Neuroprotection in Amyotrophic Lateral Sclerosis

  • Kewal K. Jain
Part of the Springer Protocols Handbooks book series (SPH)


Amyotrophic lateral sclerosis (ALS) is progressive, devastating syndrome that affects both upper and motor neurons. It results in limbs and facial motor weakness, atrophy, spasticity, and death due to respiratory paralysis occurs in 3–5 years. It is referred to as motor neuron disease in UK and some other European countries and as Charcot’s disease in France. It is also referred to as Lou Gehrig’s disease in the US.


  1. Aebischer P, Schluep M, Deglon N, et al. Intrathecal delivery of CNTF using encapsulated genetically modified xenogeneic cells in amyotrophic lateral sclerosis patients. Nat Med 1996;2:696–9.CrossRefGoogle Scholar
  2. Aggarwal SP, Zinman L, Simpson E, et al. Safety and efficacy of lithium in combination with riluzole for treatment of amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2010;9:481–8.CrossRefGoogle Scholar
  3. ALSUntangled Group. ALSUntangled No. 7: Investigating hyperimmune goat serum (Aimspro) for ALS. Amyotroph Lateral Scler 2010;11:571–3.CrossRefGoogle Scholar
  4. Arnold DL, Narayanan S, Antel S. Neuroprotection with glatiramer acetate: evidence from the PreCISe trial. J Neurol 2013;260:1901–6.CrossRefGoogle Scholar
  5. Benatar M, Wuu J, Andersen PM, et al. Randomized, double-blind, placebo-controlled trial of arimoclomol in rapidly progressive SOD1 ALS. Neurology 2018;90:e565–e574.CrossRefGoogle Scholar
  6. Bozik ME, Mather JL, Kramer WG, Gribkoff VK, Ingersoll EW. Safety, tolerability, and pharmacokinetics of KNS-760704 (dexpramipexole) in healthy adult subjects. J Clin Pharmacol 2010;51:1177–85.CrossRefGoogle Scholar
  7. Brenner D, Yilmaz R, Müller K, et al. Hot-spot KIF5A mutations cause familial ALS. Brain 2018; 141:688–697.CrossRefGoogle Scholar
  8. Brown RH, Al-Chalabi A. Amyotrophic Lateral Sclerosis. N Engl J Med 2017;377:162–172.CrossRefGoogle Scholar
  9. Burberry A, Suzuki N, Wang JY, et al. Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease. Sci Transl Med 2016;8:347ra93.CrossRefGoogle Scholar
  10. Cashman N, Tan LY, Krieger C, et al. Pilot study of granulocyte colony stimulating factor (G-CSF)-mobilized peripheral blood stem cells in amyotrophic lateral sclerosis (ALS). Muscle Nerve 2008;37:620–5.CrossRefGoogle Scholar
  11. Choi MR, Kim HY, Park JY, et al. Selection of optimal passage of bone marrow-derived mesenchymal stem cells for stem cell therapy in patients with amyotrophic lateral sclerosis. Neurosci Lett 2010;472:94–8.CrossRefGoogle Scholar
  12. Cudkowicz ME, Andres PL, Macdonald SA, et al. Phase 2 study of sodium phenylbutyrate in ALS. Amyotroph Lateral Scler 2009;10:99–106.CrossRefGoogle Scholar
  13. Cudkowicz ME, Titus S, Kearney M, et al. Safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis: a multi-stage, randomised, double-blind, placebo-controlled trial. Lancet Neurol 2014;13:1083–1091.CrossRefGoogle Scholar
  14. Cudkowicz ME, van den Berg LH, Shefner JM, et al. Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): a randomised, double-blind, phase 3 trial. Lancet Neurol 2013;12:1059–67.CrossRefGoogle Scholar
  15. Daniel B, Green O, Viskind O, Gruzman A. Riluzole increases the rate of glucose transport in L6 myotubes and NSC-34 motor neuron-like cells via AMPK pathway activation. Amyotroph Lateral Scler Frontotemporal Degener 2013;14:434–43.CrossRefGoogle Scholar
