2013B04 Discuss the physiological significance of the blood brain barrier.

Function

·   Barrier between blood and brain ECF for homeostasis and protection

·   Multiple components

·   Variable permeability

·   Entry by diffusion or active transport

Dysfunction

·   Neonate: immaturity

·   Elderly: degeneration

·   Profound hypertension: damage

·   Meningeal disease: inflammation (MS), infection (meningitis) -> damage

Factors conferring permeability

·   ↑C₁ (e.g. ↑dose)

·   ↓C₂ (e.g. glucose utilisation)

·   ↑Area (not under control)

·   ↓Thickness (e.g. dysfunction)

·   ↑Lipid solubility (e.g. propofol)

·   ↓Molecular weight (e.g. O₂)

·   Unionised (e.g. propofol 98%)

·   Non-polar (e.g. CO₂)

·   Not protein bound (e.g. ketamine)

Physical barrier

·   Endothelial cells: tight junctions, no fenestrae, low rate of transcytosis

·   Basement membrane: negative charge

·   Astrocyte foot processes

(cf. blood-CSF barrier: tight junctions between choroid epithelioctes)

Immune cells

·   Astrocytes = antigen-presenting cell: activates T and B cells

·   Microglia = macrophage: phagocytosis, inflammation, chemotaxis

Transporters

·   GLUT-1: constitutively expressed, ensures priority supply of glucose

·   Ion channels: control [Na⁺], [K⁺], [Ca²⁺] – preserve polarity, prevent excitotoxicity

Enzymes

·   e.g. MAO, AChE

·   Prevent circulating neurotransmitters from entering brain

Significance

·   “Outside” the blood-brain barrier, near the fourth ventricle

·   i.e. permeable vessels allow contact with blood

Function

·   Posterior pituitary: secretes ADH, oxytocin

·   Area postrema (contains CTZ): circulating toxin induces vomiting

·   OVLT, SFO: ↑osmolality -> ↑activation of hypothalamus -> ↑ADH release

·   Pineal gland: secretes melatonin

·   Medial eminence

Water

·   Travels up osmotic gradient

Very low MW

·   e.g. O₂

·   e.g. CO₂ (e.g. CO₂ -> H⁺ for control of breathing)

Very lipid soluble

·   e.g. ketones, propofol

Electrolytes

·   Ions are charged hence impermeable

·   Active influx (e.g. Mg²⁺, Cl^-) and efflux

·   For control of ECF environment (e.g. metabolic acidosis in exercise -> ↑H⁺)

·   For preservation of cell polarity

·   For preservation of brain cell volume, proportional to brain ECF [Na⁺]

Macronutrients

·   Glucose: via GLUT1, limited capacity

o Too much -> glycosylation

o Too little -> unconsciousness

·   Amino acids: for neurotransmitter synthesis

·   Lipids: for membrane maintenance

Neurotransmitters

·   Brain NTs barred from circulation (e.g. brain noradrenaline metabolized by MAO)

·   Peripheral NTs barred from brain (e.g. ingested serotonin metabolized by MAO)

Proteins

·   Endogenous neurotoxins (e.g. bilirubin)

·   Exogenous neurotoxins (e.g. cholera toxin)

Pathogens

·   Physical barrier

·   Immune cells

Many drugs

·   e.g. muscle relaxants (large, polar)