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Axonal and Myelin Neuroprotection by the Peptoid BN201 in Brain Inflammation

  • Pablo VillosladaEmail author
  • Gemma Vila
  • Valeria Colafrancesco
  • Beatriz Moreno
  • Begoña Fernandez-Diez
  • Raquel Vazquez
  • Inna Pertsovskaya
  • Irati Zubizarreta
  • Irene Pulido-Valdeolivas
  • Joaquin Messeguer
  • Gloria Vendrell-Navarro
  • Jose Maria Frade
  • Noelia López-Sánchez
  • Meritxell Teixido
  • Ernest Giralt
  • Mar Masso
  • Jason C Dugas
  • Dmitri Leonoudakis
  • Karen D. Lariosa-Willingham
  • Lawrence Steinman
  • Angel Messeguer
Original Article

Abstract

The development of neuroprotective therapies is a sought-after goal. By screening combinatorial chemical libraries using in vitro assays, we identified the small molecule BN201 that promotes the survival of cultured neural cells when subjected to oxidative stress or when deprived of trophic factors. Moreover, BN201 promotes neuronal differentiation, the differentiation of precursor cells to mature oligodendrocytes in vitro, and the myelination of new axons. BN201 modulates several kinases participating in the insulin growth factor 1 pathway including serum–glucocorticoid kinase and midkine, inducing the phosphorylation of NDRG1 and the translocation of the transcription factor Foxo3 to the cytoplasm. In vivo, BN201 prevents axonal and neuronal loss, and it promotes remyelination in models of multiple sclerosis, chemically induced demyelination, and glaucoma. In summary, we provide a new promising strategy to promote neuroaxonal survival and remyelination, potentially preventing disability in brain diseases.

Key Words

Neuroprotection neuroinflammation neurodegenerative diseases multiple sclerosis glaucoma 

Notes

Acknowledgments

We would like to thank Prof Stephen L Hauser, David Pearce, and Ari Green from University of California, San Francisco; Joaquim Trias and Craig Smith for their scientific advice; and Mr. Mark Sefton for the review of the language of the manuscript.

Author Contributions

VC, BM, BFD, RV, GV, IZ, JMF, NLS, MT, EG, and PV performed the experiments; PV, JMF, EG, JD, LS, and AM designed and supervised the research; JM, GM, and AM synthesized the libraries and the specific small chemicals; JMF and NLS developed the in vitro assays; MT and EG performed the blood–brain barrier assays; VC, BM, BFD, RV, GV, IZ, and PV performed the EAE experiments and evaluated CNS inflammatory infiltration; LS performed the Th17 passive transfer EAE model; VC and RV carried out the experiments with the glaucoma model; RV and PV performed the lysolecithin optic neuropathy model; JD, DL, and KLW performed the in vitro remyelination assays; BM, VC, JMF, EG, AM, and PV analyzed the data; PV prepared the manuscript, which was revised by JMF, EG, and AM; and the statistical analysis was performed by BM, RV, IZ, and PV.

Funding

This work was supported by the Fundación Ramon Areces, Madrid, Spain, and the Instituto de Salud Carlos III, Madrid Spain (RD07/0060 and PI12/01823) to PV and AM and by an unrestricted grant from Bionure SL, Barcelona, Spain.

Compliance with Ethical Standards

Competing Interest

PV and AM hold a patent covering the composition of matter and uses of BN201. PV is founder and hold stocks in Bionure SL, which has licensed the patent rights to BN201, serves in its scientific advisory board, and had received compensation for such service. MM is an employee of Bionure SL. LS has shares of Bionure SL stock and has received consulting fees.

