| First Author | Jablonski MR | Year | 2014 |
| Journal | Ann Clin Transl Neurol | Volume | 1 |
| Issue | 12 | Pages | 996-1005 |
| PubMed ID | 25574474 | Mgi Jnum | J:357697 |
| Mgi Id | MGI:7763898 | Doi | 10.1002/acn3.141 |
| Citation | Jablonski MR, et al. (2014) Inhibiting drug efflux transporters improves efficacy of ALS therapeutics. Ann Clin Transl Neurol 1(12):996-1005 |
| abstractText | OBJECTIVE: Research identified promising therapeutics in cell models of Amyotrophic Lateral Sclerosis (ALS), but there is limited progress translating effective treatments to animal models and patients, and ALS remains a disease with no effective treatment. One explanation stems from an acquired pharmacoresistance driven by the drug efflux transporters P-glycoprotein (P-gp) and breast cancer-resistant protein (BCRP), which we have shown are selectively upregulated at the blood-brain and spinal cord barrier (BBB/BSCB) in ALS mice and patients. Pharmacoresistance is well appreciated in other brain diseases, but overlooked in ALS despite many failures in clinical trials. METHODS: Here, we prove that a P-gp/BCRP-driven pharmacoresistance limits the bioavailability of ALS therapeutics using riluzole, the only FDA-approved drug for ALS and a substrate of P-gp and BCRP. ALS mice (SOD1-G93A) were treated with riluzole and elacridar, to block P-gp and BCRP, and monitored for survival as well as behavioral and physiological parameters. RESULTS: We show that riluzole, which normally is not effective when given at onset of symptoms, is now effective in the ALS mice when administered in combination with the P-gp/BCRP inhibitor elacridar. Chronic elacridar treatment increases riluzole Central nervous system (CNS) penetration, improves behavioral measures, including muscle function, slowing down disease progression, and significantly extending survival. INTERPRETATION: Our approach improves riluzole efficacy with treatment beginning at symptom onset. Riluzole will not provide a cure, but enhancing its efficacy postsymptoms by addressing pharmacoresistance demonstrates a proof-of-principle concept to consider when developing new ALS therapeutic strategies. We highlight a novel improved therapeutic approach for ALS and demonstrate that pharmacoresistance can no longer be ignored in ALS. |
