Skip to main content

Advertisement

SpringerLink
Log in

Small Molecule Agonists of Cell Adhesion Molecule L1 Mimic L1 Functions In Vivo

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Lack of permissive mechanisms and abundance of inhibitory molecules in the lesioned central nervous system of adult mammals contribute to the failure of functional recovery after injury, leading to severe disabilities in motor functions and pain. Peripheral nerve injury impairs motor, sensory, and autonomic functions, particularly in cases where nerve gaps are large and chronic nerve injury ensues. Previous studies have indicated that the neural cell adhesion molecule L1 constitutes a viable target to promote regeneration after acute injury. We screened libraries of known drugs for small molecule agonists of L1 and evaluated the effect of hit compounds in cell-based assays in vitro and in mice after femoral nerve and spinal cord injuries in vivo. We identified eight small molecule L1 agonists and showed in cell-based assays that they stimulate neuronal survival, neuronal migration, and neurite outgrowth and enhance Schwann cell proliferation and migration and myelination of neurons in an L1-dependent manner. In a femoral nerve injury mouse model, enhanced functional regeneration and remyelination after application of the L1 agonists were observed. In a spinal cord injury mouse model, L1 agonists improved recovery of motor functions, being paralleled by enhanced remyelination, neuronal survival, and monoaminergic innervation, reduced astrogliosis, and activation of microglia. Together, these findings suggest that application of small organic compounds that bind to L1 and stimulate the beneficial homophilic L1 functions may prove to be a valuable addition to treatments of nervous system injuries.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

Abbreviations

BMS:

Basso mouse scale

BrdU:

bromodeoxyuridine

BSA:

bovine serum albumin

ChAT:

choline acetyl transferase

CNS:

central nervous system

FBA:

foot-base angle

GFAP:

glial fibrillary acidic protein

HRP:

horse radish peroxidase

HTA:

heels-tail angle

MBP:

myelin basic protein

NMDA:

N-methyl-D-aspartate

PBS:

phosphate-buffered saline solution

PBST:

phosphate-buffered saline solution containing 0.05 % Triton X100

PLR:

protraction-length ratio

PNS:

peripheral nervous system

RI:

recovery index

TH:

tyrosine hydroxylase

VGAT:

vesicular GABA transporter

VGLUT:

vesicular glutamate transporter 1

References

  1. Liu K, Tedeschi A, Park KK, He Z (2011) Neuronal intrinsic mechanisms of axon regeneration. Annu Rev Neurosci 34:131–152. doi:10.1146/annurev-neuro-061010-113723

    Article  PubMed  Google Scholar 

  2. Lundborg G, Rosén B (2007) Hand function after nerve repair. Acta Physiol (Oxf) 189(2):207–217

    Article  CAS  Google Scholar 

  3. Ferguson IA, Koide T, Rush RA (2001) Stimulation of corticospinal tract regeneration in the chronically injured spinal cord. Eur J Neurosci 13(5):1059–1064

    Article  CAS  PubMed  Google Scholar 

  4. Irintchev A, Schachner M (2012) The injured and regenerating nervous system: immunoglobulin superfamily members as key players. Neuroscientist 18(5):452–466

    Article  CAS  PubMed  Google Scholar 

  5. Lavdas AA, Papastefanaki F, Thomaidou D, Matsas R (2011) Cell adhesion molecules in gene and cell therapy approaches for nervous system repair. Curr Gene Ther 11(2):90–100

    Article  CAS  PubMed  Google Scholar 

  6. Skaper SD (2012) Neuronal growth-promoting and inhibitory cues in neuroprotection and neuroregeneration. Methods Mol Biol 846:13–22. doi:10.1007/978-1-61779-536-7_2

    Article  CAS  PubMed  Google Scholar 

  7. Zhang Y, Yeh J, Richardson PM, Bo X (2008) Cell adhesion molecules of the immunoglobulin superfamily in axonal regeneration and neural repair. Restor Neurol Neurosci 26(2–3):81–96

    CAS  PubMed  Google Scholar 

  8. Lemmon V, Farr KL, Lagenaur C (1989) L1-mediated axon outgrowth occurs via a homophilic binding mechanism. Neuron 2(6):1597–1603

