CHEMICAL COMPOSITION OF BBB AND BREACH OF BBB LEARNING OBJECTIVES At the end of lecture students should be able to know,

Composition of BBB(Blood Brain Barrier).

BBB break.

Diseases effecting BBB.

Drugs targeting brain.

Drug delivery across BBB.

COMPOSITION OF BLOOD BRAIN BARRIER

The blood–brain barrier (BBB) is a separation of circulating blood from the brain extracellular fluid (BECF) in the central nervous system (CNS).

It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. BBB

The blood-brain barrier (BBB) is a membrane that controls the passage of substances from the blood into the central nervous system.

It is a physical barrier between the local blood vessels and most parts of the central nervous system itself, and stops many substances from travelling across it.

The BBB is permeable to alcohol, and some heavy metals can cross the blood-brain barrier as well.

In the brain, endothelial cells are packed much tighter together, due to the existence of zonula occludens (tight junctions) between them, blocking the passage of most molecules.

The blood-brain barrier blocks all molecules except those that cross cell membranes by means of lipid solubility (such as oxygen, carbon dioxide, ethanol, and steroid hormones) and those that are allowed in by specific transport systems (such as sugars and some amino acids).

Substances with a molecular weight higher than 500 daltons generally cannot cross

COMPOSITION OF BLOOD BRAIN BARRIER

Endothelial cells restrict the diffusion of microscopic objects (e.g., bacteria) and large or hydrophilic molecules into the cerebrospinal fluid (CSF), while allowing the diffusion of small hydrophobic molecules (O2, CO2, hormones).

Cells of the barrier actively transport metabolic products such as glucose across the barrier with specific proteins.

This "barrier" results from the selectivity of the tight junctions between endothelial cells in CNS vessels that restricts the passage of solutes.

At the interface between blood and the brain, endothelial cells are stitched together by these tight junctions, which are composed of smaller subunits, frequently biochemical dimers, that are transmembrane proteins such as occludin, claudins, junctional adhesion molecule (JAM), or ESAM.

Each of these transmembrane proteins is anchored into the endothelial cells by another protein complex that includes zo-1 and associated proteins.

The blood–brain barrier is composed of high-density cells restricting passage of substances from the bloodstream much more than endothelial cells in capillaries elsewhere in the body.

Many drugs are unable to pass the barrier, since 98 percent of them are heavier than 500 daltons.

hormones generally do not penetrate the brain from the blood, except at the 'circumventricular organs

The blood-brain barrier is an effective way to protect the brain from common infections.

as antibodies are too large to cross the blood-brain barrier, infections of the brain when they do occur can be very serious and difficult to treat.

BBB BREAK

The BBB can be broken down by:

Hypertension (high blood pressure): high blood pressure opens the BBB

Development: the BBB is not fully formed at birth.

Hyperosmolitity: a high concentration of a substance in the blood can open the BBB.

Microwaves: exposure to microwaves can open the BBB.

Radiation: exposure to radiation can open the BBB.

Infection: exposure to infectious agents can open the BBB.

Trauma, Ischemia, Inflammation, Pressure: injury to the brain can open the BBB.

DISEASES AFFECTING THE BLOOD-BRAIN BARRIER MENINGITIS

inflamed meninges disrupt blood-brain barrier

This increase penetration of various substances (including antibiotics) into the brain

third generation cephalosporin or fourth generation cephalosporin is preferred.

MULTIPLE SCLEROSIS (MS)

Normally, nervous system is inaccessible for WBC due to BBB.

using MRI in an MS "attack," BBB has broken down in brain or spinal cord, T lymphocytes crossing over and destroying the myelin.

MS is a disease of the blood-brain barrier.

The yellow ingredient turmeric, found in curry, has been shown to strengthen the blood-brain barrier to resist attacks.

LATE-STAGE NEUROLOGICAL TRYPANOSOMIASIS (SLEEPING SICKNESS)

Late-stage neurological trypanosomiasis, or sleeping sickness, is a condition in which trypanosoma protozoa have crossed the blood-brain barrier.

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)

Blood-borne immune cells such as lymphocytes, monocytes and neutrophils cannot penetrate this barrier.

A thin basement membrane, provides mechanical support and a barrier function.

BBB prevents infiltration of pathogens and restricting antibody-mediated immune responses in the central nervous system, as well as for preventing disorganisation of the fragile neural network.

On occasions, pathogens (e.g. viruses, fungi and prions) and autoreactive T cells breach the endothelial barrier and enter the brain.

A local innate immune response is mounted and pathogens are destroyed and cell debris is removed.

This, together with a generally muted immune environment within the brain itself, protects the fragile neuronal network from the risk of damage that could ensue from a full-blown immune response.

DRUGS TARGETING THE BRAIN

the BBB hinders the delivery of diagnostic and therapeutic agents

Mechanisms for drug targeting in the brain involve going either "through" or "behind" the BBB.

Modalities for drug delivery through the BBB entail disruption of the BBB by osmotic means, biochemically by the use of vasoactive substances such as bradykinin, or even by localized exposure to ultrasound.

strategies to go through the BBB may entail the use of endogenous transport systems, including carrier-mediated transporters such as glucose and amino acid carriers; receptor-mediated transcytosis for insulin or transferrin; and blocking of active efflux transporters such as p-glycoprotein.

Strategies for drug delivery behind the BBB include intracerebral implantation and convection-enhanced distribution.

Nanotechnology could also help in the transfer of drugs across the BBB.

Recently researchers have been trying to build nanoparticles loaded with liposomes to gain access through the BBB. DRUG DELIVERY AND THE BLOOD-BRAIN BARRIER

-The BBB is permeable to small and lipophilic (fat-loving) molecules (up to 800 atomic mass units), but larger molecules are not transported across unless there is an active transport system available

Thus this is one of the stumbling blocks for drug delivery

An additional problem is the very effective drug efflux systems (P-gly-coprotein – P-gp ), which pump the drug back out of cells.

There are three main methods of transport across the BBB, none of which is perfect .

Direct physical injection into site of interest.

Permeabilisation of tight junctions using either osmotic disruption or biochemical opening (RMP-7 Alkermes, vasoactive compounds – histamine).

Enhance transcytosis across the endothelial cells – (transcytosis) to the underlying brain cells can be achieved by increasing endocytosis (i.e. internalisation of small extracellular molecules) by using liposomes or nanoparticles loaded with the drug of interest. The uptake can be further enhanced by specifically targeting the delivery system to receptors on the brain endothelium surface that are capable of receptor mediated endocytosis.

This method is more selective than the tight junction disruption, especially if brain specific targeting technology is used, but tends to be less efficient.

It also requires the discovery and development of receptor specific ligands, which can be attached directly to the drug of interest or the drug delivery system itself. THANK YOU