  16. Feldman EL, Boulis NM, Hur J, et al. Intraspinal neural stem cell transplantation in amyotrophic lateral sclerosis: phase 1 trial outcomes. Ann Neurol 2014;75:363–73.CrossRefGoogle Scholar
  17. Ferraiuolo L, Meyer K, Sherwood TW, et al. Oligodendrocytes contribute to motor neuron death in ALS via SOD1-dependent mechanism. Proc Natl Acad Sci U S A 2016;113:E6496–E6505.CrossRefGoogle Scholar
  18. Fornai F, Longone P, Cafaro L, et al. Lithium delays progression of amyotrophic lateral sclerosis. PNAS 2008;105:2052–57.CrossRefGoogle Scholar
  19. Fumagalli E, Funicello M, Rauen T, et al. Riluzole enhances the activity of glutamate transporters GLAST, GLT1 and EAAC1. Eur J Pharmacol 2008;578:171–6.CrossRefGoogle Scholar
  20. Gaj T, Ojala DS, Ekman FK, et al. In vivo genome editing improves motor function and extends survival in a mouse model of ALS. Sci Adv 2017;3(12):eaar3952.CrossRefGoogle Scholar
  21. Geevasinga N, Menon P, Ng K, et al. Riluzole exerts transient modulating effects on cortical and axonal hyperexcitability in ALS. Amyotroph Lateral Scler Frontotemporal Degener 2016:1–9.Google Scholar
  22. Glass JD, Boulis NM, Johe K, et al. Lumbar intraspinal injection of neural stem cells in patients with amyotrophic lateral sclerosis: results of a phase I trial in 12 patients. Stem Cells 2012;30:1144–51.CrossRefGoogle Scholar
  23. Gribkoff VK, Bozik ME. KNS-760704 [(6R)-4,5,6,7-tetrahydro-N6-propyl-2, 6-benzothiazole-diamine dihydrochloride monohydrate] for the treatment of amyotrophic lateral sclerosis. CNS Neurosci Ther 2008;14:215–26.CrossRefGoogle Scholar
  24. Ivanov P, O’Day E, Emara MM, et al. G-quadruplex structures contribute to the neuroprotective effects of angiogenin-induced tRNA fragments. Proc Natl Acad Sci U S A 2014;111:18201–6.CrossRefGoogle Scholar
  25. Izumi Y, Sawada H, Yamamoto N, et al. Novel neuroprotective mechanisms of pramipexole, an anti-Parkinson drug, against endogenous dopamine-mediated excitotoxicity. Eur J Pharmacol 2007;557:132–40.CrossRefGoogle Scholar
  26. Jain KK. Glatiramer acetate. In, Roos RP (ed) MedLink Neurology. Medlink Publishing Corporation, San Diego, California, 2019.Google Scholar
  27. Jain KK. Riluzole. In, Roos RP (ed) MedLink Neurology. Medlink Publishing Corporation, San Diego, California, 2019a.Google Scholar
  28. Kaufmann P, Thompson JL, Levy G, et al. Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III. Ann Neurol 2009;66:235–44CrossRefGoogle Scholar
  29. Kindy M, Lupinacci P, Chau R, et al. A Phase 2A randomized, double-blind, placebo-controlled pilot trial of GM604 in patients with Amyotrophic Lateral Sclerosis (ALS Protocol GALS-001) and a single compassionate patient treatment (Protocol GALS-C). F1000Research 2017; 6:230 ( Scholar
  30. Kramer NJ, Haney MS, Morgens DW, et al. CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity. Nat Genet 2018; 50:603–612.CrossRefGoogle Scholar
  31. Landers JE, Melki J, Meininger V, et al. Reduced expression of the Kinesin-Associated Protein 3 (KIFAP3) gene increases survival in sporadic amyotrophic lateral sclerosis. PNAS 2009;106:9004–9.CrossRefGoogle Scholar
  32. Lauria G, Campanella A, Filippini G, et al. Erythropoietin in amyotrophic lateral sclerosis: a pilot, randomized, double-blind, placebo-controlled study of safety and tolerability. Amyotroph Lateral Scler 2009;10:410–5.CrossRefGoogle Scholar
  33. Lenglet T, Lacomblez L, Abitbol JL, et al. A phase II-III trial of olesoxime in subjects with amyotrophic lateral sclerosis. Eur J Neurol 2014;21:529–36.CrossRefGoogle Scholar
