blood-brain barrier
The blood-brain barrier. Credit: Shutterstock

A team of researchers published a literature review in Multiple Sclerosis and Related Disorders concerning multiple sclerosis and the importance of developing drugs that can cross the blood-brain barrier (BBB) into the central nervous system (CNS). 

Their review starts on a sobering note: “the etiology of multiple sclerosis remains unknown,” although existing literature suggests that it is an “immune-mediated disease in which both genetic and environmental factors contribute.” 

To develop therapies that do a better job of addressing the key features of multiple sclerosis, it is important to first be acquainted with them. The researchers of this study provided a handy list, with the first being the most important for the purpose of our discussion: 

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  • Breakdown of the BBB
  • Loss of oligodendrocytes
  • Multifocal inflammatory lesions
  • Reactive gliosis
  • Loss of neurons
  • Demyelination
  • Axonal damage 

The BBB serves to protect the CNS against foreign pathogens; in healthy individuals, the BBB plays a crucial role in maintaining homeostasis and regulating immune function. However, the BBB also locks drugs out of the CNS; it is estimated that 98% to 100% of small and large molecules are prevented from entering the CNS through the BBB. 

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In multiple sclerosis, the breakdown of the BBB means that it becomes more permeable and lets in autoreactive lymphocytes. When these lymphocytes are reactivated by microglia cells acting as antigen-presenting cells, inflammation in the CNS occurs. Despite the breakdown of the BBB in multiple sclerosis, studies have shown that this does not improve CNS penetration of therapeutic molecules. 

Disease-Modifying Therapies Crossing the BBB

Disease-modifying therapies (DMTs) are created to impede the pathological immune responses in the CNS and to halt disease progression. Unfortunately, many of them lack the ability to cross the BBB, “thus leaving a knowledge gap about the ability of DMTs to exert a direct effect within the CNS,” according to the authors of this review. 

As we have mentioned, neuroinflammation is believed to be driven by local mechanisms within the CNS. Yes, there is still much that we do not know about these local mechanisms. However, we do know that fewer peripheral cells are detected in brain lesions as multiple sclerosis worsens; in contrast, resident cells located within the CNS, such as astrocytes and microglial cells, are implicated in the pathogenesis of multiple sclerosis. 

In other words, we know that the pathological processes driving multiple sclerosis take place in the CNS. To target pathological sites within the CNS, medical researchers must develop DMTs that have the means to cross the BBB and initiate repair. Due to the inability of current DMTs to cross the BBB, it is presumed that they act on cytokines at the periphery that are able to cross the BBB, which in turn modifies activity taking place in the CNS. 

Strategies to Cross the BBB 

The attention of medical researchers is now turning towards helping DMTs cross the BBB, with the expectation that this will increase their potency. The theory is that once DMTs cross the BBB into the CNS, they can then distribute within the interstitial space and brain cells. 

One of the initial strategies to help DMTs cross the BBB is to increase their lipid solubility. Recently, the focus has shifted towards using the various receptors (such as transferrin) and transport proteins of the BBB to gain entry into the CNS.

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There have also been studies looking into using colloidal delivery systems, such as nanoparticles and liposomes, to gain entry into the CNS. In theory, these systems should allow significant concentrations of drugs to be incorporated into the delivery vectors to cross the BBB. An example of this is the use of monoclonal antibodies attached to liposome-drug complexes; these are recognized as ligands by the BBB and are thus allowed to pass through. 

Another strategy for drug delivery across the BBB is to inhibit efflux transport mechanisms. Essentially, this is a mechanism to retain the net uptake of drug molecules across the BBB. Efflux transporters work by transporting molecules out of the cell; inhibiting these transporters therefore helps to prevent the removal of drug molecules from the CNS. This strategy does come with a notable risk: inhibiting efflux transporters for long periods of time may cause the accumulation of neurotoxins within the CNS. 

The BBB: Mystery and Wonder 

The BBB is a subject of intense study because it may hold the key to addressing a number of CNS-related disorders. Looking at the bigger picture, the BBB is a remarkable feat of engineering. Wong et al published a paper looking at the BBB from an engineering perspective, offering mathematical formulas of how transport across the BBB works. 

The BBB inspires both mystery and wonder – it is the guardian of the CNS, but its stubborn resistance to DMTs presents a unique problem to medical researchers. While there is a basic understanding of how the BBB functions, our inability to develop drugs that permeate the BBB without causing harm shows that more studies need to be carried out. If there is a consensus around the BBB, it is that we still have a long way to go to unlock its secrets. Continued research will undoubtedly help us get there faster. 


Correale J, Halfon MJ, Jack D, Rubstein A, Villa A. Acting centrally or peripherally: a renewed interest in the central nervous system penetration of disease-modifying drugs in multiple sclerosis. Mult Scler Relat Disord. Published online September 14, 2021. doi:10.1016/j.msard.2021.103264

Wong AD, Ye M, Levy AF, Rothstein JD, Bergles DE, Searson PC. The blood-brain barrier: an engineering perspective. Front Neuroeng. 2013;6:7. doi:10.3389/fneng.2013.00007