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

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.

Keywords: P-glycoprotein; amyotrophic lateral sclerosis; blood–brain barrier; pharmacoresistance; riluzole.

Fig. 1.

Schematic diagram showing changes in P-glycoprotein expression at the BBB in ALS

Fig. 2.

Suggested pathways that regulate P-gp expression at the BBB in ALS. TNF-α tumor necrosis factor-α, TNF-R1 tumor necrosis factor receptor-1, ET-R_B endothelin receptor-B, iNOS inducible itric oxide synthase, PKCB2 protein kinase C isoform β2, ROS reactive oxygen species, Nrf2 Erythroid derived 2 like-2, NFkB nuclear factor kappa-light-chain-enhancer of activated B cells, mdr1 multidrug resistance protein-1, P-gp permeability glycoprotein or P-glycoprotein