Question 3

College Answer

There was general lack of understanding of the conceptual framework of the blood brain 
barrier (BBB) and its function. To attain a pass, candidates were required to describe the 
concept of BBB as a physical and a transport barrier, describe the role of tight junctions and 
glial cells and identify important barrier functions with some examples of things commonly 
transported across or excluded.

Discussion

• The blood brain barrier is a diffusion barrier which impedes influx of most compounds from blood to brain.
• Cellular and physical components of the blood brain barrier:
  • Endothelial cells (tight junctions, no fenestrations)
  • Basement membrane (20-30nm)
  • Pericytes
  • Perivascular fluid space (Virchow-Robin space)
  • Astrocyte foot processes
• Barrier functions of the blood brain barrier:
  • Tight junctions prevent paracellular diffusion of small hydrophilic molecules
  • Metabolic enzymes can degrade substances or biotransofrm them into daughter molecules which are less able to cross the blood-brain barrier
  • Active transport mechanisms are selective for which substances can pass
• Transport functions of the blood brain barrier:
  • Passive transport of small lipophilic molecules
  • Active facilitated diffusion and pinocytosis of molecules of interest, eg. metabolic substrates, peptides, vitamins, etc
  • Specific substances which are actively transported include glucose, amino acids, thiamine, lactate, fatty acids and antibodies.
• Drug characteristics which favour drug penetration of the blood brain barrier:
  • Small molecular weight, high lipophilicity
  • High concentration gradient (low protein binding, small volume of distribution, low potency of drug i.e. large concentration of drug)
  • Substrate for active transport (resemble endogenous ligand)
• Areas of the brain where the blood brain barrier is interrupted:
  • Area postrema (senses toxins for emesis, senses vasopressin and angiotensin for autonomic regulation)
  • Choroid plexus (secretes CSF)
  • Pineal gland (secretes melatonin into the systemic circulation)
  • Organum vasculosum lamina terminalis (acts as osmosensor)
  • Subfornical organ (osmosensor, also detects Angiotensin-II)
  • Median eminence (secretes hypothalamic hormone-releasing hormones into the pituitary portal circulation)
  • Posterior pituitary (secretes vasopressin and oxytocin)
  • Preoptic recess (senses sex hormones)

Abbott, N. Joan, et al. "Structure and function of the blood–brain barrier." Neurobiology of disease 37.1 (2010): 13-25.

Ballabh, Praveen, Alex Braun, and Maiken Nedergaard. "The blood–brain barrier: an overview: structure, regulation, and clinical implications." Neurobiology of disease 16.1 (2004): 1-13.

Daneman, Richard, and Alexandre Prat. "The blood–brain barrier." Cold Spring Harbor perspectives in biology 7.1 (2015): a020412.

Bechmann, Ingo, Ian Galea, and V. Hugh Perry. "What is the blood–brain barrier (not)?." Trends in immunology 28.1 (2007): 5-11.