative neurological diseases as well as to the neurological damage caused by traumatic brain injury and stroke.  

Ref:

Humor

Tuesday, July 24, 2012

Some Antioxidants that can cross or strength the BBB


1. Î±-lipoic acid:

Possible beneficial effects

Lipoic acid has been the subject of numerous research studies and clinical trials:
  • Prevent organ dysfunction
  • Reduce endothelial dysfunction and improve albuminuria
  • Treat or prevent cardiovascular disease
  • Accelerate chronic wound healing
  • Reduce levels of ADMA in diabetic end-stage renal disease patients on hemodialysis
  • Management of burning mouth syndrome
  • Reduce iron overload
  • Treat metabolic syndrome
  • Improve or prevent age-related cognitive dysfunction
  • Prevent or slow the progression of Alzheimer’s Disease
  • Prevent erectile dysfunction (animal models but anecdotally applies to humans as well)
  • Prevent migraines
  • Treat multiple sclerosis
  • Treat chronic diseases associated with oxidative stress
  • Reduce inflammation
  • Inhibit advanced glycation end products (AGE) 
  • Treat peripheral artery disease.

2. Vitamin C:
Ascorbic acid is well known for its antioxidant activity, acting as a reducing agent to reverse oxidation in liquids. When there are more free radical (reactive oxygen species, ROS) in the human body than antioxidant, the condition is called oxidative stress, and has an impact on cardiovascular disease, hypertension, chronic inflammatory diseases,diabetes as well as on critically ill patients and individuals with severe burns. Individuals experiencing oxidative stress have ascorbate blood levels lower than 45 µmol/L, compared to healthy individual who range between 61.4-80 µmol/L.



3.Astaxanthin:






The primary use for humans is as a food supplement. Research shows that, due to astaxanthin's potent antioxidant activity, it may be beneficial in cardiovascular, immune, inflammatory and neurodegenerative diseases. Some research supports the assumption that it may protect body tissues from oxidative damage.

4. Ginkgo Biloba Leaf Extract:

Out of the many conflicting research results, Ginkgo extract may have three effects on the human body: improvement in blood flow (including microcirculation in small capillaries) to most tissues and organs; protection against oxidative cell damage from free radicals; and blockage of many of the effects of platelet-activating factor (platelet aggregation, blood clotting) that have been related to the development of a number of cardiovascular, renal, respiratory and CNS disorders. Ginkgolides, especially ginkgolide B, are potent antagonists against  platelet-activating factor; and thus may be useful in protection and prevention of thrombus, endotoxic shock, and from myocardial ischeamia. Ginkgo can be used for intermittent claudication. 
The WHO reports that the medicinal uses of Ginkgo biloba that are supported by clinical data include treatment of the effects mild to moderate cerebrovascular insufficiency as well as the effects of  peripheral arterial occlusive diseases. Cerebrovascular insufficiency, i.e., insufficient blood flow to the brain, may manifest itself as such memory deficit, disturbed concentration or headaches. Peripheral arterial occlusive diseases are those in which the blood flow to the smaller arteries are restricted and may include claudication, i.e., painful walking, and Raynaud's disease, a condition in which the extremities such as fingers, toes, nose or ears, feel numb and cold. Preliminary studies suggested that Ginkgo might be of benefit in multiple sclerosis, but clinical trials failed to show any effect on cognitive function in MS patients.


5.Grape seed extract:
Grape seed extracts are industrial derivatives from whole grape seeds that have a great concentration of vitamin E, flavonoids, linoleic acid and phenolic OPCs (oligomeric proanthocyanidins, Proanthocyanidins). The typical commercial opportunity of extracting grape seed constituents has been for chemicals known as polypehols having antioxidant  activity in vitro.
Grape seed extract is sometimes suggested for the following, although evidence is slight:
  • Alzheimer's disease
  • Diabetes (improving blood sugar control)
  • Improving night vision
  • Protecting collagen and elastin in skin (anti-aging)
  • Treating hemorrhoids
  • Protecting against oxidative rancidity and bacterial pathogens
Chronic venous insufficiency
In chronic venous insufficiency, blood pools in the legs, causing pain, swelling, fatigue, and visible veins. A number of high quality studies have shown that OPCs from grape seed can reduce symptoms.

