In vitro and in vivo assessment of the ability of adeno-associated virus-brain-derived neurotrophic factor to enhance spiral ganglion cell survival following ototoxic insult.
OBJECTIVE
Auditory dysfunction following ototoxic insult results from loss of cochlear hair cells. Secondary degeneration of auditory neurons ensues from withdrawal of neurotrophic support from hair cells and can be prevented with administration of neurotrophins. Administration of adeno-associated virus containing the gene for brain-derived neurotrophic factor will promote spiral ganglion neuron survival after the destruction of hair cells.


METHODS
Prevention of aminoglycoside-induced spiral ganglion neuron loss through the expression of brain-derived neurotrophic factor mediated by means of the adeno-associated virus was tested in vitro in cochlear explants and in vivo in mammalian cochlea.


RESULTS
Neuronal survival was significantly enhanced in adeno-associated virus-brain-derived neurotrophic factor transfected rat cochlear explants compared with control samples (30% vs. 19%, P <.05) following exposure to aminoglycoside. Following deafening with aminoglycoside and loop diuretic and introduction of adeno-associated virus-brain-derived neurotrophic factor through osmotic minipump, the experimental group of animals infused with adeno-associated virus-brain-derived neurotrophic factor displayed enhanced spiral ganglion neuron survival in the basal turn of the cochlea when compared with the control group infused with adeno-associated virus containing green fluorescent protein reporter gene.


CONCLUSIONS
Administration of adeno-associated virus-brain-derived neurotrophic factor enhances spiral ganglion neuron survival following ototoxic exposure in vitro and in vivo. These studies lay the groundwork for further exploration of its application as an adjunct therapy for patients undergoing cochlear implantation because the success of implantation depends directly on the population of neurons available for electrical stimulation.
Lalwani
Anil K
AK
Laboratory of Molecular Otology, Epstein Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of California at San Francisco, 94143-0342, USA. lalwani@itsa.ucsf.edu
Han
Jay J
JJ
Castelein
Caley M
CM
Carvalho
Gerard J
GJ
Mhatre
Anand N
AN
D000256:Adenoviridae; D000617:Aminoglycosides / Q000008:administration & dosage; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D002470:Cell Survival; D002478:Cells, Cultured; D003638:Deafness / Q000139:chemically induced; D051381:Rats; D017208:Rats, Wistar; D013136:Spiral Ganglion / Q000166:cytology* / Q000187:drug effects*
D000617:Aminoglycosides; D019208:Brain-Derived Neurotrophic Factor