Helper Drug Boosts Response to Riluzole in ALS Mice

People with amyotrophic lateral sclerosis have one treatment option approved by the Food and Drug Administration: riluzole, which extends life by only a few months. A study in the November 21 Annals of Clinical and Translational Neurology online suggests the drug might be more powerful if it had a pharmacological sidekick. Combining riluzole with a drug called elacridar improved muscle function and lengthened the lifespan of ALS model mice compared with riluzole treatment alone. Researchers are already considering a clinical trial of the new combo, said Piera Pasinelli, a co-senior author of the paper. She and colleagues at Thomas Jefferson University in Philadelphia also suspect that elacridar, or similar treatments, might help other potential ALS drugs work better.

Excess Efflux: In people with ALS (bottom), lumbar spinal cord endothelial cells expressing von Willebrand factor (green) contain more of the molecular transporter pump P-glycoprotein (red) than do the same cells from neurologically healthy controls (top). [Image courtesy of Jablonski et al., 2014.]

Elacridar blocks the ATP-binding cassette (ABC) transporters P-glycoprotein and breast cancer resistance protein (BCRP, so named because it was first discovered in the context of breast cancer). Embedded in the endothelial cells of the blood-brain barrier, these molecular pumps eject toxins and foreign chemicals from the nervous system. Unfortunately, they often kick out useful drugs, too. This is the bane of drug developers, limiting efficacy of medications for a variety of conditions, including epilepsy, HIV, and cancer (reviewed in Löscher and Potschka, 2005). Clinical trials to see if elacridar could boost retention of chemotherapeutics found that the drug was safe, though it has not yet been approved by the FDA, Pasinelli said.

Scientists in the neurodegeneration field have, for the most part, been less concerned with drug efflux, said researchers who spoke with Alzforum. “In terms of mainstream ALS research, this is the first time that [these transporters] have come to my attention,” commented Brett Morrison of Johns Hopkins University in Baltimore, who was not involved with the study. First author Michael Jablonski, who recently moved from the laboratory of co-senior author Davide Trotti at Jefferson University to Assurex Health of Mason, Ohio, added, “People are just starting to look at these transporters in Alzheimer’s and Parkinson’s.”

Trotti first discovered that efflux pumps might be an issue in ALS in 2008. He was studying a potential therapeutic, nordihydroguaiaretic acid (NDGA), which enhanced glutamate uptake by spinal cord synapses in wild-type mice but not in ALS model mice expressing mutant superoxide dismutase 1. The researchers suspected that upregulation of the ABC transporter, P-glycoprotein (P-gp), was to blame. NDGA treatment enhances P-gp activity in vesicles, suggesting the drug could be a cargo for the transporter (Boston-Howes et al., 2008).

Following up on that paper, Jablonski observed that in addition to BCRP, P-gp was upregulated in the spinal cords of ALS mice (Jablonski et al., 2012). Moreover, he saw increased levels of P-gp (see image above) and BCRP in spinal cords of people who died of ALS. The work suggests, although it has not proven, that as people with ALS get sicker, their nervous systems could start rejecting medications. The researchers are still trying to work out what causes the upregulation of P-gp and BCRP during ALS. Jablonski suspects neuroinflammation.

Simply upping the riluzole dosage has not helped, the authors point out, and could be toxic to the liver (Traynor et al., 2006; Bruno et al., 1997). They prefer trying to inhibit P-gp and BCRP, which might increase riluzole levels in the nervous system without damaging the rest of the body. Both P-gp and BCRP pump riluzole out of cells (Milane et al., 2007; Milane et al., 2009), but elacridar blocks that transport.

Jablonski and colleagues treated mice with riluzole alone or with elacridar and riluzole. To mimic the human treatment situation, Jablonski waited until the animals were 100 days old, when symptoms start. However, Pasinelli said, riluzole alone works poorly in mice when started this late in the game; and not all studies show benefit from it (Scott et al., 2008). The scientists predicted the elacridar would increase spinal cord concentration of riluzole, and sacrificed the animals after 40 days of treatment to find out. Mass spectrometry confirmed that elacridar tripled the amount of riluzole in the spinal cord of the mice.

The addition of elacridar also slowed the disease in a separate experiment with 25 animals in each of three groups: riluzole, riluzole plus elacridar, or no treatment. Elacridar increased lifespan. Control ALS mice survived for an average of 157 days; riluzole-only mice lived for 160; and mice given the combination therapy lasted 165 days.

In another experiment, Jablonski compared 10 mice that got only riluzole with 11 that received both medications. Animals given the drug combination maintained strength in their hind legs for longer. According to electrophysiology experiments, mice on the combination also generated stronger action potentials in their spinal cord neurons. When Jablonski examined the lumbar cord, he observed more motor neurons than in riluzole-only counterparts, as well.