Supplementary material

13311_2019_717_MOESM1_ESM.pdf (499 kb)
ESM 1 (PDF 499 kb)
13311_2019_717_MOESM2_ESM.docx (1.8 mb)
ESM 2 (DOCX 1849 kb)

References

  1. 1.
    Gooch CL, Pracht E, Borenstein AR. The burden of neurological disease in the United States: a summary report and call to action. Ann Neurol 2017; 81(4): 479–484.PubMedGoogle Scholar
  2. 2.
    Baeza-Yates R, Sangal PM, Villoslada P. Burden of neurological diseases in the US revealed by web searches. PLoS One 2017; 12(5): e0178019.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Tovar YRLB, Penagos-Puig A, Ramirez-Jarquin JO. Endogenous recovery after brain damage: molecular mechanisms that balance neuronal life/death fate. J Neurochem 2016; 136(1): 13–27.Google Scholar
  4. 4.
    Gabilondo I, Martinez-Lapiscina EH, Martinez-Heras E et al. Trans-synaptic axonal degeneration in the visual pathway in multiple sclerosis. Ann Neurol 2014; 75(1): 98–107.PubMedGoogle Scholar
  5. 5.
    Luo L, O’Leary DD. Axon retraction and degeneration in development and disease. Annu Rev Neurosci 2005; 28: 127–156.PubMedGoogle Scholar
  6. 6.
    Villoslada P. Neuroprotective therapies for multiple sclerosis and other demyelinating diseases. Mult Scl Dem Dis 2016; 1(1): 1–11.Google Scholar
  7. 7.
    Almasieh M, Levin LA. Neuroprotection in glaucoma: animal models and clinical trials. Annu Rev Vis Sci 2017; 3: 91–120.PubMedGoogle Scholar
  8. 8.
    Masip I, Ferrandiz-Huertas C, Garcia-Martinez C, Ferragut JA, Ferrer-Montiel A, Messeguer A. Synthesis of a library of 3-oxopiperazinium and perhydro-3-oxo-1,4-diazepinium derivatives and identification of bioactive compounds. J Comb Chem 2004; 6(1): 135–141.PubMedGoogle Scholar
  9. 9.
    Masip I, Perez-Paya E, Messeguer A. Peptoids as source of compounds eliciting antibacterial activity. Comb Chem High Throughput Screen 2005; 8(3): 235–239.PubMedGoogle Scholar
  10. 10.
    Montolio M, Messeguer J, Masip I et al. A semaphorin 3A inhibitor blocks axonal chemorepulsion and enhances axon regeneration. Chem Biol 2009; 16(7): 691–701.PubMedGoogle Scholar
  11. 11.
    Burstein DE, Greene LA. Evidence for RNA synthesis-dependent and -independent pathways in stimulation of neurite outgrowth by nerve growth factor. Proc Natl Acad Sci U S A 1978; 75(12): 6059–6063.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Frade JM. Nuclear translocation of the p75 neurotrophin receptor cytoplasmic domain in response to neurotrophin binding. J Neurosci 2005; 25(6): 1407–1411.PubMedGoogle Scholar
  13. 13.
    Nicotra A, Parvez S. Apoptotic molecules and MPTP-induced cell death. Neurotoxicol Teratol 2002; 24(5): 599–605.PubMedGoogle Scholar
  14. 14.
    Ill-Raga G, Ramos-Fernandez E, Guix FX et al. Amyloid-beta peptide fibrils induce nitro-oxidative stress in neuronal cells. J Alzheimers Dis 2010; 22(2): 641–652.PubMedGoogle Scholar
  15. 15.
    Tanaka M, Kikuchi H, Ishizu T et al. Intrathecal upregulation of granulocyte colony stimulating factor and its neuroprotective actions on motor neurons in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 2006; 65(8): 816–825.PubMedGoogle Scholar
  16. 16.
    Lariosa-Willingham KD, Rosler ES, Tung JS, Dugas JC, Collins TL, Leonoudakis D. Development of a central nervous system axonal myelination assay for high throughput screening. BMC Neurosci 2016; 17: 16.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Zuchero JB, Fu MM, Sloan SA et al. CNS myelin wrapping is driven by actin disassembly. Dev Cell 2015; 34(2): 152–167.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Wu X, Mao H, Liu J et al. Dynamic change of SGK expression and its role in neuron apoptosis after traumatic brain injury. International Journal of Clinical and Experimental Pathology 2013; 6(7): 1282–1293.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Inoue K, Sakuma E, Morimoto H et al. Serum- and glucocorticoid-inducible kinases in microglia. Biochem Biophys Res Commun 2016; 478(1): 53–59.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Palacios R, Goni J, Martinez-Forero I et al. A network analysis of the human T-cell activation gene network identifies JAGGED1 as a therapeutic target for autoimmune diseases. PLoS ONE 2007; 2(11): e1222.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Moreno B, Hevia H, Santamaria M et al. Methylthioadenosine reverses brain autoimmune disease. Ann Neurol. 2006; 60(3): 323–334.PubMedGoogle Scholar
