BDNF‐induced survival of auditory neurons in vivo: Cessation of treatment leads to accelerated loss of survival effects

Neurotrophic factors are important for the development and maintenance of the auditory system. They have also been shown to act as survival factors for auditory neurons in animal deafness models. Studies have demonstrated recently that these neurotrophic factors not only maintain survival of auditory neurons, but that these surviving neurons retain functionality. It remains to be determined, however, if a single administration of a neurotrophic factor is sufficient to maintain auditory neuron survival after loss of hair cells, or if sustained delivery is required. This study investigated the longevity of the survival effects of BDNF on auditory neurons in deafened guinea pigs. Briefly, the left cochleae of deafened guinea pigs were infused with BDNF for 28 days via a mini‐osmotic pump, and neuronal survival was analyzed at various stages after the completion of treatment. BDNF treatment prevented the degeneration of auditory neurons that normally is seen after a loss of hair cells, supporting previous studies. Our results indicate, however, that cessation of BDNF treatment leads to an accelerated decline in auditory neuron survival as compared to that observed in deafened, untreated cochleae. These findings indicate that much work remains to be done to establish a technique for the long‐term survival of auditory neurons in the deaf ear. © 2003 Wiley‐Liss, Inc.

[1]  S. Sharma,et al.  The combined effect of brain-derived neurotrophic factor and a free radical scavenger in experimental glaucoma. , 2000, Investigative ophthalmology & visual science.

[2]  M. Takumida,et al.  Brain-derived Neurotrophic Factor and Nitric Oxide Synthase Inhibitor Protect the Vestibular Organ Against Gentamicin Ototoxicity , 2002, Acta oto-laryngologica.

[3]  R. Lousteau,et al.  Increased spiral ganglion cell survival in electrically stimulated, deafened guinea pig cochleae , 1987, The Laryngoscope.

[4]  M. Saarma,et al.  Brain-derived neurotrophic factor and neurotrophin 3 mRNAs in the peripheral target fields of developing inner ear ganglia. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[5]  T. Dawson,et al.  Differential Susceptibility to Neurotoxicity Mediated by Neurotrophins and Neuronal Nitric Oxide Synthase , 1997, The Journal of Neuroscience.

[6]  G. Gallo,et al.  Neurotrophins and the dynamic regulation of the neuronal cytoskeleton. , 2000, Journal of neurobiology.

[7]  D. Choi,et al.  Potentiated necrosis of cultured cortical neurons by neurotrophins. , 1995, Science.

[8]  Thomas R. Van De Water,et al.  Brain-derived neurotrophic factor gene therapy prevents spiral ganglion degeneration after hair cell loss , 1998, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[9]  J. Kellerth,et al.  Effects of Neurotransplants and BDNF on the Survival and Regeneration of Injured Adult Spinal Motoneurons , 1997, The European journal of neuroscience.

[10]  Ilmari Pyykkö,et al.  Neurotrophic factor intervention restores auditory function in deafened animals , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Wutian Wu,et al.  Long-term effects of a single dose of brain-derived neurotrophic factor on motoneuron survival following spinal root avulsion in the adult rat , 1999, Neuroscience Letters.

[12]  M. Saarma,et al.  Coordinated expression and function of neurotrophins and their receptors in the rat inner ear during target innervation , 1994, Hearing Research.

[13]  J. Schacht,et al.  Formation of reactive oxygen species following bioactivation of gentamicin. , 1999, Free radical biology & medicine.

[14]  M. Halterman,et al.  Gene Therapy in the Inner Ear: Mechanisms and Clinical Implications , 1999, Annals of the New York Academy of Sciences.

[15]  Bernd Fritzsch,et al.  Making and breaking the innervation of the ear: neurotrophic support during ear development and its clinical implications , 1999, Cell and Tissue Research.

[16]  M. Saarma,et al.  Expression patterns of neurotrophin and their receptor mRNAs in the rat inner ear , 1993, Hearing Research.

