#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

BDNF, NT-3 and Trk receptor agonist monoclonal antibodies promote neuron survival, neurite extension, and synapse restoration in rat cochlea ex vivo models relevant for hidden hearing loss


Autoři: Stephanie Szobota aff001;  Pranav D. Mathur aff001;  Sairey Siegel aff001;  KristenAnn Black aff001;  H. Uri Saragovi aff002;  Alan C. Foster aff001
Působiště autorů: Otonomy, Inc., San Diego, California, United States of America aff001;  Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, Quebec, Canada aff002
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0224022

Souhrn

Neurotrophins and their mimetics are potential treatments for hearing disorders because of their trophic effects on spiral ganglion neurons (SGNs) whose connections to hair cells may be compromised in many forms of hearing loss. Studies in noise or ototoxin-exposed animals have shown that local delivery of NT-3 or BDNF has beneficial effects on SGNs and hearing. We evaluated several TrkB or TrkC monoclonal antibody agonists and small molecules, along with BDNF and NT-3, in rat cochlea ex vivo models. The TrkB agonists BDNF and a monoclonal antibody, M3, had the greatest effects on SGN survival, neurite outgrowth and branching. In organotypic cochlear explants, BDNF and M3 enhanced synapse formation between SGNs and inner hair cells and restored these connections after excitotoxin-induced synaptopathy. Loss of these synapses has recently been implicated in hidden hearing loss, a condition characterized by difficulty hearing speech in the presence of background noise. The unique profile of M3 revealed here warrants further investigation, and the broad activity profile of BDNF observed underpins its continued development as a hearing loss therapeutic.

Klíčová slova:

Neurons – Nerve fibers – Synapses – Deafness – Cochlea – Neurites – Ganglia – Small molecules


Zdroje

1. Kujawa SG. Acceleration of Age-Related Hearing Loss by Early Noise Exposure: Evidence of a Misspent Youth. Journal of Neuroscience [Internet]. February 2006;26(7):2115–23. Available at: doi: 10.1523/JNEUROSCI.4985-05.2006 16481444

2. Liberman MC. Noise-induced and age-related hearing loss: new perspectives and potential therapies. F1000Res. 2017;6:927. doi: 10.12688/f1000research.11310.1 28690836

3. Pujol R, Puel JL, Gervais d’AC, Eybalin M. Pathophysiology of the glutamatergic synapses in the cochlea. Acta Otolaryngol. 1993;113:330–4. doi: 10.3109/00016489309135819 8100108

4. Ruel J, Wang J, Rebillard G, Eybalin M, Lloyd R, Pujol R, et al. Physiology, pharmacology and plasticity at the inner hair cell synaptic complex. Hear Res. 2007;227:19–27. doi: 10.1016/j.heares.2006.08.017 17079104

5. Kujawa SG, Liberman MC. Adding insult to injury: cochlear nerve degeneration after temporary noise-induced hearing loss. J Neurosci. 2009;29:14077–85. doi: 10.1523/JNEUROSCI.2845-09.2009 19906956

6. Kujawa SG, Liberman MC. Synaptopathy in the noise-exposed and aging cochlea: Primary neural degeneration in acquired sensorineural hearing loss. Hear Res. 2015;330:191–9. doi: 10.1016/j.heares.2015.02.009 25769437

7. Viana LM, O’Malley JT, Burgess BJ, Jones DD, Oliveira CA, Santos F, et al. Cochlear neuropathy in human presbycusis: Confocal analysis of hidden hearing loss in post-mortem tissue. Hear Res. 2015;327:78–88. doi: 10.1016/j.heares.2015.04.014 26002688

8. Wu PZ, Liberman LD, Bennett K, de GV, O’Malley JT, Liberman MC. Primary Neural Degeneration in the Human Cochlea: Evidence for Hidden Hearing Loss in the Aging Ear. Neuroscience. 2018;

9. Tremblay KL, Pinto A, Fischer ME, Klein BE, Klein R, Levy S, et al. Self-Reported Hearing Difficulties Among Adults With Normal Audiograms: The Beaver Dam Offspring Study. Ear Hear. 2015;36:e290–9. doi: 10.1097/AUD.0000000000000195 26164105