    Article  CAS  PubMed  Google Scholar 

  9. Wei CH, Ryu SE (2012) Homophilic interaction of the L1 family of cell adhesion molecules. Exp Mol Med 44(7):413–423. doi:10.3858/emm.2012.44.7.050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Barbin G, Aigrot MS, Charles P, Foucher A, Grumet M, Schachner M, Zalc B, Lubetzki C (2004) Axonal cell-adhesion molecule L1 in CNS myelination. Neuron Glia Biol 1:65–72. doi:10.1017/S1740925X04000092

    Article  CAS  PubMed  Google Scholar 

  11. Wood PM, Schachner M, Bunge RP (1990) Inhibition of Schwann cell myelination in vitro by antibody to the L1 adhesion molecule. J Neurosci 10(11):3635–3645

    CAS  PubMed  Google Scholar 

  12. Roonprapunt C, Huang W, Grill R, Friedlander D, Grumet M, Chen S, Schachner M, Young W (2013) Soluble cell adhesion molecule L1-Fc promotes locomotor recovery in rats after spinal cord injury. J Neurotrauma 20(9):871–882

    Article  Google Scholar 

  13. Chen J, Bernreuther C, Dihne M, Schachner M (2005) Cell adhesion molecule l1-transfected embryonic stem cells with enhanced survival support regrowth of corticospinal tract axons in mice after spinal cord injury. J Neurotrauma 22(8):896–906

    Article  PubMed  Google Scholar 

  14. He X, Knepper M, Ding C, Li J, Castro S, Siddiqui M, Schachner M (2012) Promotion of spinal cord regeneration by neural stem cell-secreted trimerized cell adhesion molecule L1. PLoS ONE 7(9):e46223. doi:10.1371/journal.pone.0046223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chen J, Wu J, Apostolova I, Skup M, Irintchev A, Kügler S, Schachner M (2007) Adeno-associated virus-mediated L1 expression promotes functional recovery after spinal cord injury. Brain 130(4):954–969

    Article  PubMed  Google Scholar 

  16. Montag-Sallaz M, Schachner M, Montag D (2002) Misguided axonal projections, neural cell adhesion molecule 180 mRNA upregulation, and altered behavior in mice deficient for the close homolog of L1. Mol Cell Biol 22(22):7967–7981

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Dahme M, Bartsch U, Martini R, Anliker B, Schachner M, Mantei N (1997) Disruption of the mouse L1 gene leads to malformations of the nervous system. Nat Genet 17(3):346–349

    Article  CAS  PubMed  Google Scholar 

  18. Schulz F, Lutz D, Rusche N, Bastús NG, Stieben M, Höltig M, Grüner F, Weller H et al (2013) Gold nanoparticles functionalized with a fragment of the neural cell adhesion molecule L1 stimulate L1-mediated functions. Nanoscale 5(21):10605–10617. doi:10.1039/c3nr02707d

    Article  CAS  PubMed  Google Scholar 

  19. Appel F, Holm J, Conscience JF, von und Bohlen Halbach F, Faissner A, James P, Schachner M (1995) Identification of the border between fibronectin type III homologous repeats 2 and 3 of the neural cell adhesion molecule L1 as a neurite outgrowth promoting and signal transducing domain. J Neurobiol 28(3):297–312

    Article  CAS  PubMed  Google Scholar 

  20. Rathjen FG, Schachner M (1984) Immunocytological and biochemical characterization of a new neuronal cell surface component (L1 antigen) which is involved in cell adhesion. EMBO J 3(1):1–10

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Chen S, Mantei N, Dong L, Schachner M (1999) Prevention of neuronal cell death by neural adhesion molecules L1 and CHL1. J Neurobiol 38(3):428–439

    Article  CAS  PubMed  Google Scholar 

  22. Loers G, Saini V, Mishra B, Papastefanaki F, Lutz D, Chaudhury S, Ripoll DR, Wallqvist A et al (2014) Nonyloxytryptamine mimics polysialic acid and modulates neuronal and glial functions in cell culture. J Neurochem 128(1):88–100. doi:10.1111/jnc.12408

