IntroductionIntroduction

• Cerebrospinal fluid (CSF)– What is it?– What does it do?– Disorders

• The Blood Brain Barrier (BBB) – What is it?– What does it do?– Disorders

Cerebrospinal FluidCerebrospinal Fluid

• Fills the spaces in the brain and spinal cord

• Acts as a cushion or shock-absorber

• Provides appropriate local environment

• Medium of exchange

Cerebrospinal FluidCerebrospinal Fluid

• Fills the spaces in the brain and spinal cord

• Acts as a cushion or shock-absorber

• Provides appropriate local environment

• Medium of exchange

FORMATION70% from choroid plexus30% from around cerebral vessels and along the walls of the ventricles

Secretory Activity of Epithelial CellsEvidence•Expose Lat. Ventricles Flow of fluid•Catheter into the 3rd ventricle can collect fluid

CSF Content in Man: 130 -150 mls of which:30 mls in ventricular system rest in subarachnoid space

CSFCSF

CompositionComposition

• Filtration and diffusion from blood

But CSF not simply an ultrafiltrate of Plasma

• Facilitated diffusion (carrier molecules) e.g. Glucose, Amino Acids

• Active Transport (ATP dependent)e.g. Ma+ K+ ATPase

CSF CompositionCSF Composition

Plasma CSF

Water Content 93% 99%

Osmalality

(mOsm/L)295 295

pH 7.41 7.33

Ionic Composition of CSF & Ionic Composition of CSF & Plasma UltrafiltratePlasma Ultrafiltrate

(mM/Kg H(mM/Kg H22O)O)

PLASMA CSF

Na++ 150 147

K+ 4.5 2.8*

Ca++ 3.0 2.0*

Mg++ 1.5 2.2

Cl- 99.0 113.0*

pH 7.4 7.33

Osmolality 289 289

PLASMA CSF

Protein

(mg/dL)6000 20

Glucose

(mg/dL)100 64

Cholesterol

(mg/dL)175 0.2

CSF Composition v PlasmaCSF Composition v Plasma

Reduced Unchanged Increased

K+ 60% Na+ Mg2+ 600%

CA2+ 45% HCO3- Cr 115%

Glucose 37%

Protein 5%

PLASMA CSF

Protein

(mg/dL)6000 20

Glucose

(mg/dL)100 64

Cholesterol

(mg/dL)175 0.2

CSF DisordersCSF Disorders

• If Pressure/volume drops (e.g. spinal tap) Headache

• If pressure/volume increases (e.g. drainage blocked, hydrocephalus) Severe brain damage/retardation

CSF DisordersCSF Disorders

• If Pressure/volume drops (e.g. spinal tap) Headache

• If pressure/volume increases (e.g. drainage blocked, hydrocephalus) Severe brain damage/retardation

Morphological BarrierMorphological Barrier

Capillary Endothelium cells of the brain capillaries have TIGHT JUNCTIONS not FENESTRATIONS as other capillaries

This limits access to molecules with MW greater than 2000

Factors Regulating PassageFactors Regulating PassageAcross BBBAcross BBB

• LIPID SOLUBITLITY– High Lipid Solubility Greater Access

• DEGREE OF IONISATION– Drugs ionised at physiological pH (7.4) Less

access– Drug pKa value = pH at which 50% of drug

molecules are ionised

• DEGREE OF PLASMA PROTEIN BINDING– In bound state too large to cross BBB

Factors Regulating PassageFactors Regulating PassageAcross BBBAcross BBB

• LIPID SOLUBITLITY– High Lipid Solubility Greater Access

• DEGREE OF IONISATION– Drugs ionised at physiological pH (7.4) Less

access– Drug pKa value = pH at which 50% of drug

molecules are ionised

• DEGREE OF PLASMA PROTEIN BINDING– In bound state too large to cross BBB

Glucose TransportGlucose Transport

• Facilitated transport of monosaccharides• Specific to D-glucose (L-glucose and fructose are not transported

• Competitive * 2-deoxyglucose > glucose > 3.0 – methyl glucose > mannose

* Not metabolised in brain Labelled form used as a marker of cell activity in PET

Amino Acid TransportAmino Acid Transport

FACILITATED TRANSPORT COMPETITIVE CARRIER SYSTEM

i.e. large neutral amino acids compete for the same carrier system

Amino Acid TransportAmino Acid TransportReadily Transported Virtually ExcludedPhenylalanine) AlanineLeucine ) Large ProlineTyrosine ) Glutamic AcidIsoleucine ) neutral Aspartic AcidTryptophan ) GAB (ال -amino butyric acid)Methionine ) amino GlycineValine )Threonine ) acidsHistidine )

L-DOPA

ESSENTIAL AMINO ACIDS TRANSMITTER AMINO ACIDS

TRANSPORTED NOT TRANSPORTED

Transmitter Precursor Amino Acid Amino Acid Synthesised from glucose metabolites

Metabolic BarriersMetabolic Barriers

• Endothelial cells, rich in certain metabolic enzymes, e.g. Monoamine Oxidase (MAO)

• Unable to use DOPAMINE to treat Parkinson’s Disease because– Ionised at pH 7.4– Metabolised by MAO

• Use precursor L-DOPA + PERIPHERAL DOPA DECARBOXYLASE INHIBITOR– L-DOPA enters CNS as unionised at pH 7.4– Inhibitor prevents conversion of L-DOPA to

dopamine outside the brain– Inhibitor does not enter CNS as ionised at pH 7.4

BBB DisordersBBB Disorders

• Tumours– Leaky BBB

• Increased nutrients, increased growth

• Infiltration– Infection

• Increased antibiotic permeability

• Ischaemia– Cellular damage

• Increased water, oedema

Non Barrier RegionsNon Barrier RegionsAreas where capillaries with “tight junctions” replaced by normal fenestrated endothelia.

Peptides and small organic mols can cross

Post-pituitary

• Median eminence: * Oxytocin, Vasopressin

• Area postrema:

• * chemoreceptor zone – vomiting

• Organum vasculosum of the lamina terminalis (OVLT)

• Angiotensin II receptors

•Subfornicular organ

• * Angiotensin II receptors

SummarySummary

• Differences between plasma and CSF• Morphological features – tight junctions• Active transport• Role of choroid plexus & arachnoid villi• Some drugs enter brain others excluded• Lipid solubility/degree of ionisation• Facilitated transport – L-glucose/some

amino acids• Non Barrier Regions