High expression levels, multispecificity, and high transport potency makes the P-glycoprotein a selective gatekeeper of the brain and blood-brain barrier and thus a primary obstacle to drug delivery in the CNS. As such, P-glycoprotein limits CNS entry of a large number of drugs and xenobiotics, contributes to the poor success rate of CNS drug candidates, and probably contributes to patient-to-patient variability in response to CNS pharmacotherapy. Modulating P-glycoprotein could therefore improve drug delivery into the CNS and drug therapy. Here, we propose to validate this concept in the context of ALS therapy. By following both genetic and pharmacologic approaches to obliterate the action of P-gp we will evaluate the therapeutic efficacy of nordihydroguaiaretic acid (NDGA) to the SOD1-G93A transgenic mouse model of ALS. We identified NDGA as a potent and specific glutamate transport activity enhancer in a cell-based screen for ALS;clinical testing in the SOD1-G93A mice indicated that its potential therapeutic efficacy could have been hampered by a disease-driven upregulation of P-gp transporters in the spinal cord. To further evaluate NDGA as candidate therapeutic we propose in Aim 1 to determine if genetic removal of P- glycoprotein-mediated pharmacoresistance will rescue NDGA-mediated glutamate uptake enhancing effect and therapeutic efficacy in a mouse model of ALS.
In Aim 2 we will determine if co-treatment of the ALS mice with NDGA and elacridar, a potent and selective inhibitor of P-gp, will therapeutically benefit the mice. If successful, these approaches not only will determine the true impact on the ALS phenotype of increasing glutamate clearance in ALS mice, but will also provide the rationale to reconsider many unsuccessful clinical trials that have been attempted in the SOD1-G93A mouse model of ALS in which the function of multidrug transporter proteins could have compromised a possible positive outcome.
Amyotrophic lateral sclerosis (ALS) is one of the most devastating and lethal progressive neuromuscular disorders. Over 30,000 people are living with ALS in the United States and approximately 5,000 Americans will be diagnosed with ALS this year. P-glycoprotein limits the entry into the brain and spinal cord for a large number of drugs and contributes to the poor success rate of drug candidates. Modulating P-glycoprotein could therefore improve drug delivery into the brain and spinal cord. Here, we propose to validate this concept in the context of ALS therapy. By following both genetic and pharmacologic approaches to obliterate the action of P-glycoprotein we will evaluate the therapeutic value of a potent glutamate transport enhancer drug, NDGA, to mice model of ALS. If successful, this approach not only will determine the true therapeutic impact of increasing glutamate clearance in ALS mice, but also will open new therapeutic venues for ALS and provide the rationale to reconsider many unsuccessful clinical trials that have been attempted in mice models of ALS in which the function of P-gp could have hampered a possible positive outcome.
| Jablonski, Michael R; Jacob, Dena A; Campos, Christopher et al. (2012) Selective increase of two ABC drug efflux transporters at the blood-spinal cord barrier suggests induced pharmacoresistance in ALS. Neurobiol Dis 47:194-200 |
