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  • Apo: apolipoprotein

  • ATP: adenosine triphosphate

  • AUC: area under the concentration-time curve

  • BBB: blood-brain barrier

  • BCRP: breast cancer resistance protein

  • BCSFB: blood–cerebrospinal fluid barrier

  • CSF: cerebrospinal fluid

  • fu,brain: unbound fraction of drug in brain homogenate

  • fu,plasma: unbound fraction of drug in plasma

  • FUS: focused ultrasound

  • IR: insulin receptor

  • ISF: interstitial fluid

  • Kp,uu,brain: partition coefficient of unbound drug in brain interstitial fluid to that in plasma

  • Kp,uu,cell: partition coefficient of unbound drug between intracellular and interstitial fluids

  • LDLRf: low-density lipoprotein receptor family

  • MRP: multidrug resistance protein

  • PET: positron emission tomography

  • PS: permeability surface area product

  • RMT: receptor-mediated transcytosis

  • Tf: transferrin

  • TfR: transferrin receptor

  • Vu,brain: unbound volume of distribution in the brain; i.e., partitioning of total drug to that unbound in the brain interstitial fluid


For a drug to be active, it must reach a certain concentration in the target tissue. The central nervous system (CNS) possesses a series of barriers that separate the neural tissue from the periphery. These barriers act to stringently regulate the movement of ions, molecules, and cells between peripheral fluids (i.e., blood) and the CNS, thus tightly regulating the extracellular environment of the CNS, which is critical to maintain homeostasis. The barriers not only control the influx of glucose and essential nutrients but also greatly limit the entry of many exogenous compounds, including drugs. The pharmaceutical industry has struggled with developing drugs that can cross these barriers and enter the brain without requiring high doses that give unwanted peripheral side effects or are too costly. For large-molecule drugs like antibodies, this problem is greater since larger molecules have an even lower ability to cross brain barriers.

The brain barriers include the blood vessels that vascularize the CNS parenchyma, the meningeal covering of the brain, and the choroid plexus within the ventricles (Figure 17–1).

Figure 17–1

Schematic representation of the major brain barriers. Top right is a schematic of a cross-section through the meningeal coverings of the brain depicting the major meningeal barrier sites including the arachnoid barrier between the dura and the subarachnoid space and the vascular barrier possessed by the blood vessels within the subarachnoid space. Bottom left is a schematic of a cross-section through the choroid plexus that sits within the brain ventricles, depicting the choroid plexus epithelial cells that form the blood-CSF barrier between the leaky fenestrated vessels within the choroid plexus and the CSF within the ventricles. Bottom right depicts a cross-section of a parenchymal capillary that forms the BBB.

The barriers are especially important to insulate the neurons from ionic fluctuations, such that the neurons can maintain appropriate ion gradients required for neural circuit function. The brain barriers also protect the CNS from toxins, pathogens, and even the body’s own immune system, ...

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