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How Critical Is the Blood-Brain Barrier to the Development of Neurotherapeutics?

Carmen Kut, BS1; Stuart A. Grossman, MD2; Jaishri Blakeley, MD2,3
[+] Author Affiliations
1Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, Maryland
2Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland
3Departments of Neurology and Neurosurgery, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland
JAMA Neurol. 2015;72(4):381-382. doi:10.1001/jamaneurol.2014.3736.
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This Viewpoint reports that the blood-brain barrier is thought to restrict access of therapeutic agents that may otherwise be effective against central nervous system diseases. However, there is controversy in the neurotherapeutics community about the degree to which this hypothesis is true.

The blood-brain barrier (BBB), with its charged, lipid-based, continuous basement membrane and specialized transporters, is optimized to exclude potentially threatening compounds from the central nervous system (CNS). In the setting of CNS diseases, the careful construction of the BBB is thought to restrict access of therapeutic agents that may otherwise be effective, contributing to poorer outcomes. However, there is controversy in the neurotherapeutics community about the degree to which this hypothesis is true; some argue that the BBB is not the critical factor because it naturally opens in the setting of brain pathology and that techniques to circumvent the BBB do not improve drug efficacy in many instances.1 Moreover, some drugs do not need direct access to brain tissue in order to have their therapeutic effect. For example, fingolimod and bevacizumab are effective in patients with multiple sclerosis and glioblastoma, respectively, although their primary mechanism of action is systemic. Additionally, in some brain tumors, achieving target drug concentrations in the brain either fails to show efficacy or, in fact, causes toxicity.2 In these instances, the factor impeding success of neurotherapeutics is clearly not the BBB.

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