    Article  CAS  PubMed  Google Scholar 

  23. Loers G, Chen S, Grumet M, Schachner M (2005) Signal transduction pathways implicated in neural recognition molecule L1 triggered neuroprotection and neuritogenesis. J Neurochem 92(6):1463–1476

    Article  CAS  PubMed  Google Scholar 

  24. Mehanna A, Mishra B, Kurschat N, Schulze C, Bian S, Loers G, Irintchev A, Schachner M (2009) Polysialic acid glycomimetics promote myelination and functional recovery after peripheral nerve injury in mice. Brain 132(6):1449–1462. doi:10.1093/brain/awp128

    Article  PubMed  Google Scholar 

  25. Simova O, Irintchev A, Mehanna A, Liu J, Dihné M, Bächle D, Sewald N, Loers G et al (2006) Carbohydrate mimics promote functional recovery after peripheral nerve repair. Ann Neurol 6(4):430–437

    Article  Google Scholar 

  26. Morrissey TK, Kleitman N, Bunge RP (1991) Isolation and functional characterization of Schwann cells derived from adult peripheral nerve. J Neurosci 11(8):2433–2442

    CAS  PubMed  Google Scholar 

  27. Lutz D, Loers G, Kleene R, Oezen I, Kataria H, Katagihallimath N, Braren I, Harauz G et al (2014) Myelin basic protein cleaves cell adhesion molecule L1 and promotes neuritogenesis and cell survival. J Biol Chem 289(19):13503–13518. doi:10.1074/jbc.M113.530238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mehanna A, Jakovcevski I, Acar A, Xiao M, Loers G, Rougon G, Irintchev A, Schachner M (2010) Polysialic acid glycomimetic promotes functional recovery and plasticity after spinal cord injury in mice. Mol Ther 18(1):34–43. doi:10.1038/mt.2009.235

    Article  CAS  PubMed  Google Scholar 

  29. Irintchev A, Simova O, Eberhardt KA, Morellini F, Schachner M (2005) Impacts of lesion severity and tyrosine kinase receptor B deficiency on functional outcome of femoral nerve injury assessed by a novel single-frame motion analysis in mice. Eur J Neurosci 22(4):802–808

    Article  PubMed  Google Scholar 

  30. Basso DM, Fisher LC, Anderson AJ, Jakeman LB, McTigue DM, Popovich PG (2006) Basso mouse scale for locomotion detects differences in recovery after spinal cord injury in five common mouse strains. J Neurotrauma 23(5):635–659

    Article  PubMed  Google Scholar 

  31. Brushart T (1988) Preferential reinnervation of motor nerves by regenerating motor axons. J Neurosci 8(3):1026–1031

    CAS  PubMed  Google Scholar 

  32. Montag D, Giese KP, Bartsch U, Martini R, Lang Y, Blüthmann H, Karthigasan J, Kirschner DA et al (1994) Mice deficient for the myelin-associated glycoprotein show subtle abnormalities in myelin. Neuron 13(1):229–246

    Article  CAS  PubMed  Google Scholar 

  33. Guseva D, Zerwas M, Xiao MF, Jakovcevski I, Irintchev A, Schachner M (2011) Adhesion molecule L1 overexpressed under the control of the neuronal Thy-1 promoter improves myelination after peripheral nerve injury in adult mice. Exp Neurol 229(2):339–352. doi:10.1016/j.expneurol.2011.02.018

    Article  CAS  PubMed  Google Scholar 

  34. Lutz D, Wolters-Eisfeld G, Schachner M, Kleene R (2014) Cathepsin E generates a sumoylated intracellular fragment of the cell adhesion molecule L1 to promote neuronal and Schwann cell migration as well as myelination. J Neurochem 128(5):713–724. doi:10.1111/jnc.12473

    Article  CAS  PubMed  Google Scholar 

  35. Godenschwege TA, Kristiansen LV, Uthaman SB, Hortsch M, Murphey RK (2006) A conserved role for Drosophila neuroglian and human L1-CAM in central-synapse formation. Curr Biol 16(1):12–23

    Article  CAS  PubMed  Google Scholar 

  36. Dityatev A, Bukalo O, Schachner M (2008) Modulation of synaptic transmission and plasticity by cell adhesion and repulsion molecules. Neuron Glia Biol 4(3):197–209. doi:10.1017/S1740925X09990111

