Drug-based Therapies for Auditory Trauma

Deafness is one of the most common health conditions in the developed countries, and worldwide, an estimated 70 million people are deaf. For people with severe to profound hearing loss, a cochlear implant is the only treatment today. The most common forms of severe hearing loss and deafness are related to morphological changes in the cochlea. Aim: The aim of these studies was to investigate several therapeutic compounds, including nucleosides and nucleotides, two types of neurotrophic factors, and two oxysterols, to determine if they could preserve spiral ganglion neuron (SGN) survival and maintain SGN electrical responsiveness, as determined by measuring electrically-evoked auditory brainstem response (eABR) in deafened guinea pigs. It was also important to investigate the compounds’ effectiveness when delivered into the inner ear several weeks after deafening (“Delayed treatment”). In some experiments, the animals stayed in the study for several weeks after cessation of treatment to determine if eABR threshold remained and the extent of SGN survival after treatment cessation. Methods: All animals in these studies were deafened with the ototoxic compound neomycin sulfate by intracochlear or transtympanic infusion. They received a cochlear implant and an osmotic pump for inner ear drug delivery. To determine any changes in hearing (i.e., SGN electrical responsiveness), electrically-evoked brainstem response was measured weekly. After the last measurement cochleae were collected for morphological analysis. Results: We found that nucleosides and nucleotides seem to have a trophic effect on spiral ganglion neurons, showing low eABR thresholds and a statistically significant (p<0.001) SGN survival compared with the control group. Results from the study with glial cell line-derived neurotrophic factor (GDNF) showed that delayed GDNF treatment helped to prevent loss of electrical responsiveness and auditory nerve cell death up to four weeks after GDNF cessation. Cometin, a new neurotrophic factor, showed low eABR thresholds but with fewer surviving SGNs. The oxysterols study showed a different pattern compared to all our previous studies. In the acute study both oxysterols showed low eABR thresholds compared to the control group, but SGN survival was equal to the control group that did not received any treatment. In the delayed treatment study only one of the oxysterols showed lower eABR thresholds during the whole experiment compared to the control group. Despite that, SGN survival was equally low in the oxysterol groups and the control group. Of the therapeutic agents tested in this study GDNF was most the promising compound. LIST OF PUBLICATIONS I. Fransson A. , Jarlebark L. and Ulfendahl M. (2009) “In vivo infusion of UTP and uridine to the deafened guinea pig inner ear: Effects on response thresholds and neural survival”. J. Neurosci. Res. 87, 1712-1717. II. Fransson A. , Maruyama J., Miller J. and Ulfendahl M. (2010) “Post-treatment effects of local GDNF administration to the inner ears of deafened guinea pigs”. J. Neurotrauma 27, 1745-1751. III. Jorgensen J., Fransson A. , Fjord-Larsen L. , Thompson L.H. , Houchins J.P., Andrade N. , Torp M. , Kalkkinen N. , Andersson E. , Lindvall O. , Ulfendahl M. , Brunak S. , Johansen T.E. and Wahlberg L.U. (2012) “Cometin is a novel neurotrophic factor that promotes neurite outgrowth and neuroblast migration in vitro and supports survival of spiral ganglion in vivo”. Exp. Neurology 233, 172181 IV. Fransson A. , Silvente-Poirot S. , Poirot M. and Ulfendahl M. “Dendrogenin A and B, two new alkylaminooxysterols increasing neural responsiveness in an animal model”. (manuscript) V. Fransson A. and Ulfendahl M. “Morphological changes in the inner ear of the experimentally deafened guinea pig over time”. (manuscript)