Blood—Brain Barrier: Drug Delivery and Brain Pathology

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The blood—brain barrier acts effectively to protect the brain from circulating pathogens. Accordingly, blood-borne infections of the brain are rare. Antibodies are too large to cross the blood—brain barrier, and only certain antibiotics are able to pass. The blood—brain barrier may become leaky in select neurological diseases , such as amyotrophic lateral sclerosis , epilepsy , brain trauma and edema, and in systemic diseases , such as liver failure. However, this also allows bacteria and viruses to infiltrate the blood—brain barrier. Some of these harmful bacteria gain access by releasing cytotoxins like pneumolysin [18] which have a direct toxic effect on brain microvascular endothelium [19] and tight junctions.

Circumventricular organs CVOs are individual structures located adjacent to the fourth ventricle or third ventricle in the brain, and are characterized by dense capillary beds with permeable endothelial cells unlike those of the blood—brain barrier.

Blood–brain barrier - Wikipedia

Permeable capillaries of the sensory CVOs area postrema, subfornical organ, vascular organ of the lamina terminalis enable rapid detection of circulating signals in systemic blood, while those of the secretory CVOs median eminence, pineal gland, pituitary lobes facilitate transport of brain-derived signals into the circulating blood. The border zones between brain tissue "behind" the blood—brain barrier and zones "open" to blood signals in certain CVOs contain specialized hybrid capillaries that are leakier than typical brain capillaries, but not as permeable as CVO capillaries.

Such zones exist at the border of the area postrema— nucleus tractus solitarii NTS , [24] and median eminence— hypothalamic arcuate nucleus. In its neuroprotective role, the blood—brain barrier functions to hinder the delivery of many potentially important diagnostic and therapeutic agents to the brain. Therapeutic molecules and antibodies that might otherwise be effective in diagnosis and therapy do not cross the BBB in adequate amounts.

Mechanisms for drug targeting in the brain involve going either "through" or "behind" the BBB. Modalities for drug delivery to the brain in unit doses through the BBB entail its disruption by osmotic means, or biochemically by the use of vasoactive substances such as bradykinin , [26] or even by localized exposure to high-intensity focused ultrasound HIFU.

Drug Transport Across the Blood Brain Barrier - Module 3, Session 6

However, vectors targeting BBB transporters, such as the transferrin receptor , have been found to remain entrapped in brain endothelial cells of capillaries, instead of being ferried across the BBB into the targeted area. Mannitol can be used in bypassing the BBB. Nanotechnology may also help in the transfer of drugs across the BBB. More research is needed to determine which strategies will be most effective and how they can be improved for patients with brain tumors. The potential for using BBB opening to target specific agents to brain tumors has just begun to be explored.

Delivering drugs across the blood—brain barrier is one of the most promising applications of nanotechnology in clinical neuroscience. Nanoparticles could potentially carry out multiple tasks in a predefined sequence, which is very important in the delivery of drugs across the blood—brain barrier.

Transport at the BBB

A significant amount of research in this area has been spent exploring methods of nanoparticle-mediated delivery of antineoplastic drugs to tumors in the central nervous system. For example, radiolabeled polyethylene glycol coated hexadecylcyanoacrylate nanospheres targeted and accumulated in a rat gliosarcoma.

Another, more promising approach, is the coating of polyalkylcyanoacrylate or poly-lactic-co-glycolic acid PLGA nanoparticles with polysorbate 80 or poloxamer Due to this coating the particles adsorb apolipoproteins E or A-1 from the blood and thus interact with the signalling protein LRP1 or with the scavenger receptor followed by transcytosis across the blood—brain barrier into the brain.

Recently, a novel class of multifunctional nanoparticles known as magneto-electric nanoparticles MENs has been discovered for externally controlled targeted delivery and release of drug s across BBB as well as wireless stimulation of cells deep in the brain. This approach depends more on the field control and less on the cellular microenvironment. In vitro and in vivo on mice experiments to prove the feasibility of using MENs to release a drug across BBB on demand and wirelessly stimulate the brain have been conducted by the research group of Prof.

Vascular endothelial cells and associated pericytes are often abnormal in tumors and the blood—brain barrier may not always be intact in brain tumors. Also, the basement membrane is sometimes incomplete. Other factors, such as astrocytes , may contribute to the resistance of brain tumors to therapy. Peptides are able to cross the blood—brain barrier BBB through various mechanisms, opening new diagnostic and therapeutic avenues. Brainpeps currently contains BBB transport information with positive as well as negative results. The database is a useful tool to prioritize peptide choices for evaluating different BBB responses or studying quantitative structure-property BBB behaviour relationships of peptides.

Because a multitude of methods have been used to assess the BBB behaviour of compounds, these methods and their responses are classified. Moreover, the relationships between the different BBB transport methods have been clarified and visualized.

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Casomorphin is a heptapeptide and could be able to pass the BBB. Meningitis is an inflammation of the membranes that surround the brain and spinal cord these membranes are known as meninges. Meningitis is most commonly caused by infections with various pathogens , examples of which are Streptococcus pneumoniae and Haemophilus influenzae. When the meninges are inflamed, the blood—brain barrier may be disrupted. 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.

A brain or cerebral abscess , like other abscesses , is caused by inflammation and collection of lymphatic cells and infected material originating from a local or remote infection. 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. Several clinical and experimental data have implicated the failure of blood—brain barrier function in triggering chronic or acute seizures.


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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. 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.

Current Strategies for Brain Drug Delivery

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. 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.


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Hayes Barton Press. Retrieved — via Google Books. Various transporter systems in the blood-brain barrier play an important role in the exchange of nutrients and can be utilized for drug delivery. Impaired blood-brain barrier in malignancies, trauma, and infections can be used to facilitate the passage of therapeutic agents.

Methods for the assessment and modulation of the blood-brain barrier are also described. For over a century it has been recognized that the entry of certain substances into the brain is restricted. The old concept of the blood-brain barrier as a passive, impermeable barrier that segregates blood and brain interstitial fluid is giving way to the idea that the blood-brain barrier is a dynamic conduit for transport between blood and brain of those nutrients, peptides, proteins, or immune cells that have access to certain transport systems localized within the blood-brain barrier membranes.

Introduction

The historical evolution of knowledge concerning the blood-brain barrier is shown in Table 1. Aniline dyes injected intravenously were rapidly taken up by all the organs except the brain Ehrlich Coining of the term blood-brain barrier to describe the phenomenon Lewandowski Expansion of the original blood-brain barrier concept by the demonstration that intrathecal administration of trypan blue results in a generalized staining of the brain tissue, whereas intravenous application does not.

Hypothesis put forward that the vehicle for substance transport was the CSF , which allegedly gained access to the brain via the choroid plexuses Goldman Intracerebral distribution of various substances was observed. Showed defects in the blood-brain barrier in brain diseases and demonstrated transient opening or disruption of the blood-brain barrier after intracarotid arterial administration of hypertonic solutions Broman Electron microscopy showed lack of extracellular fluid compartment in the gray matter, and this was given as an explanation of the failure of tracers to enter the brain.

This was later shown to be an artifact in s.

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