Download Cerebrospinal Fluid

Introduction
• 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 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 Fluid
• Fills the spaces in the brain and
spinal cord
• Acts as a cushion or shock-absorber
• Provides appropriate local
environment
• Medium of exchange
CSF
FORMATION
70% from choroid plexus
30% from around cerebral vessels and
along the walls of the ventricles
Secretory Activity of Epithelial Cells
Evidence
•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
Composition
• 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 Composition
Plasma
CSF
Water Content
93%
99%
Osmalality
(mOsm/L)
295
295
pH
7.41
7.33
Ionic Composition of CSF &
Plasma Ultrafiltrate
(mM/Kg H2O)
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 Plasma
Reduced
Unchanged
Increased
Mg2+ 600%
K+
60%
Na+
CA2+
45%
HCO3-
Glucose
37%
Protein
5%
Cr
115%
PLASMA
CSF
Protein
(mg/dL)
6000
20
Glucose
(mg/dL)
100
64
Cholesterol
(mg/dL)
175
0.2
CSF Disorders
• If Pressure/volume drops
(e.g. spinal tap)
 Headache
• If pressure/volume increases (e.g.
drainage blocked, hydrocephalus)
 Severe brain damage/retardation
CSF Disorders
• If Pressure/volume drops
(e.g. spinal tap)
 Headache
• If pressure/volume increases (e.g.
drainage blocked, hydrocephalus)
 Severe brain damage/retardation
Morphological 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 Passage
Across 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 Passage
Across 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 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 Transport
FACILITATED TRANSPORT
COMPETITIVE CARRIER SYSTEM
i.e. large neutral amino acids compete
for the same carrier system
Amino Acid Transport
Readily Transported
Phenylalanine
)
Leucine
) Large
Tyrosine
)
Isoleucine
) neutral
Tryptophan
)
Methionine
) amino
Valine
)
Threonine
) acids
Histidine
)
Virtually Excluded
Alanine
Proline
Glutamic Acid
Aspartic Acid
GAB (‫ ﻻ‬-amino butyric acid)
Glycine
L-DOPA
ESSENTIAL AMINO ACIDS
TRANSPORTED
TRANSMITTER AMINO ACIDS
NOT TRANSPORTED
Transmitter Precursor Amino Acid
Amino Acid Synthesised from
glucose metabolites
Metabolic 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 Disorders
• Tumours
– Leaky BBB
• Increased nutrients, increased growth
• Infiltration
– Infection
• Increased antibiotic permeability
• Ischaemia
– Cellular damage
• Increased water, oedema
Non Barrier Regions
Areas 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
Summary
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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