10. Takada Y, Beyer LA, Swiderski DL, O’Neal AL, Prieskorn DM, Shivatzki S, et al. Connexin 26 null mice exhibit spiral ganglion degeneration that can be blocked by BDNF gene therapy. Hear Res. 2014;309:124–35. doi: 10.1016/j.heares.2013.11.009 24333301

11. Seyyedi M, Viana LM, Nadol JBJ. Within-subject comparison of word recognition and spiral ganglion cell count in bilateral cochlear implant recipients. Otol Neurotol. 2014;35:1446–50. doi: 10.1097/MAO.0000000000000443 25120196

12. Green SH, Bailey E, Wang Q, Davis RL. The Trk A, B, C’s of neurotrophins in the cochlea. Anat Rec (Hoboken). 2012;295:1877–95.

13. Fritzsch B, Tessarollo L, Coppola E, Reichardt LF. Neurotrophins in the ear: their roles in sensory neuron survival and fiber guidance. Prog Brain Res. 2004;146:265–78. doi: 10.1016/S0079-6123(03)46017-2 14699969

14. Havenith S, Versnel H, Agterberg MJ, de GJC, Sedee RJ, Grolman W, et al. Spiral ganglion cell survival after round window membrane application of brain-derived neurotrophic factor using gelfoam as carrier. Hear Res. 2011;272:168–77. doi: 10.1016/j.heares.2010.10.003 20969940

15. Leake PA, Hradek GT, Hetherington AM, Stakhovskaya O. Brain-derived neurotrophic factor promotes cochlear spiral ganglion cell survival and function in deafened, developing cats. J Comp Neurol. 2011;519:1526–45. doi: 10.1002/cne.22582 21452221

16. Wise AK, Richardson R, Hardman J, Clark G, O’leary S. Resprouting and survival of guinea pig cochlear neurons in response to the administration of the neurotrophins brain-derived neurotrophic factor and neurotrophin-3. J Comp Neurol. 2005;487:147–65. doi: 10.1002/cne.20563 15880560

17. Wan G, Gómez-Casati ME, Gigliello AR, Liberman MC, Corfas G. Neurotrophin-3 regulates ribbon synapse density in the cochlea and induces synapse regeneration after acoustic trauma. Elife. 2014;3.

18. Suzuki J, Corfas G, Liberman MC. Round-window delivery of neurotrophin 3 regenerates cochlear synapses after acoustic overexposure. Sci Rep. 2016;6:24907. doi: 10.1038/srep24907 27108594

19. Sly DJ, Campbell L, Uschakov A, Saief ST, Lam M, O’Leary SJ. Applying Neurotrophins to the Round Window Rescues Auditory Function and Reduces Inner Hair Cell Synaptopathy After Noise-induced Hearing Loss. Otol Neurotol. 2016;37:1223–30. doi: 10.1097/MAO.0000000000001191 27631825

20. Jang SW, Liu X, Yepes M, Shepherd KR, Miller GW, Liu Y, et al. A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone. Proc Natl Acad Sci U S A. 2010;107:2687–92. doi: 10.1073/pnas.0913572107 20133810

21. Massa SM, Yang T, Xie Y, Shi J, Bilgen M, Joyce JN, et al. Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents. J Clin Invest. 2010;120:1774–85. doi: 10.1172/JCI41356 20407211

22. Longo FM, Massa SM. Small-molecule modulation of neurotrophin receptors: a strategy for the treatment of neurological disease. Nat Rev Drug Discov. 2013;12:507–25. 23977697

23. Yang T, Massa SM, Tran KC, Simmons DA, Rajadas J, Zeng AY, et al. A small molecule TrkB/TrkC neurotrophin receptor co-activator with distinctive effects on neuronal survival and process outgrowth. Neuropharmacology. 2016;110:343–61. doi: 10.1016/j.neuropharm.2016.06.015 27334657

24. Massa SM, Yang T, Xie Y, Shi J, Bilgen M, Joyce JN, et al. Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents. J Clin Invest. 2010;120:1774–85. doi: 10.1172/JCI41356 20407211