High blood pressure
Theoretically, grape seed extract might help treat hypertension or high blood pressure. Antioxidants, like the ones found in grape seed, help protect blood vessels from damage. Damaged blood vessels can lead to higher blood pressure. In several animal studies, grape seed extract substantially reduced blood pressure. But human studies are needed to see whether grape seed extract helps people with high blood pressure.

Cancer
Studies have found that grape seed extracts may prevent the growth of breast, stomach, colon, prostate, and lung cancer cells in test tubes. However, there is no clear evidence yet whether it works in humans. Antioxidants, such as those found in grape seed extract, are thought to reduce the risk of developing cancer. Grape seed extract may also help prevent damage to human liver cells caused by chemotherapy medications. Talk to your doctor or pharmacist before combining antioxidants with any chemotherapy drugs to make sure they interact safely together and that they don't interfere with effects of the chemotherapy medications.


Structures of the major flavan-3-ols identified in grape seed extract









     
      Proanthocyanidin B-1 Dimer                                         Proanthocyanidin C-1 Trimmer       

6.Pine bark extract:
Pine bark extract is made from the bark of the maritime pine tree (Pinus pinaster), which contains naturally occurring chemicals called proanthocyanidins. The maritime pine is native to the western Mediterranean, with a range extending over Portugal, Spain, France, Italy, and Morocco. Pine bark extract is commonly sold under the brand name Pycnogenol. Pycnogenol is also the name of a group of compounds that contain proanthocyanidins taken from a number of natural sources, such as grape seeds and other plants. In addition to the Pycnogenol brand, there are several other pine bark extract supplements available, which may use different types of pine bark and have different formulations. Pine bark extract is used for its antioxidant properties.
As a member of the flavonoid family, OPCs have established free radical scavenging and antioxidant activity. Pine bark extracts have been used in France since 1950 to prevent cardiovascular disease primarily on the basis of its antioxidant functionality. More recently, pine bark extracts have garnered growing research attention because of accumulating evidence regarding its diverse clinical pharmacology. Recent studies suggest that in addition to its well-known antioxidant properties, pine bark extracts may also have lowering effects on blood pressure. The blood pressure lowering effect of pine bark extracts have physiological plausibility because of its ability to antagonize the vasoconstriction caused by epinephrine and norepinephrine through increased activity of endothelial nitric oxide synthase. Pine bark extracts have also been found to reduce blood concentrations of endothelin – the most potent endothelial-derived vasoconstrictor.
Furthermore, published preliminary data of pine bark extracts suggest a myriad of additional cardiovascular benefits, including improved glycemic control, reduced body weight, improved lipid profile, improved peripheral circulation, and blunted platelet aggregation. While these studies provide promising information, relative few were as large or as rigorous as optimal for such a widely used herbal therapy. Again, please note that the published studies to date used a variety of pine bark extracts other than the specific formulation we are researching in the Pine Bark Research Study
           

        Ref:
  1. http://en.wikipedia.org/wiki/Lipoic_acid
  2. http://jeffreydach.com/2007/05/06/jeffreydachdrdachhoffer.aspx
  3. http://en.wikipedia.org/wiki/Vitamin_C
  4. http://asta-x.com/advantage.html
  5. http://supplementscience.org/antioxidants.html
  6. http://en.wikipedia.org/wiki/Astaxanthin
  7. http://en.wikipedia.org/wiki/Ginkgo_biloba
  8. http://www.umm.edu/altmed/articles/grape-seed-000254.htm
  9. http://www.webmd.boots.com/vitamins-and-minerals/grape-seed-extract
  10. http://en.wikipedia.org/wiki/Grape_seed_extract
  11. http://www.activin.com/AVSafetystudy.htm
  12. http://www.cancer.org/Treatment/TreatmentsandSideEffects/ComplementaryandAlternativeMedicine/HerbsVitaminsandMinerals/pine-bark-extract
  13. http://ppop.stanford.edu/pinebark.html
                              

Blood Brain Barrier

Blood-brain barrier (BBB) is the mechanism that controls the passage of substances from the blood into the cerebrospinal fluid and, thus, into the brain and spinal cord. The BBB lets essential metabolites, such as Oxygen and glucose, pass from the blood to the brain and central nervous system (CNS) but blocks most molecules that are more massive than about 500 Daltons. This is a low mass in biomolecular terms and means that everything from hormones and neurotransmitters to viruses and bacteria are refused access to the brain by the BBB. It also means that many drugs, which would otherwise be capable of treating CNS disorders, are denied access to the very regions where they would be affective.
  • Key functions of the BBB are:
  1. Protecting the brain from "foreign substances" in the blood that could injure the brain.
  2. Shielding the brain from hormones and neurotransmitters in the rest of the body.
  3. Maintaining a constant environment (homoestasis) for the brain.