  34. Liu AY, Mathur R, Mei N, et al. Neuroprotective drug riluzole amplifies the heat shock factor 1 (HSF1)- and glutamate transporter 1 (GLT1)-dependent cytoprotective mechanisms for neuronal survival. J Biol Chem 2011;286:2785–94.CrossRefGoogle Scholar
  35. Maier A, Deigendesch N, Müller K, et al. Interleukin-1 Antagonist Anakinra in Amyotrophic Lateral Sclerosis--A Pilot Study. PLoS One 2015;10:e0139684.CrossRefGoogle Scholar
  36. Marchetto MC, Muotri AR, Mu Y, et al. Non-cell-autonomous effect of human SOD1 G37R astrocytes on motor neurons derived from human embryonic stem cells. Cell Stem Cell 2008;3:649–57.CrossRefGoogle Scholar
  37. McCampbell A, Cole T, Wegener AJ, et al. Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models. J Clin Invest 2018;128:3558–3567.CrossRefGoogle Scholar
  38. Meininger V, Drory VE, Leigh PN, et al. Glatiramer acetate has no impact on disease progression in ALS at 40 mg/day: a double- blind, randomized, multicentre, placebo-controlled trial. Amyotroph Lateral Scler 2009;10:378–83.CrossRefGoogle Scholar
  39. Meissner F, Molawi K, Zychlinsky A. Mutant superoxide dismutase 1-induced IL-1{beta} accelerates ALS pathogenesis. PNAS 2010;107:13046–50.CrossRefGoogle Scholar
  40. Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev 2012;3:CD001447.Google Scholar
  41. Miller TM, Pestronk A, David W, et al. An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol 2013;12:435–42.CrossRefGoogle Scholar
  42. Mitropoulos K, Katsila T, Patrinos GP, Pampalakis G. Multi-Omics for Biomarker Discovery and Target Validation in Biofluids for Amyotrophic Lateral Sclerosis Diagnosis. OMICS 2018;22:52–64.CrossRefGoogle Scholar
  43. Nanou A, Azzouz M. Gene therapy for neurodegenerative diseases based on lentiviral vectors. Prog Brain Res 2009;175:187–200.CrossRefGoogle Scholar
  44. Neymotin A, Petri S, Calingasan NY, et al. Lenalidomide (Revlimid) administration at symptom onset is neuroprotective in a mouse model of amyotrophic lateral sclerosis. Exp Neurol 2009;220:191–7.CrossRefGoogle Scholar
  45. Niimori-Kita K, Tamamaki, N, Koizumi D, Niimori D. Matrin-3 is essential for fibroblast growth factor 2-dependent maintenance of neural stem cells. Sci Rep 2018;8:13412.CrossRefGoogle Scholar
  46. Pascuzzi RM, Shefner J, Chappell AS, et al. A phase II trial of talampanel in subjects with amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2010;11:266–71.CrossRefGoogle Scholar
  47. Peters OM, Ghasemi M, Brown RH Jr. Emerging mechanisms of molecular pathology in ALS. J Clin Invest 2015;125:1767–79.CrossRefGoogle Scholar
  48. Phatnani HP, Guarnieri P, Friedman BA, et al. Intricate interplay between astrocytes and motor neurons in ALS. Proc Natl Acad Sci U S A 2013;110:E756–65.CrossRefGoogle Scholar
  49. Riley J, Federici T, Polak M, et al. Intraspinal Stem Cell Transplantation in ALS: A Phase I Safety Trial, Technical Note & Lumbar Safety Outcomes. Neurosurgery 2012;71:405–16.CrossRefGoogle Scholar
  50. Rothstein JD. Current hypothesis for the underlying biology of amyotrophic lateral sclerosis. Ann Neurol 2009;65(suppl):S3–9.CrossRefGoogle Scholar
  51. Sawada H. Clinical efficacy of edaravone for the treatment of amyotrophic lateral sclerosis. Expert Opin Pharmacother 2017;18:735–8.CrossRefGoogle Scholar
  52. Shi KY, Mori E, Nizami ZF, et al. Toxic PRn poly-dipeptides encoded by the C9orf72 repeat expansion block nuclear import and export. Proc Natl Acad Sci U S A 2017;114:E1111–E1117.CrossRefGoogle Scholar