“We need to know if this translates to patients,” Morrison said. He said elacridar would be worth testing in a clinical trial in people with ALS. Pasinelli said patients and other clinicians have expressed interest in a trial, but Jablonski cautioned that more preclinical work must be done first. “Understanding the pharmacological profile and interactions between the drug efflux transporter and the ALS treating agent would be particularly important,” he told Alzforum in an email.

The next big question, Morrison said, is whether P-gp or BCRP pump out other potential ALS drugs. Although scientists have tried several experimental therapeutics in the clinic, none but riluzole have helped. Morrison suggested that it would be straightforward to look back at the last decade or two of ALS trials and determine which medications would be worth revisiting with the addition of an ABC transporter blocker. “We know that some of those drugs are substrates for at least one of these two transporters,” Pasinelli said. In addition, the authors recommend that scientists investigating novel treatments should check their chemicals for transport by P-gp or BCRP early in their research.—Amber Dance

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References

Paper Citations

  1. Löscher W, Potschka H. Drug resistance in brain diseases and the role of drug efflux transporters. Nat Rev Neurosci. 2005 Aug;6(8):591-602. PubMed.
  2. Boston-Howes W, Williams EO, Bogush A, Scolere M, Pasinelli P, Trotti D. Nordihydroguaiaretic acid increases glutamate uptake in vitro and in vivo: therapeutic implications for amyotrophic lateral sclerosis. Exp Neurol. 2008 Sep;213(1):229-37. PubMed.
  3. Jablonski MR, Jacob DA, Campos C, Miller DS, Maragakis NJ, Pasinelli P, Trotti D. Selective increase of two ABC drug efflux transporters at the blood-spinal cord barrier suggests induced pharmacoresistance in ALS. Neurobiol Dis. 2012 Aug;47(2):194-200. Epub 2012 Apr 11 PubMed.
  4. Traynor BJ, Bruijn L, Conwit R, Beal F, O'Neill G, Fagan SC, Cudkowicz ME. Neuroprotective agents for clinical trials in ALS: a systematic assessment. Neurology. 2006 Jul 11;67(1):20-7. PubMed.
  5. Bruno R, Vivier N, Montay G, Le Liboux A, Powe LK, Delumeau JC, Rhodes GR. Population pharmacokinetics of riluzole in patients with amyotrophic lateral sclerosis. Clin Pharmacol Ther. 1997 Nov;62(5):518-26. PubMed.
  6. Milane A, Fernandez C, Vautier S, Bensimon G, Meininger V, Farinotti R. Minocycline and riluzole brain disposition: interactions with p-glycoprotein at the blood-brain barrier. J Neurochem. 2007 Oct;103(1):164-73. Epub 2007 Jul 17 PubMed.
  7. Milane A, Vautier S, Chacun H, Meininger V, Bensimon G, Farinotti R, Fernandez C. Interactions between riluzole and ABCG2/BCRP transporter. Neurosci Lett. 2009 Mar 6;452(1):12-6. Epub 2009 Jan 6 PubMed.
  8. Scott S, Kranz JE, Cole J, Lincecum JM, Thompson K, Kelly N, Bostrom A, Theodoss J, Al-Nakhala BM, Vieira FG, Ramasubbu J, Heywood JA. Design, power, and interpretation of studies in the standard murine model of ALS. Amyotroph Lateral Scler. 2008;9(1):4-15. PubMed.

Further Reading

Papers

  1. Jablonski M, Miller DS, Pasinelli P, Trotti D. ABC transporter-driven pharmacoresistance in Amyotrophic Lateral Sclerosis. Brain Res. 2014 Aug 28; PubMed.
  2. Dunlop J, Beal McIlvain H, She Y, Howland DS. Impaired spinal cord glutamate transport capacity and reduced sensitivity to riluzole in a transgenic superoxide dismutase mutant rat model of amyotrophic lateral sclerosis. J Neurosci. 2003 Mar 1;23(5):1688-96. PubMed.
  3. Zoccolella S, Beghi E, Palagano G, Fraddosio A, Guerra V, Samarelli V, Lepore V, Simone IL, Lamberti P, Serlenga L, Logroscino G, . Riluzole and amyotrophic lateral sclerosis survival: a population-based study in southern Italy. Eur J Neurol. 2007 Mar;14(3):262-8. PubMed.
  4. Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N Engl J Med. 1994 Mar 3;330(9):585-91. PubMed.

Primary Papers

  1. Jablonski MR, Markandaiah SS, Jacob D, Meng NJ, Li K, Gennaro V, Lepore AC, Trotti D, Pasinelli P. Inhibiting drug efflux transporters improves efficacy of ALS therapeutics. Ann Clin Transl Neurol. 2014 Dec;1(12):996-1005. Epub 2014 Nov 21 PubMed.

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