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'B33CNS - Biology & Physiology > BBB & CSF > Flashcards

BBB & CSF Flashcards

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1
Q

What is Brain ECF, and where does it occupy?

A
  • Brain Extracellular Fluid; accounts for 15-20% brain volume
  • ECF vital for communication; cell v. close together (neurones and astrocytes separated by narrow clefts 20nm wide), ECF = fast synaptic fluid
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2
Q

How does ECF composition change with neuronal activity?

A
  • Concentrations of solutes in the ECF fluctuate w/neuronal activity; changes in ECF composition will affect neuronal behaviour
  • ECF cannot be described in isolation due to its interactions w/CSF, neurones and glial cells.
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3
Q

How does the brain regulate ECF composition?

A

1) CSF synthesised by the choroid plexus (of ventricles) influences composition of the ECF
2) BBB protects the ECF from fluctuations in blood composition (in systemic circulation) and limits entry of compounds into the ECF
3) Glial cells (astrocytes) condition the ECF; buffering K+, NTs etc.

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4
Q

What is CSF?

Where does it reside? How much is produced?

A
  • Cerebrospinal fluid
  • Fills ventricles (30 ml), and subarachnoid space (120 ml)
  • Volume of CSF is 150 ml, with 500 ml produced each day; turn over of 3 times a day
  • CSF secretion pushes existing CSF into subarachnoid space
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5
Q

What is the function of CSF?

A
  • Forms a thin layer around brain and spinal cord in the subarachnoid space (between arachnoid membrane and pia mater; of PAD)
  • Acts as a cushion/shock absorber; brain is buoyant in CSF, reduces acceleration-deceleration injuries
  • Provides appropriate local environment for neurones and glia (buffers ions to appropriate level for neurone function e.g. K+)
  • Medium of exchange between Brain ECF and systemic blood
  • Removal of waste products; metabolism, drugs, NT metabolites (e.g. lactate)
  • Interface between brain and Peripheral Endocrine functions i.e. releasing hormones from hypothalamus/pituitary gland
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6
Q

Describe the movement of CSF; from the lateral ventricles (cortex) to the subarachnoid space.

A
  • Lateral ventricles (cortex)
  • Foramina of Monroe
  • Third ventricle (thalamus)
  • Cerebral aqueduct of Sylvius
  • Fourth ventricle (brain stem)
  • Two foraminae of Luschka and/or foramina of Magendie
  • Subarachnoid space
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7
Q

How is CSF circulation achieved to permit circulation around the brainstem, cerebellum and cerebral cortex?

A
  • 3 foramina projecting into the subarachnoid space (SAS) permit CSF circulation around brainstem, cerebellum and cerebral cortex
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8
Q

What term describes the results of physical blockage of CSF circulation, and where can this occur?

A
  • Hydrocephalus ‘water on the brain’

- Blockages can occur at the foramina and the cerebral aqueduct (narrow; stent needed if blocked)

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9
Q

What are the two processes of CSF secretion?

A
  • Ultra-filtration of plasma across fenestrated capillary wall into ECF, beneath the basolateral membrane of the choroid epithelial cell
  • Choroid epithelial cells secrete fluid into the ventricles (majority of production)
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10
Q

What is the mechanism of CSF secretion at the apical membrane (into the ventricle)?

A
  • Na+/K+ ATPase pumps; Na+ efflux into CSF (3 Na+ out, 2K+ into choroid plexus cell
  • HCO3- and Cl- also leave the cell into the ECF following electrochemical gradients, with the aid of cotransporters such as KCC4
  • Aquaporins (AQP1) facilitate water transport through the cell
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11
Q

What is the mechanism of action of CSF secretion at the basolateral membrane?

A
  • Transporters mediate movement of ions into the choroid plexus epithelial cells
  • NCB transporters use the Na+ gradient to promote accumulation of HCO3-
  • Accumulation of HCO3- causes Cl- influx
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12
Q

What is an important functions of the basolateral side of the choroid plexus epithelium?

A

Important for neutralising acids produced by CNS cells.

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13
Q

How does the composition of CSF compare to that of blood plasma?

A
  • Higher water content (CSF 99%, Plasma 93%)
  • Same osmolality (proteins present in plasma equates osmolality)
  • 20 mg/dL protein compared to 6000 mg/dL
  • Glucose is 2/3 that of plasma (64 vs. 100)
  • Cholesterol = 0
  • K+; 2.9 in CSF, 4.7 in plasma (brain cells sensitive to changes in K+)
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14
Q

Why does the CSF have such a low protein level compared to blood plasma? (20 vs 6000 mg/dL)

A
  • Important to prevent proteins reaching brain

- Could trigger an immune response

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15
Q

What are the sites of absorption of CSF?