a | The blood–brain barrier (BBB) is formed by endothelial cells at the level of the cerebral capillaries. These endothelial cells interact with perivascular elements such as basal lamina and closely associated astrocytic end-feet processes, perivascular neurons (represented by an interneuron here) and pericytes to form a functional BBB. b | Cerebral endothelial cells are unique in that they form complex tight junctions (TJ) produced by the interaction of several transmembrane proteins that effectively seal the paracellular pathway. These complex molecular junctions make the brain practically inaccessible for polar molecules, unless they are transferred by transport pathways of the BBB that regulate the microenvironment of the brain. There are also adherens junctions (AJ), which stabilize cell–cell interactions in the junctional zone. In addition, the presence of intracellular and extracellular enzymes such as monoamine oxidase (MAO), Î³-glutamyl transpeptidase (γ-GT), alkaline phosphatase, peptidases, nucleotidases and several cytochrome P450 enzymes endow this dynamic interface with metabolic activity. Large molecules such as antibodies, lipoproteins, proteins and peptides can also be transferred to the central compartment by receptor-mediated transcytosis or non-specific adsorptive-mediated transcytosis. The receptors for insulin, low-density lipoprotein (LDL), iron transferrin (Tf) and leptin are all involved in transcytosis. P-gp, P-glycoprotein; MRP, multidrug resistance-associated protein family.

Discovery of the BBB:

The special properties of the BBB were first observed in the late 19th century by the German bacteriologist Paul Ehrlich. He found that when he injected coloured dyes into the blood stream they leaked out of capillaries in most regions of the body to stain the surrounding tissues; the brain, however, remained unstained. Ehrlich wrongly surmised that the brain had a low affinity for the dyes. It was his student, Edwin Goldmann, who did the other half of the experiment and realized the truth of what was going on. Goldmann injected a dye into the cerebrospinal fluid that surrounds the brain and observed that it stained the brain, but nothing else. Goldmann correctly concluded that the dyes was unable to cross the specialized walls of brain capillaries. 

Anatomy of the BBB:

The key aspect of the BBB is the presence of the thin, flat cells known as Endothelial cells which form the walls of capillaries. In most the body, the Endothelial cells in the capillaries overlap at what is called junctions. These junctions are leaky enough to let a lot of different materials move through the wall of the blood vessel into the tissue and back again. These materials include normally beneficial stuff such as hormones and nutrient molecules as well as potentially harmful agents like toxins, viruses, and bacteria. Substances can get into the surrounding tissues either by leaking out of the junctions or passing straight through the Endothelial cells.
However, in the brain there is a different arrangement where the Endothelial cells joins up. The Endothelial cells meet each other at what is called TIGHT JUNCTIONS. These junctions block the passage of most things except for small molecules and are a crucial components of the BBB. 
In order to traverse the walls of the brain capillaries, substances must move through the Endothelial cell membranes. Because the main constitute of cell membranes are lipids, it would seem that a molecule could only can get into the brain if it was lipid-soluble. However, many ions and small molecules that are not readily soluble is lipids do move quite readily from brain capillaries into brain tissue. A molecule like glucose, the primary source of metabolic energy for neurons and glial cells, is an obvious example. The explanation for this is the presence of specific transporters for glucose and other critical molecules and ions.
In addition to tight junctions, the "end feet" of Astrocytes (Astraglia)[ the terminal regions of astrocytic processes] surround the outside of capillary Endothelial cells. 






Barriers are present at three main sites: the brain endothelium forming the blood–brain barrier (BBB) (1), the arachnoid epithelium (2) forming the middle layer of the meninges, and the choroid plexus epithelium (3), which secretes cerebrospinal fluid (CSF). At each site, the physical barrier is caused by tight junctions that reduce the permeability of the paracellular (intercellular cleft) pathway. In circumventricular organs (CVOs, not shown), which contain neurons specialized for neurosecretion and/or chemosensitivity, the endothelium is leaky. This allows tissue–blood exchange, but as these sites are separated from the rest of the brain by an external glial barrier, and from CSF by a barrier at the ependyma, CVOs do not form a leak across the BBB. Modified, with permission, from Ref.163 © (1990) Kluwer Academic.

