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

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 3 rd ventricle can collect fluid CSF Content in Man: mls of which: 30 mls in ventricular system rest in subarachnoid spaceCSF

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 PlasmaCSF Water Content93%99% Osmalality (mOsm/L) 295 pH

Ionic Composition of CSF & Plasma Ultrafiltrate (mM/Kg H 2 O) PLASMACSF Na K+K * Ca * Mg Cl * pH Osmolality289

PLASMACSF Protein (mg/dL) Glucose (mg/dL) Cholesterol (mg/dL)

CSF Composition v Plasma ReducedUnchanged Increased K+K+ 60%Na + Mg % CA 2+ 45%HCO 3 - Cr115% Glucose37% Protein5%

PLASMACSF Protein (mg/dL) Glucose (mg/dL) Cholesterol (mg/dL)

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 TransportedVirtually Excluded Phenylalanine)Alanine Leucine) LargeProline Tyrosine)Glutamic Acid Isoleucine) neutralAspartic Acid Tryptophan)GAB ( -amino butyric acid) Methionine) aminoGlycine Valine) Threonine) acids Histidine) L-DOPA ESSENTIAL AMINO ACIDSTRANSMITTER AMINO ACIDS TRANSPORTEDNOT TRANSPORTED Transmitter Precursor Amino AcidAmino 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 Parkinsons 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 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