Barriers of the CNS Flashcards
How is the tightness of the BBB maintained?
- Tight junctions (adherens junctions)
- Pericyte
- Astrocyte end foot
List pathways across the BBB
- Paracellular aqueous pathway (water soluble agents)
- Transcellular lipophilic pathway (lipid soluble agents)
- Transport proteins (glucose, amino acids)
- Receptor mediated transcytosis (insulin, transcytosis)
- Adsorptive transcytosis (albumin, other plasma proteins)
List barrier interfaces
- Neurovascular unit
- Choroid plexus (blood-CSF barrier)
- Meninges (arachnoid barrier)
- Neuropendyma (fetal CSF brain barrier)
- Adult ependyma (free exchange)
Describe CSF circulation
- Secreted by choroid plexus in each lateral ventricle
- Flows through the interventricular foramina into the third ventricle
- Choroid plexus in third ventricle adds more CSF
- CSF flows down cerebral aqueduct to fourth ventricle
- Choroid plexus adds more CSF
- CSF flows down the central canal of the spinal cord and into the subarachnoid space via two lateral apertures and a median aperture
- CSF fills subarachnoid space
- CSF reabsorbed into venous blood of dural venous sinuses at arachnoid villi
Compare the young and old BBB
- Young tight junctions
- Aged: pericyte loss, shift from RMT to caveolar transcytosis, dysregulated plasma uptake and reversible transport shift
Describe route through the BBB in infection
- Transcellular route, damage endothelium
- May be from infected contagious tissue (eg. nasal cavity)
- Neuroinvasion (via. nerves)
Describe inflammation in the CNS
- Once regarded as immuno privileged, but now we know CNS can be subjected to inflammation
- In particular, pericytes, perivascular macrophages and microglia are important
- Microglia reseal the endothelial cells, though in some cases they will make the BBB more permeable . Activated T cells can then enter the subarachnoid space
Describe effects of peripheral inflammation in the CNS
- Sickness behaviour
- Triggering or worsening neurodegenerative events and priming the microglia
Communication occurs by:
- PAMPS (pro inflammatory cytokines) can enter the brain through CVO
- Sensing of peripheral events by BBB components
- Peripheral afferent nervous termini (eg. vagus nerve)
List pathological situations where BBB breakdown occurs
- Stroke
- Trauma
- Infections
- MS
- HIV
- Alzheimer’s
- Parkinson’s
- Epilepsy
- Brain tumours
- Pain
Describe pharamacological approach to cross BBB
- The ability of a drug to pass the BBB depends on the molecular size being less than 500D, charge(low hydrogen binding capabilities) and lipophilicity (the more lipophilic, the better the transport)
- This approach consists of modifying, through medicinal chemistry,
a molecule that is known to be active against a CNS target to enable it to penetrate the BBB - Epilepsies-Drugs Acetazolamide, Carbamazepine, Clobazam,
Clonazepam, Eslicarbazepine acetate, Ethosuximide,
Gabapentin, Lacosamide - Glaucoma where an INCREASED pressure in the eyes is controlled/treated with TIMOLOL
Describe physiological approach of crossing BBB
At the moment the most successful the use of the low lipoprotein
receptor related protein (LRP) Receptor-mediated transcytosis.
- Lipophilic Analogs (Delivery of poorly lipid-soluble molecules, osmotic opening of the BBB)
- Prodrugs (solubility and permeability- GABA, Levopoda, valproate)
- Receptor mediated drug delivery
(Chimeric peptide technology-conjugation of drugs with antibodies)
- Carrier Mediated Drug Delivery (colloidal carriers: liposomes, nanoparticles)
