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The brain, an inscrutable organ?

The brain is protected by four protective structures, each of which plays a very specific role:

  • The bones of the skull
  • The meninges
  • The cerebrospinal fluid (CSF)
  • The blood-brain barrier (BBB)

The bones of the skull1

The skull forms the external layer of the brain. The skull bones constitute the first solid barrier, protecting us in particular from impacts.

The cerebrospinal fluid barrier1 ,3

This fluid is the liquid in which the central nervous system (spinal cord and encephalon) bathes. Also called cerebrospinal fluid (CSF), it plays a metabolic role for the brain, supplying it with nutrients (vitamins, glucose or nucleotides through the blood). This back-and-forth “shuttle” function is made possible by the “barrier” formed by ependymal cells, which is extremely porous and is located at the interface between the cerebrospinal fluid and the brain.

In addition, it provides the brain with a second barrier that protects it against mechanical shock, as well as regulating intra-cranial pressure.

The meninges4

The meninges are layers that surround the nervous system. They form the brain’s most external protective barrier.

Located immediately underneath the bone structure, this barrier is divided into three protective layers:

  • An external layer that encapsulates the brain in a single structure, called the “dura mater.”
  • An intermediate layer called arachnoid, which is very selective, like the blood-brain barrier.
  • The deepest layer of the meninges, and the only one in contact with brain cells, known as the “pia mater”.

The blood-brain barrier2

Lastly, the blood-brain barrier is undoubtedly the most selective barrier of the “fortress” that is the brain. Among the four presented in this article, it is the only one that acts to protect against chemical damage. The role of this anatomical layer is to regulate the circulation of substances from the blood to the brain. To achieve such a task, it must be able to filter out any toxin before it reaches the brain. This role is therefore a double-edged sword, because it can prevent medications from reaching the brain to achieve therapeutic effect.


The blood-brain barrier has been estimated to span a total 650 km of brain capillaries!2

As you can see, penetrating the blood-brain barrier involves a highly regulated process. How then can we ensure that the medicines developed to treat brain conditions can readily cross this barrier to reach its target?

The passage of a substance for therapeutic use in the brain has been the subject of several years of active research. Several approaches have been tested.

Molecule size and composition

Very small molecules can cross the BBB more easily. For these molecules, the ratio between their concentration in the brain and their plasma concentration is higher. Referred to as brain-to-plasma concentration ratio, this indicator allows the degree of penetration of a molecule relative to another to be measured, among other things. Nonetheless, this measure is not sufficient for selecting a molecule designed to act on the brain. While it can tell us whether a drug readily crosses the BBB, it does not indicate the dosage required to reach its target safely.

Another method for improving the therapeutic efficacy of a molecule in the brain consists in increasing its lipid solubility level. This characteristic favors penetration of the BBB.

Direct administration to the cerebrospinal fluid

An alternative route of administration is called “intra-thecal injection” where a medicine is injected directly into the subarachnoid space located between the arachnoid mater and the pia mater.

By injecting the drug directly into the CSF, the drug can diffuse into the brain. This approach is used commonly in anesthesia and sometimes for certain chemotherapy agents.

Permeabilize the brain barrier using ultrasounds

Ultrasounds are another method for penetrating the blood-brain barrier. They can be used to temporarily disrupt the BBB at a specific point to allow the therapeutic molecule to reach the brain transiently.

Using a transporter molecule

In order to treat tumors or metastases located in the brain, one solution is to use the “Trojan horse”.

It involves identifying a “ligand”, i.e. a molecule with “affinity” to one of the BBB receptors5, in order to facilitate introduction of the therapeutic solution into the brain. Once it is in the intra-cephalic medium, the molecule can then be released and diffused in the brain.

The main advantage to using ligands, beyond their high level of absorption, is that they generally have a targeted action. Therefore, ligands enable the use of a less invasive approach, and reinforced efficacy.


“Treating the brain is one of the greatest scientific challenges and the potential for medical innovation is immense for patients. The challenge lies in finding the right balance between the therapeutic efficacy of a molecule, its brain penetration rate, and its safety profile.”

Islam Hassan Senior Medical Director, Late stage and Life cycle management, Servier.

[1] Un organe bien protégé – Le cerveau ( (consulted on March, 26th 2024) 
[2],-La%20barri%C3%A8re%20h%C3%A9mato&text=Elle%20intervient%20quotidiennement%20dans%20la,la%20composent%20(Figure%201) (consulted in April 2024)
[3] Brain Barrier4 you (consulted on March, 26th 2024)
[4] (consulté le 26/03/2024)