Cellular constituents of the blood–brain barrier



























The barrier is formed by capillary endothelial cells, surrounded by basal lamina and astrocytic perivascular endfeet. Astrocytes provide the cellular link to the neurons. The figure also shows pericytes and microglial cells. a | Brain endothelial cell features observed in cell culture. The cells express a number of transporters and receptors, some of which are shown. EAAT1–3, excitatory amino acid transporters 1–3; GLUT1, glucose transporter 1; LAT1, L-system for large neutral amino acids; Pgp, P-glycoprotein. b | Examples of bidirectional astroglial–endothelial induction necessary to establish and maintain the BBB. Some endothelial cell characteristics (receptors and transporters) are shown. 5-HT, 5-hydroxytryptamine (serotonin); ANG1, angiopoetin 1; bFGF, basic fibroblast growth factor; ET1, endothelin 1; GDNF, glial cell line-derived neurotrophic factor; LIF, leukaemia inhibitory factor; P2Y2, purinergic receptor; TGFbeta, transforming growth factor-beta; TIE2, endothelium-specific receptor tyrosine kinase 2. Data obtained from astroglial–endothelial co-cultures and the use of conditioned medium.


Molecular composition of endothelial tight junctions
























Simplified and incomplete scheme showing the molecular composition of endothelial tight junctions. Occludin and the claudins — proteins with four transmembrane domains and two extracellular loops — are the most important membranous components. The junctional adhesion molecules (JAMs) and the endothelial selective adhesion molecule (ESAM) are members of the immunoglobulin superfamily. Within the cytoplasm are many first-order adaptor proteins, including zonula occludens 1, 2 and 3 (ZO-1–3) and Ca2+-dependent serine protein kinase (CASK), that bind to the intramembrane proteins. Among the second-order adaptor molecules, cingulin is important, and junction-associated coiled-coil protein (JACOP) may also be present. Signalling and regulatory proteins include multi-PDZ-protein 1 (MUPP1), the partitioning defective proteins 3 and 6 (PAR3/6), MAGI-1–3 (membrane-associated guanylate kinase with inverted orientation of protein–protein interaction domains), ZO-1-associated nucleic acid-binding protein (ZONAB), afadin (AF6), and regulator of G-protein signalling 5 (RGS5). All of these adaptor and regulatory/signalling proteins control the interaction of the membranous components with the actin/vinculin-based cytoskeleton. In epithelial cells, tight and adherens junctions are strictly separated from each other, but in endothelial cells these junctions are intermingled. The most important molecule of endothelial adherens junctions is vascular endothelial cadherin (VE-cadherin). In addition, the platelet–endothelial cell adhesion molecule (PECAM) mediates homophilic adhesion. The chief linker molecules between adherens junctions and the cytoskeleton are the catenins, with desmoplakin and p120 catenin (p120ctn) also involved. Itch, E3 ubiquitin protein ligase. Modified, with permission, from Ref. 20 © (2005) Wiley-VCH.


General Properties of the BBB

  1. Large molecules do not pass through the BBB easily.
  2. Low lipid (fat) soluble molecules do not penetrate into the brain. However, lipid soluble molecules, such as barbituate drugs, rapidly cross through into the brain.
  3. Molecules that have a high electrical charge are slowed.
  What can weaken BBB ?
  1. Hypertension (high blood pressure): high blood pressure opens the BBB.
  2. Development: the BBB is not fully formed at birth.
  3. Hyperosmolitity: a high concentration of a substance in the blood can open the BBB.
  4. Microwaves: exposure to microwaves can open the BBB.
  5. Radiation: exposure to radiation can open the BBB.
  6. Infection: exposure to infectious agents can open the BBB.
  7. Trauma, Ischemia, Inflammation, Pressure: injury to the brain can open the BBB.

