Christy (The Blood Brain Barrier) Flashcards
What is the blood brain barrier (BBB)?
It is composed of a network of blood vessels that form a physical and chemical barrier between the brain parenchyma and systemic circulation.
BBB is situated at the interface of the blood and the brain, and its primary function is to maintain the homeostasis of the brain- functions as a physical, metabolic, and immunological barrier.
Total blood vessel length of approx 600km and estimated surface area of about 20m^2.
It is mainly formed by brain capillary endothelial cells (BCECs) although other cell types, such as pericytes, astrocytes, and neuronal cells, also play an important role in its function.
There is no BBB on the vomiting centre and chemoreceptor trigger zone (The area postrema (AP)). This is because it sits in the 4th ventricle and there is no BBB in the fourth ventricle.
Capillary permeability in different microvascular beds can differ
Continuous
- basement membrane is completely intact
- in CNS, Lymph nodes, muscles
- function- BBB, lymphocyte homing, metabolic exchange
Fenestrated
- an elastic membrane of the inner coat of large arteries composed of broad elastic fibres that become fused to form a perforated sheet
- in endocrine glands, gastrointestinal tract, choroid plexus, kidney glomeruli
- function- secretion, absorption, filtration
Discontinuous
- discontinuous helices are integrated in the membrane
- in liver, bone marrow, spleen (in organs for filtration)
- function- particle exchange, haematopoiesis, blood cell filter
Brain capillary endothelial cells (BCECs)
BCECs= principal barrier forming components.
Different from peripheral endothelial cells.
Have tight junctions, which prevent paracellular transport of small and large (water soluble) compounds from the blood to the brain.
Barriers to drug delivery across the BBB
Endothelium, surrounded by a basement membrane and further supported by pericytes, astrocytes, neurons, and microglia. Pericytes also play a role at the BBB- their phagocytic activity forms an additional BBB property.
Tight junctions- prevent paracellular transport of small and large (water soluble) compounds from the blood to the brain.
Drug efflux pumps serve to transport materials from within the brain to within BCECs or from BCECs into the systemic circulation.
Enzymatic barrier
- Various enzymes are highly expressed in cerebral vessels (BCECs)
- Convert numerous compounds to inactive metabolites. Examples include arachidonic acid, testosterone, progesterone, and desipramine (tricyclic antidepressant)
Efflux barrier
- Several different energy-dependant efflux transporters are present in the BBB, both on the luminal and abluminal sides of BCECs
- The BBB efflux pumps are transmembrane P-glycoprotein and multi drug resistance-associated proteins
- These transporters recognise a wide diversity of xenobiotics/drugs
Transport pathways across the BBB
1- Paracellular aqueous pathway
- Involves the movement of ions through the intercellular spaces between epithelial cells.
- The gatekeeper is the tight junction
- Aquaporins allow water soluble molecules across
2- Transcellular lipophilic pathway
- Allows the passive diffusion of small, lipophilic (lipid soluble) molecules through the epithelial cell
3- Transport proteins
- Carrier (passive and active) and channel (passive) proteins
- More than 20 carrier mediated transporter proteins have been identified on the luminal or abluminal side of BCECs
4- Receptor-mediated transcytosis
- Specific ligands bind receptors and are endocytosed and transported through the cell
- Selective pathway as they require the initial binding of a ligand. Selective to certain peptide sequences
- E.g. insulin, transferrin
5- Adsorptive transcytosis
- Cationic molecules can be endocytosed via adsorptive transcytosis nonspecifically and transported through the cell
- E.g. albumin, other plasma proteins
Transport across the BBB
- The central role of BBB is to protect the brain from entering of toxic compounds.
- Many compounds, particularly those of lipophilic nature can passively enter via transcellular route.
- Nutrients are actively transported into the brain.
- Potentially toxic compounds are expelled via active efflux pumps.
- This means that the BBB permeation is a multifactorial and intricate process.
- Poor BBB penetration applies to approximately 98% of new small molecule drugs and nearly 100% of large molecule drugs, such as proteins therapeutics with proven CNS activity.
- Tight junctions- prevent paracellular transport of small and large (water soluble) compounds from the blood to the brain.
- Transcellular transport form the blood to the brain is limited as a result of low vesicular transport, high metabolic activity and a lack of fenestrae.
- Passive diffusion depends on the lipophilicity and molecular weight of the drug.
Drug permeation across the BBB
- Most small module CNS drugs reach the brain via passive diffusion across the BBB
- This depends heavily on certain physiochemical and molecular properties of the drug, including:
- Molecular weight- drugs <400-500Da usually diffuse across the BBB
- Lipophilicity- ideal logP range for BBB permeability is 1.5-2.5
- Polar surface area, charge, hydrogen bonding, and molecular flexibility- molecules with large polar surface area and significant electrostatic charge do not passively diffuse across the BBB
BBB and drug delivery
BBB is the bottleneck in brain drug development limiting the future growth of neurotherapeutics.
98% of all small molecules do not cross the BBB.
Only 1% drugs cross BBB- due to this there are issues treating diseases of the brain e.g. alzheimers, Parkinsons.
The industry is not providing solutions to the BBB problem and pharmaceutical companies don’t want to invest in invention of new drugs.
It is therefore not surprising that most disorders of the CNS could benefit from improved drug therapy.
BBB and drug therapy
For a small molecule drug to cross the BBB in pharmacologically significant amounts, the molecule must have
- Molecular mass under 400-500Da threshold
- High lipid solubility
There are only 4 categories of CNS disorders that consistently respond to such molecules
- Affective disorders (schizophrenia, mania)
- Chronic pain
- Epilepsy
- Migranes
Approaches to improve drug permeation across the BBB
Mainly attempt to harness transporters or receptors:
- via at the ‘Trojan horse’ strategy, whereby a substance that does not cross the BBB is coupled to a substance that does (if they don’t couple properly it will induce an immune response)
- via ‘nanomedicine’, whereby nano-sized drug carriers, loaded with drugs, or decorated with ligands or substances that are transported across the BBB
Several essential nutrients and carrier proteins are thought to cross the BBB by receptors expressed on BCECs through receptor-mediated transcytosis.
Transferrin receptor (TfR) is a protein that is highly expressed on BCECs.
TfR normally carries iron atoms bound to transferrin across the BBB.
TfR has been actively explored to deliver protein therapeutics to the brain.
Bypassing the BBB
Intrathecal administration
- may be an option for biologics (e.g. protein drugs) with negligible transport across the BBB
Nose to brain delivery
- research in this area has shown some promise
Summary of the BBB
The brain is a privilege to organ, shout it from the systemic circulation by the BBB.
Most organs of the body are perfused by capillaries lined with endothelial cells that have small pores.
However, the capillary endothelium of the brain and spinal cord lack these pores because the endothelial cells of brain capillary are sealed together by continuous tight junctions- this gives rise to the BBB.
Creates a huge barrier to drug permeation into the brain.