    Article  PubMed  Google Scholar 

  37. Kamiguchi H, Lemmon V (1997) Neural cell adhesion molecule L1: signaling pathways and growth cone motility. J Neurosci Res 49(1):1–8

    Article  CAS  PubMed  Google Scholar 

  38. Maness P, Schachner M (2007) Neural recognition molecules of the immunoglobulin superfamily: signaling transducers of axon guidance and neuronal migration. Nat Neurosci 10(1):19–26

    Article  CAS  PubMed  Google Scholar 

  39. Cui YF, Xu JC, Hargus G, Jakovcevski I, Schachner M, Bernreuther C (2011) Embryonic stem cell-derived L1 overexpressing neural aggregates enhance recovery after spinal cord injury in mice. PLoS ONE 6:e17126. doi:10.1371/journal.pone.0017126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lavdas AA, Chen J, Papastefanaki F, Chen S, Schachner M, Matsas R, Thomaidou D (2010) Schwann cells engineered to express the cell adhesion molecule L1 accelerate myelination and motor recovery after spinal cord injury. Exp Neurol 221(1):206–216. doi:10.1016/j.expneurol.2009.10.024

    Article  CAS  PubMed  Google Scholar 

  41. Loers G, Cui Y-F, Neumaier I, Schachner M, Skerra A (2014) A Fab fragment directed against the neural cell adhesion molecule L1 enhances functional recovery after injury of the adult mouse spinal cord. Biochem J 460(3):437–446. doi:10.1042/BJ20131677

    Article  CAS  PubMed  Google Scholar 

  42. Xu G, Nie DY, Wang WZ, Zhang PH, Shen J, Ang BT, Liu GH, Luo XG et al (2004) Optic nerve regeneration in polyglycolic acid-chitosan conduits coated with recombinant L1-Fc. Neuroreport 15(14):2167–2172

    Article  CAS  PubMed  Google Scholar 

  43. Witheford M, Westendorf K, Roskams AJ (2013) Olfactory ensheathing cells promote corticospinal axonal outgrowth by a L1 CAM-dependent mechanism. Glia 61(11):1873–1889. doi:10.1002/glia.22564

    Article  PubMed  Google Scholar 

  44. Ball SG, Desaiah D, Zhang Q, Thase ME, Perahia DG (2013) Efficacy and safety of duloxetine 60 mg once daily in major depressive disorder: a review with expert commentary. Drugs Context 2013:212245. doi:10.7573/dic.212245

    PubMed  PubMed Central  Google Scholar 

  45. Li J, Yang L, Pu C, Tang Y, Yun H, Han P (2013) The role of duloxetine in stress urinary incontinence: a systematic review and meta-analysis. Int Urol Nephrol 45(3):679–686. doi:10.1007/s11255-013-0410-6

    Article  CAS  PubMed  Google Scholar 

  46. Calabrese F, Guidotti G, Molteni R, Racagni G, Mancini M, Riva MA (2012) Stress-induced changes of hippocampal NMDA receptors: modulation by duloxetine treatment. PLoS ONE 7(5):e37916. doi:10.1371/journal.pone.0037916

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Husi H, Ward MA, Choudhary JS, Blackstock WP, Grant SG (2000) Proteomic analysis of NMDA receptor-adhesion protein signaling complexes. Nat Neurosci 3(7):661–669

    Article  CAS  PubMed  Google Scholar 

  48. Welzl H, Stork O (2003) Cell adhesion molecules: key players in memory consolidation? News Physiol Sci 18:147–150

    CAS  PubMed  Google Scholar 

  49. Shipton OA, Paulsen O (2013) GluN2A and GluN2B subunit-containing NMDA receptors in hippocampal plasticity. Philos Trans R Soc Lond Ser B Biol Sci 369:20130163. doi:10.1098/rstb.2013.0163

    Article  Google Scholar 

  50. Sandi C, Bisaz R (2007) A model for the involvement of neural cell adhesion molecules in stress-related mood disorders. Neuroendocrinology 85(3):158–176

