W 81 Xwh -‐ 11 -‐ 1 -‐ 0767

The views, opinions and/or findings contained in this report are those of the author(s) and should not be construed as an official Department of the Army position, policy or decision unless so designated by other documentation. Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. 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. Abstract Objective: Research identified promising therapeutics in cell models of Amyo-trophic Lateral Sclerosis (ALS), but there is limited progress translating effective treatments to animal models and patients, …