Alterations in drug efflux at the blood-spinal cord barrier in amyotrophic lateral sclerosis
Amyotrophic Lateral Sclerosis (ALS) is a slowly progressing neurodegenerative disease, characterized by selective motor neuron degeneration. Currently, there is only one FDA-approved treatment option, riluzole, which only modestly extends patient survival by approximately 3-6 months. ALS is a non-cell-autonomous disease with astrocytes contributing to toxicity and selective loss of motor neurons. The blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) are formed by endothelial cells in association with pericytes and astrocytes, forming the neurovascular unit. Astrocytic end-feet encapsulate approximately 90% of endothelial cells and maintain homeostasis of the barrier. ABC drug efflux transporters, highly localized in endothelial cells, prevent a wide range of neurotoxicants and therapeutics from entering the CNS. The studies presented in this thesis are aimed to test the hypothesis that ABC drug efflux transporters are altered in ALS leading to bioavailability issues of intended therapeutics. Furthermore, targeting the ABC drug efflux transporters will enhance treatment options and efficacy of ALS therapeutics. Initial studies characterized the alterations of ABC drug efflux transporters and reported a disease-driven increase in expression and function of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in ALS mouse spinal cord capillaries and expression increases in human spinal cord tissue, suggesting these transporters could mediate ALS pharmacoresistance. Due to the toxic contribution by astrocytes in ALS, we hypothesized that toxic astrocytes impart increases of ABC transporters in endothelial cells, leading to a decrease in bioavailability of therapeutics in the CNS. Astrocytes expressing ALS-causative mutations upregulated P-gp expression in endothelial cells, which is, at least in part, mediated by the transcription factor, NFkB. Finally, a preclinical drug trial was performed to examine the pharmacological blockade of P-gp and BCRP and the ability of transporter inhibition to enhance the effectiveness of riluzole. The combination therapy of riluzole and elacridar, a dual P-gp and BCRP inhibitor, significantly extended survival, improved behavior, and preserved physiological muscle function in the ALS (SOD1-G93A) mice compared to control ALS mice or ALS mice treated with riluzole alone.This study shows the relevance of pharmacoresistance and impact of altered bioavailability in the context of ALS. Moving forward, drug efflux alterations should be considered in preclinical and clinical studies of ALS.
Jablonski, Michael R, "Alterations in drug efflux at the blood-spinal cord barrier in amyotrophic lateral sclerosis" (2014). ETD Collection for Thomas Jefferson University. AAI3617736.