  22. 22.
    Villoslada P, Abel K, Heald N, Goertsches R, Hauser S, Genain C. Frequency, heterogeneity and encephalitogenicity of T cells specific for myelin oligodendrocyte glycoprotein in naive outbred primates. Eur J Immunol. 2001; 31(10): 2942–2950.PubMedGoogle Scholar
  23. 23.
    Moreno B, Fernandez-Diez B, Di Penta A, Villoslada P. Preclinical studies of methylthioadenosine for the treatment of multiple sclerosis. Mult Scler 2010; 16(9): 1102–1108.PubMedGoogle Scholar
  24. 24.
    Reick C, Ellrichmann G, Thone J et al. Neuroprotective dimethyl fumarate synergizes with immunomodulatory interferon beta to provide enhanced axon protection in autoimmune neuroinflammation. Exp Neurol 2014; 257: 50–56.PubMedGoogle Scholar
  25. 25.
    Kataoka H, Sugahara K, Shimano K et al. FTY720, sphingosine 1-phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T cell infiltration. Cell Mol Immunol 2005; 2(6): 439–448.PubMedGoogle Scholar
  26. 26.
    Hao K, Liu XQ, Wang GJ, Zhao XP. Pharmacokinetics, tissue distribution and excretion of gambogic acid in rats. Eur J Drug Metab Pharmacokinet 2007; 32(2): 63–68.PubMedGoogle Scholar
  27. 27.
    Bourrie B, Bribes E, Esclangon M et al. The neuroprotective agent SR 57746A abrogates experimental autoimmune encephalomyelitis and impairs associated blood-brain barrier disruption: implications for multiple sclerosis treatment. Proc Natl Acad Sci U S A 1999; 96(22): 12855–12859.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Grant JL, Ghosn EE, Axtell RC et al. Reversal of paralysis and reduced inflammation from peripheral administration of beta-amyloid in TH1 and TH17 versions of experimental autoimmune encephalomyelitis. Sci Transl Med 2012; 4(145): 145ra105.PubMedPubMedCentralGoogle Scholar
  29. 29.
    You Y, Klistorner A, Thie J, Graham SL. Latency delay of visual evoked potential is a real measurement of demyelination in a rat model of optic neuritis. Invest Ophthalmol Vis Sci 2011; 52(9): 6911–6918.PubMedGoogle Scholar
  30. 30.
    Kim JY, Shen S, Dietz K et al. HDAC1 nuclear export induced by pathological conditions is essential for the onset of axonal damage. Nat Neurosci 2010; 13(2): 180–189.PubMedGoogle Scholar
  31. 31.
    Moreno B, Vila G, Fernandez-Diez B, et al. Methylthioadenosine promotes remyelination by inducing oligodendrocyte differentiation. Mult Scl Dem Dis 2017; 2(3): 1–13.Google Scholar
  32. 32.
    Palacios R, Comas D, Elorza J, Villoslada P. Genomic regulation of CTLA4 and multiple sclerosis. J Neuroimmunol. 2008; 203(1): 108–115.PubMedGoogle Scholar
  33. 33.
    Park SH, Sim YB, Lee JK, Lee JY, Suh HW. Characterization of temporal expressions of FOXO and pFOXO proteins in the hippocampus by kainic acid in mice: involvement of NMDA and non-NMDA receptors. Arch Pharm Res 2016; 39(5): 660–667.PubMedGoogle Scholar
  34. 34.
    Martinez-Forero I, Garcia-Munoz R, Martinez-Pasamar S et al. IL-10 suppressor activity and ex vivo Tr1 cell function are impaired in multiple sclerosis. Eur J Immunol. 2008; 38(2): 576–586.PubMedGoogle Scholar
  35. 35.
    Sugano K, Hamada H, Machida M, Ushio H. High throughput prediction of oral absorption: improvement of the composition of the lipid solution used in parallel artificial membrane permeation assay. J Biomol Screen 2001; 6(3): 189–196.PubMedGoogle Scholar
  36. 36.
    Gaillard PJ, de Boer AG. 2B-Trans technology: targeted drug delivery across the blood-brain barrier. Methods Mol Biol 2008; 437: 161–175.PubMedGoogle Scholar
  37. 37.
    Gil ES, Li J, Xiao H, Lowe TL. Quaternary ammonium beta-cyclodextrin nanoparticles for enhancing doxorubicin permeability across the in vitro blood-brain barrier. Biomacromolecules 2009; 10(3):505-16PubMedGoogle Scholar
  38. 38.
    Gaillard PJ, Voorwinden LH, Nielsen JL et al. Establishment and functional characterization of an in vitro model of the blood-brain barrier, comprising a co-culture of brain capillary endothelial cells and astrocytes. Eur J Pharm Sci 2001; 12(3): 215–222.PubMedGoogle Scholar
  39. 39.
    Madgula VL, Avula B, Reddy VLN, Khan IA, Khan SI. Transport of decursin and decursinol angelate across Caco-2 and MDR-MDCK cell monolayers: in vitro models for intestinal and blood-brain barrier permeability. Planta Med 2007; 73(4): 330–335.PubMedGoogle Scholar
