Rethinking Drug Treatment Approaches in ALS by Targeting ABC Efflux Transporters
Final rept. 30 Sep 2011-29 Sep 2014
THOMAS JEFFERSON UNIV PHILADELPHIA PA
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Despite multiple therapeutic efforts targeting a variety of underlying pathogenic mechanisms, approaches to cure the mouse the models amyotrophic lateral sclerosis ALS have failed. With the exception of Riluzole the only drug approved by the FDA for treatment of ALS, we have been unsuccessful at translating promising results from pre-clinical mouse trials to effective pharmacotherapies for ALS patients. One of the problems in finding highly efficacious treatments in ALS may derive from the so far underestimated issue of disease-driven pharmacoresistance mediated by the multi-drug resistance mdr efflux transporter, P-glycoprotein P-gp. These are proteins that are present at the blood and spinal cord brain barrier whose function is to protect the brain from xenobiotics including drugs. These proteins actively pump out from the nervous system CNS foreign substances. We have shown that in ALS, both in patients and in the ALS mice, there is an increased expression and activity of these efflux transporter P-gps and hypothesized that one of the problem in treating ALS derives from a disease-driven acquired pharmacoresistance due to increased P-gps. Riluzole, which only has a modest effect in patients, is a Pg-p substarate. Thus, it is plausible that administration of Riluzole in combination with a P-gp inhibitor could improve its therapeutic outcome. With this proposal we test the hypothesis that co-administration of Riluzole with a potent P-gp inhibitor Elacridar will enhance Riluzole bioavailability and therefore will improve its therapeutic efficacy the SOD1-G93A ALS mice.
- Medicine and Medical Research