  53. Sorenson EJ, Windbank AJ, Mandrekar JN, et al. Subcutaneous IGF-1 is not beneficial in 2-year ALS trial. Neurology 2008;71:1770–5.CrossRefGoogle Scholar
  54. Strong MJ. The evidence for altered RNA metabolism in amyotrophic lateral sclerosis (ALS). J Neurol Sci 2010;288:1–12.CrossRefGoogle Scholar
  55. Sun MM, Bu H, Li B, et al. Neuroprotective potential of phase II enzyme inducer diallyl trisulfide. Neurol Res 2009;31:23–7.CrossRefGoogle Scholar
  56. Therrien M, Dion PA, Rouleau GA. ALS: recent developments from genetics studies. Curr Neurol Neurosci Rep 2016;16: 59–71.CrossRefGoogle Scholar
  57. Vaccaro A, Patten SA, Aggad D, et al. Pharmacological reduction of ER stress protects against TDP-43 neuronal toxicity in vivo. Neurobiol Dis 2013;55:64–75.CrossRefGoogle Scholar
  58. Van Hoecke A, Schoonaert L, Lemmens R, et al. EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans. Nat Med 2012;18:1418–22.CrossRefGoogle Scholar
  59. van Zundert B, Brown RH Jr. Silencing strategies for therapy of SOD1-mediated ALS. Neurosci Lett 2017;636:32–39.CrossRefGoogle Scholar
  60. Wang H, Larriviere KS, Keller KE, et al. R+ pramipexole as a mitochondrially focused neuroprotectant: initial early phase studies in ALS. Amyotroph Lateral Scler 2008;9:50–8.CrossRefGoogle Scholar
  61. Wang H, O’Reilly EJ, Weisskopf MG, et al. Vitamin E intake and risk of amyotrophic lateral sclerosis: a pooled analysis of data from 5 prospective cohort studies. Am J Epidemiol 2011;173:595–602.CrossRefGoogle Scholar
  62. Williams AH, Valdez G, Moresi V, et al. MicroRNA-206 delays ALS progression and promotes regeneration of neuromuscular synapse in mice. Science 2009;326;1549–54.CrossRefGoogle Scholar
  63. Wu R, Wang H, Xia XG, et al. Nerve injection of viral vectors efficiently transfers transgenes into motor neurons and delivers RNAi therapy against ALS. Antioxid Redox Signal 2009;11:1523–34.CrossRefGoogle Scholar
  64. Yonashiro R, Tahara EB, Bengtson MH, et al. The Rqc2/Tae2 subunit of the ribosome-associated quality control (RQC) complex marks ribosome-stalled nascent polypeptide chains for aggregation. Elife 2016;5. pii: e11794.CrossRefGoogle Scholar
  65. Zhang F, Strom AL, Fukada K, et al. Interaction between Familial Amyotrophic Lateral Sclerosis (ALS)-linked SOD1 Mutants and the Dynein Complex. J Biol Chem 2007;282:16691–9.CrossRefGoogle Scholar
  66. Zhang Y, Cook A, Kim J, et al. Melatonin inhibits the caspase-1/cytochrome c/caspase-3 cell death pathway, inhibits MT1 receptor loss and delays disease progression in a mouse model of amyotrophic lateral sclerosis. Neurobiol Dis 2013;55:26–35.CrossRefGoogle Scholar
  67. Zhong Z, Ilieva H, Hallagan L, et al. Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells. J Clin Invest 2009;119:3437–49.PubMedPubMedCentralGoogle Scholar
  68. Zhu C, Beck MV, Griffith JD, et al. Large SOD1 aggregates, unlike trimeric SOD1, do not impact cell viability in a model of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 2018;115:4661–4665.CrossRefGoogle Scholar
  69. Zoccolella S, Bendotti C, Beghi E, Logroscino G. Homocysteine levels and amyotrophic lateral sclerosis: A possible link. Amyotroph Lateral Scler 2010;11:140–7.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Kewal K. Jain
    • 1
  1. 1.Jain PharmaBiotechBaselSwitzerland

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