  40. 40.
    You Y, Joseph C, Wang C et al. Demyelination precedes axonal loss in the transneuronal spread of human neurodegenerative disease. Brain 2019; 42(2):426-442Google Scholar
  41. 41.
    Winkler C, Yao S. The midkine family of growth factors: diverse roles in nervous system formation and maintenance. Br J Pharmacol 2014; 171(4): 905–912.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Chen X, Tagliaferro P, Kareva T, Yarygina O, Kholodilov N, Burke RE. Neurotrophic effects of serum- and glucocorticoid-inducible kinase on adult murine mesencephalic dopamine neurons. J Neurosci 2012; 32(33): 11299–11308.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Lauro D, Pastore D, Capuani B et al. Role of serum and glucocorticoid-inducible kinase (SGK)-1 in senescence: a novel molecular target against age-related diseases. Curr Med Chem 2015; 22(33): 3765–3788.PubMedGoogle Scholar
  44. 44.
    Loffing J, Flores SY, Staub O. Sgk kinases and their role in epithelial transport. Annual Review of Physiology 2006; 68: 461–490.PubMedGoogle Scholar
  45. 45.
    Sahin P, McCaig C, Jeevahan J, Murray JT, Hainsworth AH. The cell survival kinase SGK1 and its targets FOXO3a and NDRG1 in aged human brain. Neuropath Appl Neuro 2013; 39(6): 623–633.Google Scholar
  46. 46.
    Yang YC, Lin CH, Lee EHY. Serum- and glucocorticoid-inducible kinase 1 (SGK1) increases neurite formation through microtubule depolymerization by SGK1 and by SGK1 phosphorylation of tau. Molecular and Cellular Biology 2006; 26(22): 8357–8370.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Ransohoff RM, Brown MA. Innate immunity in the central nervous system. J Clin Invest 2012; 122(4): 1164–1171.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Ransohoff RM. A polarizing question: do M1 and M2 microglia exist? Nat Neurosci 2016; 19(8): 987–991.PubMedGoogle Scholar
  49. 49.
    Di Penta A, Moreno B, Reix S et al. Oxidative stress and proinflammatory cytokines contribute to demyelination and axonal damage in a cerebellar culture model of neuroinflammation. PloSONE 2013; 8(2): e54722.Google Scholar
  50. 50.
    Blakemore WF, Franklin RJM. Remyelination in experimental models of toxin-induced demyelination. Curr Top Microbiol 2008; 318: 193–212.Google Scholar
  51. 51.
    Colafrancesco V, Parisi V, Sposato V et al. Ocular application of nerve growth factor protects degenerating retinal ganglion cells in a rat model of glaucoma. J Glaucoma 2011; 20(2): 100–108.PubMedGoogle Scholar
  52. 52.
    David S, Stegenga SL, Hu P et al. Expression of serum- and glucocorticoid-inducible kinase is regulated in an experience-dependent manner and can cause dendrite growth. J Neurosci 2005; 25(30): 7048–7053.PubMedGoogle Scholar
  53. 53.
    Lang F, Bohmer C, Palmada M, Seebohm G, Strutz-Seebohm N, Vallon V. (Patho) physiological significance of the serum- and glucocorticoid-inducible kinase isoforms. Physiol Rev 2006; 86(4): 1151–1178.PubMedGoogle Scholar
  54. 54.
    Yoshida Y, Sakakima H, Matsuda F, Ikutomo M. Midkine in repair of the injured nervous system. Br J Pharmacol 2014; 171(4): 924–930.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Gramage E, Li J, Hitchcock P. The expression and function of midkine in the vertebrate retina. Br J Pharmacol 2014; 171(4): 913–923.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Powell JD, Pollizzi KN, Heikamp EB, Horton MR. Regulation of immune responses by mTOR. Annu Rev Immunol 2012; 30: 39–68.PubMedGoogle Scholar
  57. 57.
    Heikamp EB, Patel CH, Collins S et al. The AGC kinase SGK1 regulates TH1 and TH2 differentiation downstream of the mTORC2 complex. Nat Immunol 2014; 15(5): 457–464.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Norton M, Screaton RA. SGK1: master and commander of the fate of helper T cells. Nat Immunol 2014; 15(5): 411–413.PubMedGoogle Scholar
  59. 59.
    Dejean AS, Hedrick SM, Kerdiles YM. Highly specialized role of Forkhead box O transcription factors in the immune system. Antioxidants & Redox Signaling 2011; 14(4): 663–674.Google Scholar
  60. 60.
    Hur EM, Youssef S, Haws ME, Zhang SY, Sobel RA, Steinman L. Osteopontin-induced relapse and progression of autoimmune brain disease through enhanced survival of activated T cells. Nat Immunol 2007; 8(1): 74–83.PubMedGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2019

