Blood Brain Barrier

What makes up 95% of the blood brain barrier?

Capillary beds/cerebral vasculature

What does the cerebral vasculature allow?

Allows brain to take in nutrients such as glucose but get rid of waste such as CO2

What is the blood pathway in the BBB?

Carotid artery → arterioles → capillaries → venules → veins

What are the 3 main cell types in the brain?

• astrocyte

• pericyte

• endothelial cell

What is the diagram to show the composition of cells in the BBB?

What is a pericyte?

Type of smooth muscle cell that contracts and controls the blood flow

Why does the BBB exist?

Ensures toxic compounds e.g., lymphocytes can’t enter the brain

What are the endothelial cells function in the brain?

Line the capillaries - has a basement membrane with collagen, fibronectin and laminin that surrounds endothelial cells

What do astrocyte foot processes do?

Secrete paracrine which promotes tight junction formation

What are tight junctions?

Prevent solute movement between endothelial cells

What is the structure of a pericyte?

What types of junctions are in the BBB?

• tight junctions formed by claudins and occludins that are attached to actin

• adherens junctions sealed by cadherins

What are the integral membrane proteins in tight junctions?

Claudins, occludin and junctional adhesion molecules

What are the cytoplasmic accessory proteins?

ZO - zonula occludens and cingulin

What are the differences in neural vs non-neural capillaries?

• Tight junctions in the brain, in usual capillaries there is an intercellular cleft and pinocytotic vesicles

• More mitochondria in the brain capillaries as more metabolism need

What is the comparison of BBB and peripheral organs structure?

What are the 3 levels of barrier in the brain?

• capillaries - 95%

• Blood - CSF in the ventricles and tight junctions, along with endothelial cells

• Subdural space - arachnoid cells that secrete CSF from the blood

What is the diagram to show the choroid plexus in the brain?

What is the rate of CSF replacement in the brain?

4-5x a day

Where is CSF made in the brain?

Choroid plexus

Where is the choroid plexus in the brain?

What are the functions of the CSF?

• mechanical protection

• stable extracellular environment

• remove some waste products

• nutrition

• convey messages such as hormones/neurotransmitters

What is the BBB NOT?

A WALL! Not a solid barrier

What are the transport mechanisms in the brain?

• passive diffusion

• transporter diffusion

• solute carriers

• transcytosis - receptor or adsorptive mediated

• mononuclear cell migration

Why are 95% of drugs not suitable for use in the brain?

Brain will efflux them out - can leave the brain

How does diffusion work in the BBB?

• High to low concentration

• Aqueous to lipids, small lipophilic molecules of <300Da

What are the 2 methods of carrier mediated transport in the brain?

Facilitated diffusion and active transport - against conc gradient

What are the different transporters in the brain?

• Glucose (GLUT1)

• Lactate - MCT1

• Essential amino acids - L1

• Organic anion transporter OATP3

Which carrier mediated transporters can move in and out of the brain?

Glucose, lactate and amino acids

What is transcytosis?

Movement of large molecules using vesicles across the BBB. Endocytosis and exocytosis

What are the 2 ways of transcytosis in the BBB?

Receptor mediated e.g., insulin, erythropoietin and transferrin and adsorptive mediated transcytosis e.g., albumin

What larger molecules effluxes out of the brain?

• P glycoprotein p in the kidneys

• Multidrug resistance protein - pumps the drug out

• excitotoxic amino acids

• sodium potassium ATPase

• peptide transporter system

What molecular properties mean molecules CAN’T enter the brain easily?

• larger molecules - over 400Da

• Low lipid fat soluble molecules

• High electrical charge molecules

What are the functions of the BBB?

• Protects brain from foreign substances that can harm it

• Protects brain from hormones and neurotransmitters in the rest of the body

• transports nutrients into the brain’

• moves out toxins of the brain

• maintains a constant environment for the brain

• essential for brain normal functions

Why are there problems delivering drugs into the brain?

BBB likes smaller and lipophilic molecules but larger molecules can’t be transported unless it has an active transport system and there are effective efflux systems

What are the go through strategies for drug delivery to the brain?

• endogenous system - use transporters and make drugs with similar structures

• disrupting BBB osmotically - increase conc of reagents and temporarily disrupt the barrier

• prodrugs - becomes a drug when metabolised

What are some examples of go behind strategies in the brain for drug delivery?

• intraventricular/intrathecal - inject into spinal cord or ventricles

• olfactory - drugs given in the nose via olfactory nerve

• interstitial - direct injection