    Article  CAS  PubMed  Google Scholar 

  51. Tsoory MM, Guterman A, Richter-Levin G (2010) “Juvenile stress” alters maturation-related changes in expression of the neural cell adhesion molecule L1 in the limbic system: relevance for stress-related psychopathologies. J Neurosci Res 88(2):369–380. doi:10.1002/jnr.22203

    Article  CAS  PubMed  Google Scholar 

  52. Venero C, Tilling T, Hermans-Borgmeyer I, Schmidt R, Schachner M, Sandi C (2002) Chronic stress induces opposite changes in the mRNA expression of the cell adhesion molecules NCAM and L1. Neuroscience 115(4):1211–1219

    Article  CAS  PubMed  Google Scholar 

  53. Du QH, Peng C, Zhang H (2013) Polydatin: a review of pharmacology and pharmacokinetics. Pharm Biol 51(11):1347–1354. doi:10.3109/13880209.2013.792849

    Article  CAS  PubMed  Google Scholar 

  54. Lanzilli G, Cottarelli A, Nicotera G, Guida S, Ravagnan G, Fuggetta MP (2012) Anti-inflammatory effect of resveratrol and polydatin by in vitro IL-17 modulation. Inflammation 35(1):240–248. doi:10.1007/s10753-011-9310-z

    Article  CAS  PubMed  Google Scholar 

  55. Pasinetti GM, Wang J, Ho L, Zhao W, Dubner L (2015) Roles of resveratrol and other grape-derived polyphenols in Alzheimer’s disease prevention and treatment. Biochim Biophys Acta 852(6):1202–1208. doi:10.1016/j.bbadis.2014.10.006

    Article  Google Scholar 

  56. Rocha-González HI, Ambriz-Tututi M, Granados-Soto V (2008) Resveratrol: a natural compound with pharmacological potential in neurodegenerative diseases. CNS Neurosci Ther 14(3):234–247. doi:10.1111/j.1755-5949.2008.00045.x

    Article  PubMed  Google Scholar 

  57. Crismon ML (1994) Tacrine: first drug approved for Alzheimer’s disease. Ann Pharmacother 28(6):744–751

    CAS  PubMed  Google Scholar 

  58. Djogo N, Jakovcevski I, Müller C, Lee HJ, Xu JC, Jakovcevski M, Kügler S, Loers G et al (2013) Adhesion molecule L1 binds to amyloid beta and reduces Alzheimer’s disease pathology in mice. Neurobiol Dis 56:104–115. doi:10.1016/j.nbd.2013.04.014

    Article  CAS  PubMed  Google Scholar 

  59. Cui X, Weng YQ, Frappé I, Burgess A, Girão da Cruz MT, Schachner M, Aubert I (2011) The cell adhesion molecule L1 regulates the expression of choline acetyltransferase and the development of septal cholinergic neurons. Brain Behav 1(2):73–86. doi:10.1002/brb3.15

    Article  PubMed  PubMed Central  Google Scholar 

  60. Zhong ZG, Yokoyama S, Noda M, Higashida H (1997) Overexpression of adhesion molecule L1 in NG108-15 neuroblastoma X glioma hybrid cells enhances dibutyryl cyclic AMP-induced neurite outgrowth and functional synapse formation with myotubes. J Neurochem 68(6):2291–2299

    Article  CAS  PubMed  Google Scholar 

  61. Matsumoto-Miyai K, Ninomiya A, Yamasaki H, Tamura H, Nakamura Y, Shiosaka S (2003) NMDA-dependent proteolysis of presynaptic adhesion molecule L1 in the hippocampus by neuropsin. J Neurosci 23(21):7727–7736

    CAS  PubMed  Google Scholar 

  62. Casacalenda N, Perry JC, Looper K (2002) Remission in major depressive disorder: a comparison of pharmacotherapy, psychotherapy, and control conditions. Am J Psychiatry 159(8):1354–1360

    Article  PubMed  Google Scholar 

  63. Norman TR, Burrows GD (1989) Monoamine oxidase, monoamine oxidase inhibitors, and panic disorder. J Neural Transm 28:53–63

