Blood Brain Barrier

Question 1

Blood Brain Barrier

Definition

Answer 1

A layer of cells that seperates the peripheral fluids (blood) from the intercellular spaces in the brain.

Regulates the movement of molecules into and out of the nervous system.

Question 2

BBB

Clinical Significance

Answer 2

• Restricts access of the nervous system.
  
  • Microorganisms and Ab’s are normally excluded.
• Creates unique extracellular environment required for nervous system function.
• Attenuates or prevents the brain’s reaction to peripheral disturbances:
  
  • Hydration
  • Electrolyte balance
• Obstacle to drug delivery to the brain

Question 3

Brain Blood Suppy

Answer 3

• Main routes:
  
  • Internal carotid arteries
  • Vertebral arteries
• Venous drainage via dural sinuses ⇒ internal jugular vein
• ~ 12 m² of circulatory system surface in brain parenchyma
• No neuron > 100 microns from a blood vessel

Question 4

BBB

Structure

Answer 4

Two components:

• Barrier between CNS vasculature and brain parenchyma.
• Barrier between CNS vasculature and CSF.
  
  • Blood-CSF barrier
• Function derived from:
  
  • structural & cytological properties of cerebral microvasculature
    
    • capillary endothelial cells
    • basement membrane
  • glial cells surrounding blood vessels in the brain
    
    • astrocytes with end feet
    • pericytes

Question 5

Nervous System

Endothelial Cells

Answer 5

• Continuous layer joined by tight junctions
  
  • Occludins block:
    
    • paracellular protein movement
    • hydrophilic transfer
    • ionic diffusion
  • Cut off size for an ionized soluble compound to pass is 180 daltons (~AA size)
• Transcellular movement via endocytosis or receptor-medicated transport g_reatly reduced_
• High density of mitochondria to support active transport
• 1/3 thinner ⇒ higher risk for hemorrhage

Question 6

Astrocytes

Answer 6

• Can induce capillary endothelial cells to form and maintain BBB
• Have processes with “end feet” which covers over 95% of capillary endothelial outer surface

Question 7

Pericytes

Answer 7

Phagocytic microglial cells.

• Stimulates endothelial cell proliferation
• Regulates vessel contractility
• Closes up holes when there is a breach

Question 8

Endothelial Basement Membrane

Answer 8

• Main components:
  
  • laminin
  • fibronectin
  • tenascin
  • collagens
  • proteoglycans
• Contributes to exclusion of molecules movement due to net charge

Question 9

Mechanisms of Transport

Across BBB

Answer 9

• Diffusion
• Facilitated diffusion
• Active transport and ion exchange
• Receptor-mediated transcytosis
• Transcytosis via P-glycoprotein
• Diapedesis

Question 10

Diffusion

Answer 10

Passage through the membrane.

• Small inorganic molecules highly permeable
  
  • Ex. gases: O₂, CO₂, NO, H₂O
• Lipophilic substances
• Two non-polar molecules with high diffusion rates through BBB:
  
  • nicotine
  • ethanol

Question 11

Facilitated Diffusion

Answer 11

Concentration-dependent.

Energy-dependent.

Saturable.

• Amino acid transporter
  
  • Different ones for neutral, basic, or acidic AA
  • Ex. L-system for leucine and phenylalanine
    
    • Sodium dependent
• Glucose transporter: GLUT-1
  
  • Found on luminal and adluminal endothelial cell membranes
  • Exits in neuronal and astrocytic membranes
• Monocarboxylates
  
  • Lactate, pyruvate, acetate, SCFA, salicylic acid, nicotinc acid, some 𝛽-lactam Abx
• Hexose amines
  
  • glucosamine, glutathione
• Nucleosides
  
  • Adenosine, guanosine

Question 12

Active Transport

&

Ion-Exchange Systems

Answer 12

Concentration-independent.

Energy dependent.

Saturable.

