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Blood–Brain Barrier Driven Pharmacoresistance in Amyotrophic Lateral Sclerosis and Challenges for Effective Drug Therapies

  • Review Article
  • Theme: CNS Barriers in Health and Disease
  • Published:
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Abstract

The blood–brain barrier (BBB) is essential for proper neuronal function, homeostasis, and protection of the central nervous system (CNS) microenvironment from blood-borne pathogens and neurotoxins. The BBB is also an impediment for CNS penetration of drugs. In some neurologic conditions, such as epilepsy and brain tumors, overexpression of P-glycoprotein, an efflux transporter whose physiological function is to expel catabolites and xenobiotics from the CNS into the blood stream, has been reported. Recent studies reported that overexpression of P-glycoprotein and increase in its activity at the BBB drives a progressive resistance to CNS penetration and persistence of riluzole, the only drug approved thus far for treatment of amyotrophic lateral sclerosis (ALS), rapidly progressive and mostly fatal neurologic disease. This review will discuss the impact of transporter-mediated pharmacoresistance for ALS drug therapy and the potential therapeutic strategies to improve the outcome of ALS clinical trials and efficacy of current and future drug treatments.

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Acknowledgements

This work was supported by the National Institutes of Health (grant number RO1-NS074886 to DT) and Target ALS (to DT and PP).

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  1. Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University Hospitals, 900 Walnut Street, Philadelphia, Pennsylvania, 19107, USA

    Loqman A. Mohamed, Shashirekha Markandaiah, Silvia Bonanno, Piera Pasinelli & Davide Trotti

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  1. Loqman A. Mohamed
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  2. Shashirekha Markandaiah
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Mohamed, L.A., Markandaiah, S., Bonanno, S. et al. Blood–Brain Barrier Driven Pharmacoresistance in Amyotrophic Lateral Sclerosis and Challenges for Effective Drug Therapies. AAPS J 19, 1600–1614 (2017). https://doi.org/10.1208/s12248-017-0120-6

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