Question 8

College Answer

Candidates were expected to state the purpose of the blood brain barrier (BBB), define what
constituted the BBB, what its function is, and what parts of the brain lie outside of this barrier
(and why). Further candidates should have mentioned what substances cross the BBB, and
how this is achieved.
Common omissions included not mentioning the presence of astrocyte foot processes in
addition to the tight junctions between the capillary endothelial cells, the presence of active
pumps for sugars amines, and some ions, and what parts of the brain lay outside of the BBB.
Characteristics of a drug that will penetrate the BBB included low molecular weight, good
lipid solubility, a low volume of distribution, low potency and low protein binding. Also
expected was a discussion of Fick’s Law and the drug features that would allow a high
concentration gradient in the cerebral blood vessels to be achieved and a high diffusion
coefficient and mention of drugs that resemble natural ligands for active transport
mechanisms.
Syllabus - G12d G2a
References: Pharmacology, Rang and Dale 6th edition page 476, Principles of physiology for
the anaesthetist, Kam page39-40, Pharmacology and Physiology in Anaesthetic Practice,
Stoelting, Pg 681, Textbook of medical physiology, Guyton and Hal11th edition page 766.
Foundations of Anesthesia. Hemmings and Hopkins. 2nd edition.

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.