[17]  J. Schacht,et al.  Stimulation of free radical formation by aminoglycoside antibiotics 1 The data in this paper have been presented, in part, at the meeting of the Association for Research in Otolaryngology, February 1996. 1 , 1999, Hearing Research.

[18]  J M Miller,et al.  Effectiveness of different electrical stimulation conditions in preservation of spiral ganglion cells following deafness. , 1995, The Annals of otology, rhinology & laryngology. Supplement.

[19]  P. Mestres,et al.  BDNF, but not NT-3, promotes long-term survival of axotomized adult rat corticospinal neurons in vivo. , 1999, NeuroReport.

[20]  A. Kay,et al.  Trophic Support of Cultured Spiral Ganglion Neurons by Depolarization Exceeds and Is Additive with that by Neurotrophins or cAMP and Requires Elevation of [Ca2+]i within a Set Range , 1997, The Journal of Neuroscience.

[21]  J. Wersäll,et al.  Degeneration of neural elements in the cochlea of the guinea-pig after damage to the organ of corti by ototoxic antibiotics. , 1974, Acta oto-laryngologica. Supplementum.

[22]  M. Bothwell,et al.  Expression of BDNF and NT-3 mRNA in hair cells of the organ of Corti: Quantitative analysis in developing rats , 1994, Hearing Research.

[23]  G. Moonen,et al.  Neurotrophins affect survival and neuritogenesis by adult injured auditory neurons in vitro. , 1994, Neuroreport.

[24]  Alfred L. Nuttall,et al.  Osmotic pump implant for chronic infusion of drugs into the inner ear , 1993, Hearing Research.

[25]  B Malgrange,et al.  NT‐3 and/or BDNF therapy prevents loss of auditory neurons following loss of hair cells , 1996, Neuroreport.

[26]  H. Spoendlin,et al.  Retrograde degeneration of the cochlear nerve. , 1975, Acta oto-laryngologica.

[27]  Barbara Canlon,et al.  Protection of auditory neurons from aminoglycoside toxicity by neurotrophin-3 , 1996, Nature Medicine.

[28]  Molly Webster,et al.  Spiral ganglion neuron loss following organ of corti loss: A quantitative study , 1981, Brain Research.

[29]  G. Clark,et al.  Growth factors, auditory neurones and cochlear implants: a review. , 1999, Acta oto-laryngologica.

[30]  J. Kellerth,et al.  Brain-derived neurotrophic factor promotes axonal regeneration and long-term survival of adult rat spinal motoneurons in vivo , 1997, Neuroscience.

[31]  A. Cellerino,et al.  Free Radical Scavenging and Inhibition of Nitric Oxide Synthase Potentiates the Neurotrophic Effects of Brain-Derived Neurotrophic Factor on Axotomized Retinal Ganglion Cells In Vivo , 1998, The Journal of Neuroscience.

[32]  I. Fariñas,et al.  Effects of neurotrophin and neurotrophin receptor disruption on the afferent inner ear innervation. , 1997, Seminars in cell & developmental biology.

[33]  R. Altschuler,et al.  Protective Effect of Electrical Stimulation in the Deafened Guinea Pig Cochlea , 1991, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[34]  T. Dawson,et al.  NITRIC OXIDE ACTIONS IN NEUROCHEMISTRY , 1996, Neurochemistry International.

[35]  Stephen J. Rebscher,et al.  Consequences of chronic extracochlear electrical stimulation in neonatally deafened cats , 1995, Hearing Research.

[36]  Paul Kruszka,et al.  Neurotrophins can enhance spiral ganglion cell survival after inner hair cell loss , 1997, International Journal of Developmental Neuroscience.

[37]  R R Stewart,et al.  Neurotrophin-4/5 enhances survival of cultured spiral ganglion neurons and protects them from cisplatin neurotoxicity , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.