18.1 CNS compartments Flashcards
What is the function of the blood brain barrier?
It is involved in homeostasis of the internal environment of the brain:
- Produces interstitial fluid
- Allows selective transport of substance between blood and brain parenchyma
- Astrocytes maintain stable ionic composition and clearance of neurotransmitters and other molecules/metabolites
- Neurovascular coupling allows control of blood flow in response to neuronal demand
Describe the structure of the blood brain barrier.
- Endothelial cells form the inner barrier
- Pericytes cover these
- Astrocytes extend feet onto the blood vessel (communicating with the endothelial cells and pericytes)
- Endothelial cells and pericytes are embedded in the basal membrane
- Microglia are also frequently considered to be involved
What is the role of endothelial cells in the blood-brain barrier and how does their structure reflect this?
- Form the main barrier, enabling selective transport across it
- The adaptations:
- Are connected by tight junctions
- High number of mitochondria, indicating high metabolic activity
- Very few intracellular transport vesicles
Explain the concept of astrocyte induction.
- Astrocytes contribute to induction and maintenance of the blood–brain barrier
- This is done by paracrine interactions with the pericytes and endothelial cells.
- The astrocytes secrete factors with either barrier-promoting or barrier-disrupting effects depending on signals received from neurons and/or endothelial cells.
What are the different modes of transport through the BBB?
What is paracellular transport? What does it favour?
passive diffusion through TJs depending on their leakiness. Favours small, water-soluble molecules
What does transcellular passive favour?
favours small, non-polar, lipid-soluble molecules
What is efflux via ABC-transporters? What consequences does this have on drug transport?
Efflux vis ABC-transporters → interrupt passively diffusing solutes + pump out of cell to protect brain from exogenous substances.
*Usually in luminal membrane. *Function as extruders.
*Form dimers w/ 2ATP binding/ hydrolysis domains + 2-3 transmembrane ligand binding + transport domains.
*Pgp → multi Drug resistance 1 (MDR1) = ABCB1. Extrudes 50% of commonly used drugs.
What is solute carrier-mediated transport? Give an example of a drug that uses these transporters.
Solute carrier-mediated transport → passive diffusion through protein channels or 10/20 transport. Multiple directions. E.g. GLUT1 mediated glucose transport
*LAT1 → aa transporter used for L-DOPA uptake. Decarboxylated → dopamine. Treats endogenous dopamine insufficiency in PD (due to loss of dopaminergic neurons in substantia nigra pars compacta.
What is transcytosis?
Transcytosis → receptor/ absorptive mediated. Generally for macromolecules (e.g. proteins/ peptides)
RMT - macromolecular binds to ligands specific receptors triggering endocytotic event.
AMT - cationic ligand interacts w/ cell surface binding site → transcytosis
What cells move across the BBB via mononuclear cell migration?
Immune cells.
Diapedesis.
How many PMNs and monocytes enter the brain?
Diapedesis by following inflammatory signals released by microglial cells
What is the significance in transporters in multidrug resistance? Give a specific example.
ABC1 (MDR1) transporter extrudes lipophilic substances before they can interact with the neuronal microenvironment e.g. cholesterol
E.G. Phenytoin used to treat epilepsy is more lipophilic than nicotine or ethanol but has a lower extraction into the CSF because it gets pumped back out by an MDR1 transporter
What is the ventricular system?
The ventricular system in neuroanatomy is a set of four interconnected cavities known as cerebral ventricles in the brain. These ventricles contain cerebrospinal fluid (CSF), which is produced by the choroid plexus within the ventricles.
What cells line the ventricles in the brain and what is their function?
- Ependymal cells (a type of glial cells)
- They are involved in the production and regulation of CSF
At what sites, and by what mechanisms, is cerebrospinal fluid (a) produced and (b) absorbed?
a - Choroid plexus; secretion by ependymal cells
b - Absorbed into dural venous sinuses via arachnoid granulations in the subarachnoid space
What are the 3 key interfaces separating the brain and CNS from the body?
*BBB
*Blood-CSF barrier
*Arachnoid barrier
What is the BBB
Blood-brain barrier (BBB) - main
*formed by microvascular endothelial cells lining cerebral capillaries that penetrate brain + spinal cord.
*Largest interface for blood-brain exchange (combined SA 12-18 m2 in adults)
*All brain cells at least 25 μm from capillary
What is the Blood-CSF barrier?
Blood-CSF barrier (BCB)
*Formed by epithelial cells of choroid plexus
*Control CSF secretion into ventricular brain system.
*Regulation of substance movement between blood + CSF
What is the arachnoid barrier?
Arachnoid barrier - Avascular arachnoid epithelium underlying dura matter.
*Dura mater → covers CNS. *Completes seal between ECF of CNS and rest of body.
*Avascular → insignificant exchange between blood + brain
*Small SA compared to other barriers.
BBB
How does the vasculature respond to an increase in metabolic demand of nearby neural tissue? How is this action achieved?
DILATE to increase blood flow and reduce the chance of ischaemia. Achieved via action of PERICYTES which act as contractile and phagocytic cells
How does the CSF exit the ventricle system?
Through the Foramen of Magendie and Foramen of Luschka (from the fourth ventricle) into the subarachnoid space (around both the brain and the spinal cord).