    CAS  Google Scholar 

  64. Simpson SM, Hickey AJ, Baker GB, Reynolds JN, Beninger RJ (2012) The antidepressant phenelzine enhances memory in the double Y-maze and increases GABA levels in the hippocampus and frontal cortex of rats. Pharmacol Biochem Behav 102(1):109–117. doi:10.1016/j.pbb.2012.03.027

    Article  CAS  PubMed  Google Scholar 

  65. Guan H, Maness PF (2010) Perisomatic GABAergic innervation in prefrontal cortex is regulated by ankyrin interaction with the L1 cell adhesion molecule. Cereb Cortex 20(11):2684–2693. doi:10.1093/cercor/bhq016

    Article  PubMed  PubMed Central  Google Scholar 

  66. Chenu F, El Mansari M, Blier P (2009) Long-term administration of monoamine oxidase inhibitors alters the firing rate and pattern of dopamine neurons in the ventral tegmental area. Int J Neuropsychopharmacol 12(4):475–485. doi:10.1017/S1461145708009218

    Article  CAS  PubMed  Google Scholar 

  67. Singh IN, Gilmer LK, Miller DM, Cebak JE, Wang JA, Hall ED (2013) Phenelzine mitochondrial functional preservation and neuroprotection after traumatic brain injury related to scavenging of the lipid peroxidation-derived aldehyde 4-hydroxy-2-nonenal. J Cereb Blood Flow Metab 33(4):593–599. doi:10.1038/jcbfm.2012.211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Itoh K, Shimono K, Lemmon V (2005) Dephosphorylation and internalization of cell adhesion molecule L1 induced by theta burst stimulation in rat hippocampus. Mol Cell Neurosci 29(2):245–249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Saghatelyan AK, Nikonenko AG, Sun M et al (2004) Reduced GABAergic transmission and number of hippocampal perisomatic inhibitory synapses in juvenile mice deficient in the neural cell adhesion molecule L1. Mol Cell Neurosci 26:191–203

    Article  CAS  PubMed  Google Scholar 

  70. Woodbury A, Yu SP, Wei L, García P (2013) Neuro-modulating effects of honokiol: a review. Front Neurol 4:130. doi:10.3389/fneur.2013.00130

    Article  PubMed  PubMed Central  Google Scholar 

  71. Wang H, Liao Z, Sun X, Shi Q, Huo G, Xie Y, Tang X, Zhi X et al (2014) Intravenous administration of honokiol provides neuroprotection and improves functional recovery after traumatic brain injury through cell cycle inhibition. Neuropharmacology 86:9–21. doi:10.1016/j.neuropharm.2014.06.018

    Article  CAS  PubMed  Google Scholar 

  72. Hu Z, Bian X, Liu X, Zhu Y, Zhang X, Chen S, Wang K, Wang Y (2013) Honokiol protects brain against ischemia-reperfusion injury in rats through disrupting PSD95-nNOS interaction. Brain Res 1491:204–212. doi:10.1016/j.brainres.2012.11.004

    Article  CAS  PubMed  Google Scholar 

  73. Zhang P, Liu X, Zhu Y, Chen S, Zhou D, Wang Y (2013) Honokiol inhibits the inflammatory reaction during cerebral ischemia reperfusion by suppressing NF-κB activation and cytokine production of glial cells. Neurosci Lett 534:123–127. doi:10.1016/j.neulet.2012.11.052

    Article  CAS  PubMed  Google Scholar 

  74. Reidy M, Zihlmann P, Hubbell JA, Hall H (2006) Activation of cell-survival transcription factor NFkappaB in L1Ig6-stimulated endothelial cells. J Biomed Mater Res A 77(3):542–550

    Article  PubMed  Google Scholar 

  75. Picazo O, Becerril-Montes A, Huidobro-Perez D, Garcia-Segura LM (2010) Neuroprotective actions of the synthetic estrogen 17alpha-ethynylestradiol in the hippocampus. Cell Mol Neurobiol 30(5):675–682. doi:10.1007/s10571-009-9490-3

    Article  CAS  PubMed  Google Scholar 

  76. Vega-Rivera NM, López-Rubalcava C, Estrada-Camarena E (2013) The antidepressant-like effect of ethynyl estradiol is mediated by both serotonergic and noradrenergic systems in the forced swimming test. Neuroscience 250:102–111. doi:10.1016/j.neuroscience.2013.06.058