A
  • Arachnoid villi within the subarachnoid space

- Vascular epithelium of the choroid plexus

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16
Q

What are the mechanisms of absorption of CSF?

A
  • Bulk flow via arachnoid villi 500mls/day
  • Diffusion
  • Active transport via choroid plexus (e.g. weak organic acids)
17
Q

What is the journey that CSF and ECF undertake, from cerebral/spinal blood to venous blood?

A
  • Cerebral spinal blood

Path 1:

  • Blood-CSF barrier (choroid plexus); blood is filtered, CSF is produced
  • CSF in ventricles and the SA space
  • Which either goes to the ECF, or is absorbed by Arachnoid villi
  • Which then enters venous blood

Path 2:

  • Conventional blood supply to BBB
  • Forms ECFl which can go to (and from) glia and neurones, of to CSF in ventricles/SA space
  • From ECF, it goes to cerebral veins ‘drained’
  • Where it then ends up in venous blood
18
Q

What are the diagnostic uses of CSF?

A
  • Spinal tap/lumbar puncture allows sampling of CSF for detection of ‘pathogens’ e.g. MS, meningitis. Also used to measure CSF pressure for detection of hydrocephalus (foramina/aqueduct blockage), sub-arachnoid haemorrhage.
  • Routine clinical procedure at L3-5
19
Q

What is the clinical use of CSF?

A
  • Application of spinal block to anaesthetise spinal nerves (epidural) to distal to the site of application
  • Intrathecal
  • Injection into the third ventricle; unlimited access to ECF and thus neurones and glia (not routine)
20
Q

What is the function of the BBB?

A
  • CNS requires ultrastable internal environment

- BBB regulates transport between blood and brain

21
Q

Why do capillary endothelium cells of brain capillaries have tight junctions instead of fenestrations?

A
  • So that only small molecules can pass

- Limits passage to molecules w/MW < 2000

22
Q

What factors regulate passage across BBB?

A

Lipid solubility
- High lipid solubility; greater access

Ionisation

  • Drugs ionised at pH 7.4 = less access
  • More ionisation = less access

Plasma protein binding
- Bound state is too large to cross BBB

23
Q

What is pKa?

A

The pH at which 50% of the drug is ionised

24
Q

What type of glucose has facilitated transport to the brain?

A
  • D-glucose
  • Competitive
  • Precursor of 2-deoxyglucose, which becomes:
    > glucose
    > 3-methylglucose
    > mannose
25
Q

What monosaccharide can be labelled, and how is this beneficial?

A
  • 2-deoxyglucose can be labelled
  • Labelled form used as a marker of cell activity in PET scans
  • 2-deoxyglucose is not metabolised in the brain
26
Q

What type of amino acids are and aren’t transported to the brain?

A
  • Essential amino acids; transported
  • Transmitter precursor amino acids

> Transmitter amino acids not transported; produced from glucose metabolites in the brain

27
Q

What are BBB’s metabolic barriers?

A
  • Endothelial cells rich in certain metabolic enzymes, e.g. monoamine oxidase (MAO)
28
Q

Why can dopamine OG not be used to treat Parkinson’s Disease?

A
  • It is ionised at pH 7.4; won’t cross BBB

- DA is metabolised by MAO (futile to give DA even if unionised)

29
Q

How is L-DOPA used for Parkinson’s therapy instead of DA? What is it given with?

A
  • Precursor of DA
  • Use L-DOPA and peripheral DOPA decarboxylase inhibitor
  • L-DOPA enters CNS unionised at pH 7.4 (by specific transporters)
  • Inhibitor prevents conversion of L-DOPA to DA outside the brain (doesn’t hit other targets)
  • Inhibitor does not enter CNS as ionised at pH 7.4
30
Q

What BBB disorders are there, and their resulting effect?

A

Tumours:
- Leaky BBB (broken down); increased nutrients, increased growth

Infiltration:
- Infection; increased antibiotic permeability (HIV)

Ischaemia:
- Cellular damage; increased water, oedema (stroke)

31
Q

What are the brain areas lacking a BBB known as? What do they have instead of a specialised BBB?

A
  • Circumventricular organs

- Tight junctions are replaced by normal fenestrated endothelia

32
Q

What are some examples of circumventricular organs, and what do they do?

A

Posterior-pituitary gland:
- Hormones release here have direct access to general circulation

Median eminence:

  • Oxytocin, Vasopressin (ADH)
  • Pick up releasing hormones for carriage via pituitary portal system to the anterior pituitary

Area postrema:
- CMZ (chemoreceptor zone - vomiting)

Organum vasculosum of the lamina terminalis (OVLT):
- Important for actions of cytokines in the periphery (fever)

'B33CNS - Biology & Physiology (3 decks)

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