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Summary Drug delivery across BBB
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Summary of 6 pages for the course Mpharm at UOM (both lectures)
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Drug delivery via BBBMain purposes of the BBB
maintain homeostasis of neuronal activity
good control of what can enter and leave the brain
hence a precise structure of blood vessels
What is the layout of blood vessels in the brain?
Brain has a complex vasculature
Carotid artery, vertebral artery and jugular vein surround the subarachnoid space
forming smaller capillaries
these branch out of the subarachnoid space and into the brain tissue
bringing nutrients to the brain tissue
What is the affect of capillaries on drug delivery in the BBB?
- Blood vessels have lower permability compared to other tissues
- Due to the presence of tight junctions
- Limits passive diffusion of drugs into the brain parenchyma
- However, there is high vascular density which allows opportunities for drug delivery
- But mostly tightly regulated
- Changes in blood flow can affect distribution and clearance of drugs
- Impacting their therapeutic efficacy
Main arteries in the brain
Carotid and vertebral
Main vein in the brain
Jugular vein: carries blood back to the heart
What is the subarachnoid space?
- Between arachnoid matter and pia matter
- Innermost membrane surrounding the brain and spinal cord
- Filled with cerebrospinal fluid: cushions the spinal cord and facilitates exchange of
nutrients and waste
What is sinuses?
Specialised cavaties or spaces within the skull
Drains venous blood and circulates cerebrospinal fluid
Effect of CSF on drug delivery in the brain
- CSF circulates the ventricular system and subarachnoid space
- Drugs administered into CSF can be rapidly distributed to brain
- E.g. via intrathecal injections
- Drugs can be transported in the CSF
- Can target the brainstem, cerebellum and spinal cord
- The CSF can receive drug from blood stream via large normal vessels in the
subarachnoid space
- But loses these drugs to large venous sinuses
, How do capillaries interact with other brain cells?
Astrocytes: star shaped glial cells, provide structural support, secrete molecules to regulate
tight junctions, regulates capillary diameter. E.g. via prostaglandins and potassium ions
Pericytes: regulates blood flow, signalling pathways with endothelial cells to influence
permeability and vascular tone, stabilizes capillary structure.
Neurons: capillaries supply oxygen and nutrients to neurons
Endothelial cells: primary barrier of BBB, interior surface of capillaries
Structure of capillaries
Closely packed endothelial cells
Tight junctions instead of fenestrations
These are smaller pores than fenestrations
Surrounding cells making junctions even tighter e., astrocytes, pericytes
Where are efflux pumps found?
Luminal surface of capillaries
Astrocyte foot processes
CSF subarachnoid membranes
What is the astrocyte foot process?
Astrocytes have specialized structures called astrocytic endfeet
Or astrocyte foot processes
Thin-sheet like extensions of the astrocyte cell body
Wrap around blood vessels
Forms a structural interface with capillaries
Releases signalling molecules here to open tight junctions
Altering blood vessel permeability
What is neurovascular coupling?
Regulates cerebral blood flow
Via releasing vasoactive substances
o Potassium ions or prostaglandins
Modulating the diameter of blood vessels
Done by astrocytic foot processes
What diseases impair BBB permeability? What occurs?
- Ischaemic stroke
- Haemorhhagic stroke
- These can result in hyperpermeability
- Increasing leakage of plasma proteins, immune cells and fluid
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