    Article  CAS  PubMed  Google Scholar 

  77. Poynard T, Regimbeau C, Benhamou Y (2001) Meta-analysis of smooth muscle relaxants in the treatment of irritable bowel syndrome. Aliment Pharmacol Ther 15(3):355–361

    Article  CAS  PubMed  Google Scholar 

  78. Buffet M, Dupin N (2003) Current treatments for scabies. Fundam Clin Pharmacol 17(2):217–225

    Article  CAS  PubMed  Google Scholar 

  79. Kalus I, Schnegelsberg B, Seidah NG, Kleene R, Schachner M (2003) The proprotein convertase PC5A and a metalloprotease are involved in the proteolytic processing of the neural adhesion molecule L1. J Biol Chem 278(12):10381–10388

    Article  CAS  PubMed  Google Scholar 

  80. Loers G, Makhina T, Bork U, Dörner A, Schachner M, Kleene R (2012) The interaction between cell adhesion molecule L1, matrix metalloproteinase 14, and adenine nucleotide translocator at the plasma membrane regulates L1-mediated neurite outgrowth of murine cerebellar neurons. J Neurosci 32(11):3917–3930. doi:10.1523/JNEUROSCI.6165-11.2012

    Article  CAS  PubMed  Google Scholar 

  81. Maretzky T, Schulte M, Ludwig A, Rose-John S, Blobel C, Hartmann D, Altevogt P, Saftig P et al (2005) L1 is sequentially processed by two differently activated metalloproteases and presenilin/gamma-secretase and regulates neural cell adhesion, cell migration, and neurite outgrowth. Mol Cell Biol 25(20):9040–9053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Lutz D, Kataria H, Kleene R, Loers G, Chaudhary H, Guseva D, Wu B, Jakovcevski I et al (2015) Myelin basic protein cleaves cell adhesion molecule L1 and improves regeneration after injury. Mol Neurobiol 2015

  83. Zhou L, Barão S, Laga M, Bockstael K, Borgers M, Gijsen H, Annaert W, Moechars D et al (2012) The neural cell adhesion molecules L1 and CHL1 are cleaved by BACE1 protease in vivo. J Biol Chem 287(31):25927–25940. doi:10.1074/jbc.M112.377465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We thank Eva Kronberg and Ulrike Wolters for excellent animal caretaking and Ute Bork for genotyping of mice, Dagmar Drexler and Barbara Holstermann for help with electron microscopy, and Torsten Renz and Fritz Kutschera for technical support. Melitta Schachner is supported by the New Jersey Commission for Spinal Cord Research and the Li Kashing Foundation at the Shantou University Medical College.

Conflict of interest

The authors declare no conflict of interest.

Author contributions

All authors have contributed substantially to this research study. GL, DL, and MS conceived and designed the experiments. HK, DL, GL, and HC performed the experiments. HK and DL analyzed the data. GL and MS wrote the paper.

Author information

Author notes

    Authors and Affiliations

    1. Institut für Biosynthese Neuraler Strukturen, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum-Hamburg Eppendorf, Falkenried 94, 20251, Hamburg, Germany

      Hardeep Kataria, David Lutz, Harshita Chaudhary & Gabriele Loers

    2. Keck Center for Collaborative Neuroscience and Department of Cell Biology and Neuroscience, Rutgers University, 604 Allison Road, Piscataway, NJ, 08854, USA

      Melitta Schachner

    3. Center for Neuroscience, Shantou University Medical College, 22 Xin Ling Road, Shantou, Guangdong, 515041, China

      Melitta Schachner

    Authors
    1. Hardeep Kataria
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. David Lutz
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Harshita Chaudhary
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Melitta Schachner
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Gabriele Loers
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Melitta Schachner.

    Additional information

    Hardeep Kataria and David Lutz contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Kataria, H., Lutz, D., Chaudhary, H. et al. Small Molecule Agonists of Cell Adhesion Molecule L1 Mimic L1 Functions In Vivo. Mol Neurobiol 53, 4461–4483 (2016). https://doi.org/10.1007/s12035-015-9352-6

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12035-015-9352-6

    Keywords

    Search

    Navigation