• Vitamins
  
  • Entry limited when blood levels abnormally high
• Na/K-ATPase
• Neutral amino acids
  
  • “A” system
    
    • alanine, glutamine, histadine
  • “ASC” system
    
    • serine, cysteine

Question 13

Receptor-Mediated Transcytosis

Answer 13

Similar to pinocytosis but required receptor activation.

• Transferrin
• Insulin
• Leptins
• IGF-I and IGF-II
• Angiotensin II
• Albumin

Question 14

Transcytosis via P-glycoprotein

Answer 14

ATP-dependent Flippase

Member of the multi-drug resistance (MDR) protein family.

• Transports back into the blood a variety of molecules that enter ECs or brain.
• Typically organophosphate substrages:
  
  • Anti-neoplastic agents
  • Immunosuppresive drugs
  • Abx
  • Digoxin
  • Pesticides
  • Protease inhibitors

Question 15

Diapedesis

Answer 15

• Certain cells can break tight junctions and move between endothelial cells
  
  • Activated T cells, monocytes, and macrophages
    
    • But not unactivated ones
  • Metastatic cells
• Not influenced by specific Ag, MHC, or T-cell type
• Exits CNS unless specific Ag recognized
• Some leave via lymphatic drainage
• Can induce astrocytes and miroglia to present MHC:peptide
• Can induce BBB breakdown

Question 16

Blood-CSF Barrier

Answer 16

• Exists at the choroid plexus of lateral and 4th ventricles
  
  • Sites of CSF production
  • Develops from invagination of neuroepithelial wall
    
    • Penetrated by capillaries of choroid arteries
• Concentrations of Na, K, Mg, Cl, Ca, H, bicarb, glutamate, and others held at steady state in CSF and brain extracellular fluids
• Endothelial cells of blood vessels in choroid plexus do no have tight junctions
• Rather, there are apical tight junctions on neuroepithelial cells of chroid plexus surrounding capillary structures

Question 17

Other Barriers

Answer 17

Tight junction-based barriers exist wherever vascular system abuts CNS.

• Blood-Labyrinth barrier
• Blood-nasal mucosa barrier
• Blood-retinal barrier
• Blood-nerve barrier

Question 18

Places Lacking

BBB

Answer 18

• NMJ and other peripheral axon terminals
• Barrier around dorsal root ganglia
• Circumvenricular organs:
  
  • Examples:
    
    • neurohypophysis
    • pineal gland
    • median eminence
    • area postrema
    • subfornical organ
    • organum vasculosum of lamina terminalis
  • Neurons in these regions needed to release into the blood or detect specific blood contents
  • Tanycytes line ventricular surface near these areas
    
    • have tight junctions
    • generally prevents free fluid exchange with CSF

Question 19

Methods of CNS Exit

Answer 19

• Membrane diffusion
• Saturable transport systems
  
  • Na-dependent AA co-transporters
  • Lactate and other metabolic products
• Lymphatic drainage
  
  • meninges form a perivascualr sheath around larger vessels
  • demarcates the Virchow-Robin spaces
• P-glycoprotein CSF reabsorption

Question 20

CSF Bulk Flow

Answer 20

In an average human:

• 150 ml CSF
  
  • 80% in subarchnoid space
• replaced ~ 4x per day at a rate of 500 mL/day
• creates a “sink effect”
  
  • difficult for microorganisms to move up CSF flow
• Flow from subarachnoid space ⇒ dural sinuses via arachnoid granulations

Question 21

Disorders Involving

BBB

Answer 21

• Trauma
• Vascular dysfunction
  
  • cerebral ischemia
  • HTN
  • VEGF increased at injury sites ⇒ increaes capillary permeability via NO
• Infection
  
  • Some neuroinvasive microorganisms can cross BBB
  • Encephalitis
    
    • entry through BBB endothelium
  • Meningitis
    
    • entry through meninges
• Age
• Autoimmune disorders
  
  • MS
• Alzheimer’s disease
  
  • Beta-amyloid peptide allowed to enter brain
  • Leads to amyloid angiopathy and formation of amyloid plaques
• Epilepsy
  
  • increased pinocytotic activity during seizures
• Prolonged stress