25. Kramer B, Tropitzsch A, Müller M, Löwenheim H. Myelin-induced inhibition in a spiral ganglion organ culture—Approaching a natural environment in vitro. Neuroscience [Internet]. August 2017;357:75–83. Available at: doi: 10.1016/j.neuroscience.2017.05.053 28596120

26. Schwieger J, Warnecke A, Lenarz T, Esser K-H, Scheper V. Neuronal Survival Morphology and Outgrowth of Spiral Ganglion Neurons Using a Defined Growth Factor Combination. Forsythe J, editor. PLOS ONE [Internet]. August 2015;10(8):e0133680. Available at: doi: 10.1371/journal.pone.0133680 26263175

27. Jin Y, Kondo K, Ushio M, Kaga K, Ryan AF, Yamasoba T. Developmental changes in the responsiveness of rat spiral ganglion neurons to neurotrophic factors in dissociated culture: differential responses for survival, neuritogenesis and neuronal morphology. Cell Tissue Res. 2013;351:15–27. doi: 10.1007/s00441-012-1526-1 23149719

28. Schwieger J, Warnecke A, Lenarz T, Esser K-H, Scheper V. Neuronal Survival Morphology and Outgrowth of Spiral Ganglion Neurons Using a Defined Growth Factor Combination. Forsythe J, editor. PLOS ONE [Internet]. August 2015;10(8):e0133680. Available at: doi: 10.1371/journal.pone.0133680 26263175

29. Kondo K, Pak K, Chavez E, Mullen L, Euteneuer S, Ryan AF. Changes in responsiveness of rat spiral ganglion neurons to neurotrophins across age: differential regulation of survival and neuritogenesis. Int J Neurosci. 2013;123:465–75. doi: 10.3109/00207454.2013.764497 23301942

30. Wang Q, Green SH. Functional role of neurotrophin-3 in synapse regeneration by spiral ganglion neurons on inner hair cells after excitotoxic trauma in vitro. J Neurosci. 2011;31:7938–49. doi: 10.1523/JNEUROSCI.1434-10.2011 21613508

31. Cazorla M, Arrang JM, Prémont J. Pharmacological characterization of six trkB antibodies reveals a novel class of functional agents for the study of the BDNF receptor. Br J Pharmacol. 2011;162:947–60. doi: 10.1111/j.1476-5381.2010.01094.x 21039416

32. Lin JC, Tsao D, Barras P, Bastarrachea RA, Boyd B, Chou J, et al. Appetite enhancement and weight gain by peripheral administration of TrkB agonists in non-human primates. PLoS One. 2008;3:e1900. doi: 10.1371/journal.pone.0001900 18382675

33. Qian MD, Zhang J, Tan XY, Wood A, Gill D, Cho S. Novel agonist monoclonal antibodies activate TrkB receptors and demonstrate potent neurotrophic activities. J Neurosci. 2006;26:9394–403. doi: 10.1523/JNEUROSCI.1118-06.2006 16971523

34. Todd D, Gowers I, Dowler SJ, Wall MD, McAllister G, Fischer DF, et al. A monoclonal antibody TrkB receptor agonist as a potential therapeutic for Huntington’s disease. PLoS One. 2014;9:e87923. doi: 10.1371/journal.pone.0087923 24503862

35. Merkouris S, Barde YA, Binley KE, Allen ND, Stepanov AV, Wu NC, et al. Fully human agonist antibodies to TrkB using autocrine cell-based selection from a combinatorial antibody library. Proc Natl Acad Sci U S A. 2018;115:E7023–E7032. doi: 10.1073/pnas.1806660115 29987039

36. Traub S, Stahl H, Rosenbrock H, Simon E, Florin L, Hospach L, et al. Pharmaceutical Characterization of Tropomyosin Receptor Kinase B-Agonistic Antibodies on Human Induced Pluripotent Stem (hiPS) Cell-Derived Neurons. J Pharmacol Exp Ther. 2017;361:355–65. doi: 10.1124/jpet.117.240184 28351853