Authors and Affiliations

  • Pablo Villoslada
    • 1
    Email author
  • Gemma Vila
    • 1
  • Valeria Colafrancesco
    • 1
  • Beatriz Moreno
    • 1
  • Begoña Fernandez-Diez
    • 1
  • Raquel Vazquez
    • 1
  • Inna Pertsovskaya
    • 1
  • Irati Zubizarreta
    • 1
  • Irene Pulido-Valdeolivas
    • 1
  • Joaquin Messeguer
    • 2
  • Gloria Vendrell-Navarro
    • 2
  • Jose Maria Frade
    • 3
  • Noelia López-Sánchez
    • 3
  • Meritxell Teixido
    • 4
  • Ernest Giralt
    • 4
  • Mar Masso
    • 5
  • Jason C Dugas
    • 6
  • Dmitri Leonoudakis
    • 6
  • Karen D. Lariosa-Willingham
    • 6
  • Lawrence Steinman
    • 7
  • Angel Messeguer
    • 2
  1. 1.Center for NeuroimmunologyInstitut d’Investigacions Biomediques August Pi SunyerBarcelonaSpain
  2. 2.Institute for Advanced Chemistry of CataloniaConsejo Superior de Investigaciones CientificasBarcelonaSpain
  3. 3.Instituto CajalConsejo Superior de Investigaciones CientificasMadridSpain
  4. 4.Institute for Research in BiomedicineBarcelonaSpain
  5. 5.Bionure Farma SLBarcelonaSpain
  6. 6.Myelin Repair FoundationSaratogaUSA
  7. 7.Stanford UniversityPalo AltoUSA

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