Clinical significance of BBB Flashcards
What is the structure of the BBB?
- Capillary endothelial cells in brain and spinal cord differ to those in the peripheral tissues :
Brain- joined by tight junctions of high electrical resistance - provides an effective barrier against molecules except water and gases
- Periphery - have gaps, through ehich water, ions and molecules up to the size of large proteins can easily diffuse
What are examples of areas of the brain without a BBB?
- The circumventricular organs
Area postrema, chemoreceptive area - Water balance and other homeostatic functions
- Sensses toxins in blood and triggers nausea/vomiting
- Posterior pituitary gland
- to allow passage of hormones (oxytocin,vasopressin etc into circulation
- Median eminence of hypothamus = connects hypothalamus to pituitary gland
- Lack of barrier allows secretion of regulatory hormones into bloodstream
What is the function of the BBB?
- Neurones and astrocytes = packed tightly
Cells are separated by only ~20% of brain volume - Small changes in extracellular fluid composition can affect neronal activity
- Needs tight control
- maintains brain homeostasis and optimal conditions for neuronal function
- Protects brain against surging fluctuations in plasma ion concentrations
- Restricts entrance of potentially harmful macromolecules (albumin, prothrombin, plasminohen and neurtoxic substances from diet/environment
- Allows selective transport of essential nutrients into brain
What factors affect whether or not compunds pass into the brain?
- Tight junctions prevent paracellullar transport of water soluble molecules
- Transporters regulate nutrients ( e.g. glucose) and ion transport
- Gases diffuse readily
- Water is transported by an aquarion
- Passive diffusion
- Substrate for transporter (s)
- Allow in
- Push out
- Metabolism
- Transcytosis
What are the physiological implications of BBB?
- Central chemoreceptors do not directly detect the arterial CO2 tension rather they detect changes in CSF pH
- Arterial CO2 diffuses through BBB into CSF
- Carbonic anhydrase converts CO2 to carbonic acid
- This decreases CSF pH
What is the impact of the BBB on drug delivery to the brain?
- Small, uncharged and lipid-soluble molecules cross readily
- E.g. ethanol, caffeine, nicotine, heroin and methadone
- Hydrophillic compounds are almost universally excluded from the brain (gentamicin)
What is the impact of the BBB on drug delivery to the brain (enzymes)?
- Central capillaries express enzymes that degrade certain chemicals (e.g. peptidases,acid hydrolases, monoamine oxidase
- Break down ekephalins, noradrenaline, dopamine
What is the impact of the BBB on drug delivery to the brain (transporters and pumps)?
- Transporter proteins : used for amino acids, glucose etc
- Solute carrier superfamily (SLC) - Don’t directly use ATP or couple to electron transport - facilitated diffusion (transporters for glutamate, glucose, nucleosides, ions, exchangers
-ATP-binding cassette transporters (ABC) - Active transport
E.g P-glycoproteins, multi-drug resistance proteins (MDRs)- have broad specificty
some drugs use these transporters to get in e.g. system L (heterodimer of SLC7A8 and SLC3A2)
- Transports :
L-DOPA (Parkinson’s disease)
Baclofen (for spasticity)
Gabapentin (for chronic pain and epilepsy)
What was the impact of the BBB on drug delivery to the brain : efflux pumps?
- Some drugs are extruded from the brain by
transporters — these are efflux pumps - Members of ABC (ATP-binding cassette) transporter superfamily e.g. P-glycoprotein, Multi Drug Resisant proteins, breat cancer resistance protein
- Actively transport range of lipid-soluble compunds out of brain
- Vital neuroprotective and detoxifying function
- Clinical consequences = minimal effectiveness of some drugs in some patients (e.f.)
- HIV drugs in AIDS dementia
- Anti-bacterials in CNS infections
- Anticonvulsants in epilepsy
- Chemotherapy on brain tumours
- P-glycoproteins
- Loperamide (antidiarrhoeal agent, potent opioid)
- Domperidone vs haloperidol
- HIV protease inhibitors e.g. Tenforvir, ritonavir, atazanavir
- Multidrug resistance (MDR) - associated protein
- first non-P-glycoprotein MDR conferring transporter identified
- Transports wide range of compounds e.g. many chemotherapy and anti-HIV agents out of brain
What is the relationship between disease and the BBB : inflammation?
- Inflammation can drastically increase access of drugs to the brain
- Bacterial protein lipopolysaccharide can increase permeability of BBB
- Plasma and cerebrospinal fluid concentrations of an antibiotic (thienamycin) following an IV dose.
What is the relation beween strokes and the BBB?
Relationship between disease & the BBB:
Stroke
* cerebral ischaemia following e.g. stroke; cardiac/respiratory arrest;
carbon monoxide poisoning involves loss of blood flow plus depletion of
oxygen & essential nutrients
* in vitro models of BBB indicate that hypoxia & hypoxia/reoxygenation
lead to increased permeability and/or disruption of BBB tight junctions
* hypoxic stress may also increase permeability via transcellular route
* probably involved in progression of ischaemic brain injury
What is the relationship between trauma and the BBB?
- Bradykinin produced
- Stimulates production and release of IL-6
- Opening of BBB
What is the relationship between disease and the BBB?
- HIV
- Alzheimer’s disease
- Parkinson’s disease
- Epliepsy
- Brain tumours
- Inflammatory pain
What are ways to get drugs across the BBB?
Ways to get drugs across the BBB:
Nanoparticulate delivery systems
* TCNS drug penetration by incorporating drug into biodegradable polymers 10nm + diameter
* provide protective envelope for hydrophobic drugs or peptides to hide inside
* provides vehicle which carries normally impermeant drug across BBB
* via receptor/adsorptive mediated endocytosis or uptake by monocytes or macrophages
* some nanoparticles don’t cross BBB themselves but stick to capillaries in brain & give drug longer time to diffuse across
* work ongoing to establish mechanisms & optimise delivery system for wide range of drugs
Nanoparticulate delivery systems
What are future develops in drug transport of the BBB?
Ways to get drugs across the BBB: future
developments
* development of novel & specific inhibitors of efflux pumps -
CAUTION!!
* design of drugs with reduced affinity for efflux transporters
* e.g. ceftriaxone & imipenem
* designing drugs that are recognised by endogenous BBB transport
systems “Trojan horses” to “smuggle” drug cargo across
* using exosomes - tiny lipid bilayer-bound bubbles produced in cells -
body’s own transport vehicles