37. Ruiz R, Lin J, Forgie A, Foletti D, Shelton D, Rosenthal A, et al. Treatment with trkC agonist antibodies delays disease progression in neuromuscular degeneration (nmd) mice. Hum Mol Genet. 2005;14:1825–37. doi: 10.1093/hmg/ddi189 15888478

38. Sahenk Z, Galloway G, Edwards C, Malik V, Kaspar BK, Eagle A, et al. TrkB and TrkC agonist antibodies improve function, electrophysiologic and pathologic features in Trembler J mice. Exp Neurol. 2010;224:495–506. doi: 10.1016/j.expneurol.2010.05.013 20553714

39. Guillemard V, Ivanisevic L, Garcia AG, Scholten V, Lazo OM, Bronfman FC, et al. An agonistic mAb directed to the TrkC receptor juxtamembrane region defines a trophic hot spot and interactions with p75 coreceptors. Dev Neurobiol. 2010;70:150–64. doi: 10.1002/dneu.20776 19953569

40. Clary DO, Weskamp G, Austin LR, Reichardt LF. TrkA cross-linking mimics neuronal responses to nerve growth factor. Mol Biol Cell. 1994;5:549–63. doi: 10.1091/mbc.5.5.549 7919537

41. LeSauteur L, Maliartchouk S, Le JH, Quirion R, Saragovi HU. Potent human p140-TrkA agonists derived from an anti-receptor monoclonal antibody. J Neurosci. 1996;16:1308–16. 8778282

42. Bothwell M. NGF, BDNF, NT3, and NT4. Handb Exp Pharmacol. 2014;220:3–15. doi: 10.1007/978-3-642-45106-5_1 24668467

43. Huang EJ, Reichardt LF. Trk receptors: roles in neuronal signal transduction. Annu Rev Biochem. 2003;72:609–42. doi: 10.1146/annurev.biochem.72.121801.161629 12676795

44. Jang SW, Liu X, Yepes M, Shepherd KR, Miller GW, Liu Y, et al. A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone. Proc Natl Acad Sci U S A. 2010;107:2687–92. doi: 10.1073/pnas.0913572107 20133810

45. Boltaev U, Meyer Y, Tolibzoda F, Jacques T, Gassaway M, Xu Q, et al. Multiplex quantitative assays indicate a need for reevaluating reported small-molecule TrkB agonists. Sci Signal. 2017;10.

46. Josephy-Hernandez S, Jmaeff S, Pirvulescu I, Aboulkassim T, Saragovi HU. Neurotrophin receptor agonists and antagonists as therapeutic agents: An evolving paradigm. Neurobiol Dis. 2017;97:139–55. doi: 10.1016/j.nbd.2016.08.004 27546056

47. Yu Q, Chang Q, Liu X, Gong S, Ye K, Lin X. 7,8,3’-Trihydroxyflavone, a potent small molecule TrkB receptor agonist, protects spiral ganglion neurons from degeneration both in vitro and in vivo. Biochem Biophys Res Commun. 2012;422:387–92. doi: 10.1016/j.bbrc.2012.04.154 22575512

48. Yu Q, Chang Q, Liu X, Wang Y, Li H, Gong S, et al. Protection of spiral ganglion neurons from degeneration using small-molecule TrkB receptor agonists. J Neurosci. 2013;33:13042–52. doi: 10.1523/JNEUROSCI.0854-13.2013 23926258

49. Kobayashi K, Suzuki H. Synapse-selective rapid potentiation of hippocampal synaptic transmission by 7,8-dihydroxyflavone. Neuropsychopharmacol Rep. 2018;38:197–203. doi: 10.1002/npr2.12033 30280523

50. Chao MV. Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci. 2003;4:299–309. doi: 10.1038/nrn1078 12671646

51. Huang EJ, Reichardt LF. Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci. 2001;24:677–736. doi: 10.1146/annurev.neuro.24.1.677 11520916

52. Pirvola U, Arumäe U, Moshnyakov M, Palgi J, Saarma M, Ylikoski J. Coordinated expression and function of neurotrophins and their receptors in the rat inner ear during target innervation. Hear Res. 1994;75:131–44. doi: 10.1016/0378-5955(94)90064-7 8071140

