CNS Disorders

Question 1

Disorders of the CNS can cause

Answer 1

Breakdown of the BBB

Question 2

What forms the BBB?

Answer 2

Tight junctions

Question 3

Barriers of the CNS

Answer 3

Arachnoid barrier
BBB
Blood-cerebrospinal fluid barrier

Question 4

Transport pathways across the BBB

Answer 4

Paracellular—aqueous
Transcellular—lipophilic
Transport proteins—glucose, AA, nucleosides
Efflux pumps
Receptor mediated transcytosis—insulin, transferrin
Absorptive transcytosis—albumin, plasma proteins
Cell mediated transcytosis—monocytes, liposomes

Question 5

How does the BBB prohibit transport?

Answer 5

1) physiochemical properties
—too large
—highly charged
—not lipophilic
2) multi-drug resistant transporters
—Pgp
—~50% all drugs
—upregulated in drug resistance

Question 6

Passive strategies for nanoparticle drug delivery

Answer 6

Diffusion

Question 7

Invasive approaches

Answer 7

Intracerebroventicular
Intrathecal
Intraparenchymal

Question 8

Intracerebroventricular

Answer 8

Infusion into lateral ventricles
Circulation of CSF throughout brain
More invasive/higher risk

Question 9

Intrathecal

Answer 9

Infusion into cisterna at site just below cerebellum, less commonly used clinically
Infusion into the lumbar region, commonly used in clinical sites with clinical trials ongoing

Question 10

Pros to invasive approaches

Answer 10

Targeted
Much experience
Great promise based on animal studies

Question 11

Cons of invasive approaches

Answer 11

Can be lethal
Less invasive than intraparenchymal (but still invasive)
Much experience (many failures)
Risk of infection

Question 12

Intraparenchymal Infusion

Answer 12

Micro infusion pump infuses through cannula
Targeted to brain parenchyma
Continuous positive pressure
Pressure gradient provides convective flow
Limitations:
—highly invasive
—diffusion barrier

Question 13

Diffusion barrier

Answer 13

Drugs must distribute through small brain extra cellular spaces for effect

Question 14

Disruption of the BBB

Answer 14

Osmotic disruption
Chemical disruption
Ultrasound disruption

Question 15

Osmotic disruption

Answer 15

Injection of high concentration of mannitol into carotid artery
Mannitol draws water from endothelial cells, resulting in shrinkage
Open tight junctions, allows for paracellular entry

Question 16

Chemical disruption

Answer 16

Vasoactive molecules: histamine, prostaglandins, bradykinin
Disrupt endothelial cell tight junctions
Not proven useful in trials

Question 17

Ultrasound disruption

Answer 17

Micro bubbles activated by focused ultrasound waves exerts a mechanical force
—MRI-guided
—Cavitation followed by sonoporation

Question 18

Disruption of BBB limitations

Answer 18

All carry risk of permanently damaging BBB
Risk of pathogens/harmful xenobiotics entering the brain
Serum albumin entry associated with seizures

Question 19

Most important factor limiting development of new CNS drugs

Answer 19

BBB