The Blood Brain Barrier - WIP Flashcards
(10 cards)
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
only small molecules with a mass under 400-500Da and high lipid solubility can cross the BBB in pharmacologically significant amounts
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 (Trojan horse strategy)
Nanoparticle-based drug carriers loaded with drugs and decorated with ligands that transport across the BBB
Adeno-associated virus based gene therapy for Parkinson’s disease *
Adeno-associated virus (AAV) has minimal pathogenicity, are replication-defective, and have the ability to establish long-term gene expression in different tissues.
Recombinant AAV enhances specificity and is used to treat various diseased.
One common strategy is gene replacement therapy, where a functional copy of the faulty gene is introduced to living cells.
BBB disruption techniques
focused ultrasound - temporarily opens the BBB for drug entry
hyperosmotic agents - shrinks endothelial cells loosening tight junctions
Case study - issues with treating Schizophrenia
Patient diagnosed with schizophrenia. Symptoms persist after starting on Risperidone
Challenges of schizophrenia treatment - limited BBB penetration of antipsychotics, need to avoid efflux transporters
Strategies:
long acting injectables - provide steady drug levels, bypass first pass metabolism, and reduce plasma fluctuations
prodrug - modify drug structure to enhance BBB permeability then convert into active form in the CNS
Lipid based drugs - improved lipophilicity increases passive diffusion across BBB
Case study - issues with treating epilepsy
Patient with drug-resistant epilepsy, still experiencing seizures on Carbamazepine
challenges - needs to avoid efflux transporters (actively pumps drug out of brain), limited drug concentration reaches the CNS
Strategies:
Second generation AEDs less affected by efflux transporters due to fewer interactions
Surgical intervention - for refractory epilepsy
neuromodulation - vagus nerve/deep brain stimulation, adjunct for resistant cases
Case study - issues with treating brain tumours with chemotherapy
Challenges -
BBB restricts chemotherapy entry into brain tumour sites (tight junctions in BBB prevent large and hydrophilic molecules from crossing)
high interstitial fluid pressure in tumours creates barrier to diffusion, reducing drug accumulation
