The Blood Brain Barrier - WIP Flashcards
What is the Blood Brain Barrier?
A selective barrier separating blood circulation from brain tissue, formed by brain capillary endothelial cells (BCECs) with tight junctions.
The BBB:
Maintains homeostasis of the brain, prevents harmful substances/toxins and pathogens from entering the CNS, and limits delivery of therapeutic drugs to CNS. poor BBB penetration applies to 98% of new small molecule drugs and nearly 100% of large molecule drugs
What are the cells of the BBB?
Endothelial cells
Pericytes - embedded in the basement membrane lining blood capillaries. Regulate blood flow, angiogenesis (formation of new vessels) and maintain the BBB
Astrocyte end-foot - glial cells that maintain homeostasis within nervous tissue, and maintain the BBB
Efflux transporters – blood side of endothelial cells
Nutrient transporters – down concentration gradient, into the brain
What are some CNS diseases affected by the BBB?
Alzheimer’s disease – BBB becomes dysfunctional, allowing amyloid-beta to accumulate. Increased permeability contributes to neuroinflammation
Parkinson’s disease – Direct dopamine therapy is ineffective due to BBB. Levodopa crosses the BBB via LAT1 transporters and is converted to dopamine in the brain
Brain tumors – partially disrupted BBB in tumor areas, limits chemotherapy drug penetration
Epilepsy – BBB dysfunction leads to increased inflammation and seizure activity. Efflux transporters contribute to drug-resistant epilepsy
What are the drug challenges that come with the BBB?
Blocks most hydrophilic drugs to tight junctions, some essential hydrophilic molecules (e.g. amino acids, glucose) cross via transporters
Large molecule entry is limited, efflux transporters actively pump drugs out of brain which increases drug dosage needed and therefore increases risk of side effects
Enzymatic barrier – limits CNS drug effectiveness by breaking down certain drugs before they reach their target, found here as there are various enzymes highly expressed in BCECs
Efflux barrier – several energy-dependent efflux transporters are present in the BBB, the BBB efflux pumps are transmembrane P-glycoprotein and multidrug resistance-associated proteins
How do you improve the permeation across the BBB?
Coupling a substance that does not cross the BBB to a substance that does
Nanoparticle-based drug carriers loaded with drugs and decorated with ligands that transport across the BBB
Case studies? *