53. Malgrange B, Lefebvre P, Van de WTR, Staecker H, Moonen G. Effects of neurotrophins on early auditory neurones in cell culture. Neuroreport. 1996;7:913–7. doi: 10.1097/00001756-199603220-00016 8724672

54. Mou K, Adamson CL, Davis RL. Time-dependence and cell-type specificity of synergistic neurotrophin actions on spiral ganglion neurons. J Comp Neurol. 1998;402:129–39. 9831050

55. Sommerfeld MT, Schweigreiter R, Barde YA, Hoppe E. Down-regulation of the neurotrophin receptor TrkB following ligand binding. Evidence for an involvement of the proteasome and differential regulation of TrkA and TrkB. J Biol Chem. 2000;275:8982–90. doi: 10.1074/jbc.275.12.8982 10722747

56. Widmer HR, Ohsawa F, Knüsel B, Hefti F. Down-regulation of phosphatidylinositol response to BDNF and NT-3 in cultures of cortical neurons. Brain Res. 1993;614:325–34. doi: 10.1016/0006-8993(93)91051-s 8348325

57. Frank L, Ventimiglia R, Anderson K, Lindsay RM, Rudge JS. BDNF down-regulates neurotrophin responsiveness, TrkB protein and TrkB mRNA levels in cultured rat hippocampal neurons. Eur J Neurosci. 1996;8:1220–30. doi: 10.1111/j.1460-9568.1996.tb01290.x 8752592

58. Liberman MC, Kujawa SG. Cochlear synaptopathy in acquired sensorineural hearing loss: Manifestations and mechanisms. Hear Res. 2017;349:138–47. doi: 10.1016/j.heares.2017.01.003 28087419

59. Kalra S, Genge A, Arnold DL. A prospective, randomized, placebo-controlled evaluation of corticoneuronal response to intrathecal BDNF therapy in ALS using magnetic resonance spectroscopy: feasibility and results. Amyotroph Lateral Scler Other Motor Neuron Disord. 2003;4:22–6. 12745614

60. Sahenk Z, Nagaraja HN, McCracken BS, King WM, Freimer ML, Cedarbaum JM, et al. NT-3 promotes nerve regeneration and sensory improvement in CMT1A mouse models and in patients. Neurology. 2005;65:681–9. doi: 10.1212/01.wnl.0000171978.70849.c5 16157899

61. Ochs G, Penn RD, York M, Giess R, Beck M, Tonn J, et al. A phase I/II trial of recombinant methionyl human brain derived neurotrophic factor administered by intrathecal infusion to patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000;1:201–6. 11464953

62. Group TBDNFS. A controlled trial of recombinant methionyl human BDNF in ALS (Phase III). Neurology. 1999;52:1427–33. doi: 10.1212/wnl.52.7.1427 10227630

63. Pardridge WM, Kang YS, Buciak JL. Transport of human recombinant brain-derived neurotrophic factor (BDNF) through the rat blood-brain barrier in vivo using vector-mediated peptide drug delivery. Pharm Res. 1994;11:738–46. doi: 10.1023/a:1018940732550 8058646

64. Goycoolea MV. Clinical aspects of round window membrane permeability under normal and pathological conditions. Acta Otolaryngol. 2001;121:437–47. doi: 10.1080/000164801300366552 11508501

65. Piu F, Tsivkovskaia N, Fernandez R, Wang X, Harrop-Jones A, Altmann T, et al. A sustained-exposure formulation of the neurotrophic factor BDNF protects against noise-induced cochlear synaptopathy in young adult and aged rats. Assoc Res Otolaryngol Abs. 2018.

66. Saragovi HU, Piu F, Foster AC, Black K. TrkB or TrkC agonist compositions and methods for the treatment of otic conditions. Vol. US20170029511A1, Patent application. 2015.


Článok vyšiel v časopise

PLOS One


2019 Číslo 10
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Aktuální možnosti diagnostiky a léčby litiáz
nový kurz
Autori: MUDr. Tomáš Ürge, PhD.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#