Selective increase of two ABC drug efflux transporters at the blood–spinal cord barrier suggests induced pharmacoresistance in ALS

Abstract

ATP-binding cassette (ABC) drug efflux transporters in the CNS are predominantly localized to the luminal surface of endothelial cells in capillaries to impede CNS accumulation of xenobiotics. Inflammatory mediators and cellular stressors regulate their activity. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of upper and lower motor neurons characterized by extensive neuroinflammation. Here we tested the hypothesis that disease-driven changes in ABC transporter expression and function occur in ALS. Given the multitude of ABC transporters with their widespread substrate recognition, we began by examining expression levels of several ABC transporters. We found a selective increase in only two transporters; P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) both at mRNA and protein levels, in the SOD1-G93A mouse model of ALS, specifically in disease-affected CNS regions. Detailed analysis revealed a similar disease-driven increase in P-gp and BCRP levels in spinal cord microvessels, indicating that their altered expression occurs at the blood spinal cord barrier. Transport activity of P-gp and BCRP increased with disease progression in spinal cord and cerebral cortex capillaries. Finally, P-gp and BCRP protein expression also increased in spinal cords of ALS patients. Preclinical drug trials in the mouse model of ALS have failed to decisively slow or arrest disease progression; pharmacoresistance imparted by ABC transporters is one possible explanation for these failures. Our observations have large implications for ALS therapeutics in humans and suggest that the obstacle provided by these transporters to drug treatments must be overcome to develop effective ALS pharmacotherapies.

In Vivo Imaging of Human MDR1 Transcription in the Brain and Spine of MDR1-Luciferase Reporter Mice

“…Ex vivo analysis of Pgp in rodent brain tissue found that BBB Pgp is induced by seizures (van Vliet et al, 2007) and in amyotrophic lateral sclerosis (Jablonski et al, 2012), and that phenobarbital induced Pgp only in the hippocampus of epileptic rats (van Vliet et al, 2007) (a phenobarbital induction pattern strikingly different from what we observed in MDR1-luc mice). MDR1-luc mice would permit in vivo analysis of the temporal effects of these disease states and their treatments on regional human MDR1 transcription.…”

Inhibiting drug efflux transporters improves efficacy of ALS therapeutics

“…Our prior observations showed that P-gp and BCRP function increased beginning at symptom onset and peaked at symptomatic stage,12 so we initiated the riluzole and elacridar treatment at onset (P100). In addition, we wanted to mimic, to the extent possible, the therapeutic regimen of the patients who are treated with riluzole after they are diagnosed with the disease.…”

Cross-Sectional Survey of Relevant Literatures as to the Current Proposed Disease Mechanisms and Treatments of Amyotrophic Lateral Sclerosis (ALS)

“…One proposed explanation for the failures of pharmacologic therapy has been an upregulation of ABC drug transporter proteins such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) both at mRNA and protein levels as seen in the SOD1-G93A mouse model. 164 This research clearly illustrates that a cellular resistance mechanism is being utilized to some degree and presents its own set of unique challenges in future treatment strategies.…”