There are several areas of the brain where the BBB is weak. This allows substances to cross into the brain somewhat freely. These areas are known as "circumventricular organs". Through the circumventricular organs the brain is able to monitor the makeup of the blood. The circumventricular organs include:
* Pineal body: Secretes melatonin and neuroactive peptides. Associated with circadian rhythms.
* Neurohypophysis (posterior pituitary): Releases neurohormones like oxytocin and vasopressin into the blood.
* Area postrema: "Vomiting center": when a toxic substance enters the bloodstream it will get to the area postrema and may cause the animal to throw up. In this way, the animal protects itself by eliminating the toxic substance from its stomach before more harm can be done.
* Subfornical organ: Important for the regulation of body fluids.
* Vascular organ of the lamina terminalis: A chemosensory area that detects peptides and other molecules.
* Median eminence: Regulates anterior pituitary through release of neurohormones.

Pathophysiology:
The blood–brain barrier acts very effectively to protect the brain from many common bacterial infections. Thus, infections of the brain are very rare. However, since antibodies and antibiotics are too large to cross the blood–brain barrier, infections of the brain that do occur are often very serious and difficult to treat. However, the blood–brain barrier becomes more permeable during inflammation. This allows some antibiotics and phagocytes to move across the BBB; although, this can allow bacteria/viruses to also move across.
Astroglial–endothelial signalling under pathological conditions


























Examples of astroglial–endothelial signalling in infection or inflammation, stroke or trauma, leading to opening of the blood–brain barrier (BBB) and disturbance of brain function. bradykinin, produced during inflammation in stroke or brain trauma, acts on endothelial and astroglial bradykinin B2 receptors, leading to an increase in the concentration of intracellular Ca2+. In astrocytes, this can trigger the production of interleukin-6 (IL-6) through activation of nuclear factor-kappaB (NF-kappaB) (1). Bradykinin, substance P, 5-hydroxytryptamine (5-HT, serotonin) and histamine acting on astrocytes can lead to the formation of ATP and prostaglandins (PGs), with effects on vascular tone and endothelial permeability (2) by mechanisms that are known to involve endothelium. Lipopolysaccharide (LPS), formed in infections, leads to the release from microglia of tumour necrosis factor-alpha (TNFalpha), IL-1beta and reactive oxygen species (including O2filled circle-), all of which have the ability to open the BBB (3). Astrocytes downregulate tissue plasminogen activator (tPA) production via transforming growth factor-beta (TGFbeta), but there is still sufficient tPA to open the BBB, leading to an influx of tPA from the blood (4). Following disruption of the BBB involving a decrease in agrin expression, K+ and glutamate (Glu) from the blood can reach the brain extracellular space. Aquaporin 4 (AQP4) is upregulated on the astroglial endfeet, leading to astroglial swelling (5). ET1, endothelin 1.

Meningitis

Meningitis is an inflammation of the membranes that surround the brain and spinal cord. Meningitis is most commonly caused by infections with various pathogens, examples of which are Streptococcus pneumoniae and Haemophilus influenza. When the meninges are inflamed, the blood–brain barrier may be disrupted. This disruption may increase the penetration of various substances (including either toxins or antibiotics) into the brain. Antibiotics used to treat meningitis may aggravate the inflammatory response of the central nervous system by releasing neurotoxins from the cell walls of bacteria-like lipopolysaccharide (LPS). Depending on the causative pathogen, whether it is bacterial, fungal, or protozoan, treatment with 3rd generation or 4th generation cephalosporins or amphotericin B is usually prescribed.

De Vivo disease

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. Genetic defects in glucose transporter type 1 (GLUT1) appears to be the primary cause of De Vivo disease.

Pathways across the BBB:


A schematic diagram of the endothelial cells that form the blood–brain barrier (BBB) and their associations with the perivascular endfeet of astrocytes. The main routes for molecular traffic across the BBB are shown. a | Normally, the tight junctions severely restrict penetration of water-soluble compounds, including polar drugs. b | However, the large surface area of the lipid membranes of the endothelium offers an effective diffusive route for lipid-soluble agents. c | The endothelium contains transport proteins (carriers) for glucose, amino acids, purine bases, nucleosides, choline and other substances. Some transporters are energy-dependent (for example, P-glycoprotein) and act as efflux transporters. AZT, azidothymidine. d | Certain proteins, such as insulin and transferrin, are taken up by specific receptor-mediated endocytosis and transcytosis. e | Native plasma proteins such as albumin are poorly transported, but cationization can increase their uptake by adsorptive-mediated endocytosis and transcytosis. Drug delivery across the brain endothelium depends on making use of pathwaysbe; most CNS drugs enter via route b. Modified, with permission, from Ref. 8 © (1996) Elsevier Science.