Blood-brain barrier

K K Jain MD (

Dr. Jain is a consultant in neurology and has no relevant financial relationships to disclose.

Originally released August 10, 1998; last updated November 1, 2020; expires November 1, 2023


The blood-brain barrier is a dynamic conduit for transport between blood and brain of those nutrients, peptides, proteins, or immune cells that have access to certain transport systems localized within the blood-brain barrier membranes. Designed to protect the brain from harmful agents, it is also a barrier to CNS therapeutics. This article examines the anatomy and physiology of the blood-brain barrier as a basis for understanding neurologic disorders and for strategies to deliver therapeutics to the brain. Various transporter systems in the blood-brain barrier play an important role in the exchange of nutrients and can be utilized for drug delivery. Impaired blood-brain barrier in malignancies, trauma, and infections can be used to facilitate the passage of therapeutic agents. Methods for the assessment and modulation of the blood-brain barrier are also described.

Key points


• The blood-brain barrier is an important conduit of nutrients and cells from the blood to the brain.


• It also has an important function in protecting the brain from the entry of harmful substances.


• Knowledge of impairment of permeability of the blood-brain barrier in various neurologic disorders is important in understanding the pathomechanisms and devising strategies for management.


• Permeability of the blood-brain barrier is manipulated for drug delivery to the brain.

Historical note and terminology

For over a century it has been recognized that the entry of certain substances into the brain is restricted. The old concept of the blood-brain barrier as a passive, impermeable barrier that segregates blood and brain interstitial fluid is giving way to the idea that the blood-brain barrier is a dynamic conduit for transport between blood and brain of those nutrients, peptides, proteins, or immune cells that have access to certain transport systems localized within the blood-brain barrier membranes. The historical evolution of knowledge concerning the blood-brain barrier is shown in Table 1.

Table 1. Historical Evolution of Knowledge about the Blood-Brain Barrier


Observation, concept, and comments


Aniline dyes injected intravenously were rapidly taken up by all the organs except the brain (Ehrlich 1885).


Coining of the term blood-brain barrier to describe the phenomenon (Lewandowski 1900).


Expansion of the original blood-brain barrier concept by the demonstration that intrathecal administration of trypan blue results in a generalized staining of the brain tissue, whereas intravenous application does not. Hypothesis put forward that the vehicle for substance transport was the CSF, which allegedly gained access to the brain via the choroid plexuses (Goldman 1913).

1921 to 1922

Intracerebral distribution of various substances was observed. "Barriére hémato-encephalique" was defined as a cerebral blood vessel compartment in which choroid plexus was semipermeable, facilitating the flow of substances from the blood into the CSF (Stern and Gautier 1921; Stern and Gautier 1922).


Showed defects in the blood-brain barrier in brain diseases and demonstrated transient opening or disruption of the blood-brain barrier after intracarotid arterial administration of hypertonic solutions (Broman 1941).


Electron microscopy showed lack of extracellular fluid compartment in the gray matter, and this was given as an explanation of the failure of tracers to enter the brain. This was later shown to be an artifact in 1960s.


Further electron microscopy studies on "freeze-substituted" tissue demonstrated extracellular fluid in the cortex (van Harreveld 1966).


Tight junctions between brain endothelial cells established as the location of the blood-brain barrier (Reese and Karnovsky 1967).


Blood-brain barrier permeability to hexoses, amino acids, and amines demonstrated by radiolabeled substances (Oldendorf 1971).


Description of the "sink effect" gradient favoring the passage of substances in extracellular fluids from brain to CSF with the CSF constantly circulating and carrying substances away (Davson 1978).


Studies in molecular biology of the blood-brain barrier. Cloning and sequencing of glucose transporter gene (Weiler-Guttler et al 1989).

Other neural barriers are the blood-cerebrospinal fluid barrier, the blood-retinal barrier, the blood-labyrinth barrier, and the blood-nerve barrier, which is applicable only to the peripheral nervous system. The blood-brain barrier has been much more extensively investigated than the blood-nerve barrier. Several enzymes, transporters, and receptors have been investigated at both the blood-nerve barrier and blood-brain barrier, as well as in the perineurium of peripheral nerves, which is also a metabolically active diffusion barrier. A neurovascular unit, consisting of endothelial cells, neurons, and glia, regulates the blood-brain barrier. Knowledge of the blood-brain barrier is important in neurology for the following reasons:


• Understanding of brain function
• Pathophysiology of neurologic disorders
• Drug delivery to the brain

An understanding of specific interactions between the brain endothelium, astrocytes, and neurons that may regulate blood-brain barrier function and how these interactions are disturbed in pathological conditions could lead to the development of neuroprotective and restorative therapies.

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