DX243 counteracts both acoustic trauma-induced reduction in cortical brain oscillations and cochlear synaptopathy

Stefan Fink¹Csaba Harasztosi¹Li Xie^1,2Stephane Silvente³Pierre Attali³Nicolas Caron³Wibke Singer¹Lukas Rüttiger¹Marlies Knipper^1*

• ¹Universitatsklinikum Tubingen Universitats-Hals-Nasen-Ohren-Klinik Tubingen, Tübingen, Germany
• ²Huazhong University of Science and Technology Tongji Medical College Tongji Hospital, Wuhan, China
• ³Dendrogenix S.A., Avenue de l'Hôpital, 11, SPS Bâtiment 34, 3e étage, 4000 Liège, Belgium, Liege, Belgium

Background: With age, even mild acoustic injuries can accumulate - ultimately leading to characteristic clinical picture of age-related hearing loss with the risk of cognitive decline. Age-related hearing loss is currently attributed to the loss of a most vulnerable auditory fiber type contributing to hearing in background noise. Here, we investigated the potential of a new drug, a more stable chemical variant of Dendrogenin B (DX243) that is predicted to display a protective function on neurite outgrowth, rather than on cell survival. Methodology: In the rat animal model, DX243 was tested on hearing thresholds, cortical local field (LFP), auditory steady state responses (ASSR), auditory brainstem response (ABR) growth function of NOTCH-noise stimuli, IHCs ribbon numbers, and multi-click pulse responses (MCP) before and after auditory trauma (AT). Results: No auditory evoked LFP response changes were seen in the prefrontal cortex, visual cortex, or hippocampus. In contrast a permanent decline of auditory evoked LFP amplitudes in the auditory cortex (AC) was measured 2 weeks after AT. Daily injection of DX243 for 2 weeks prevented the AT-induced decline in LFP activity, a protective effect that continued for 6 weeks following the final injection. Through a protective effect of DX243 on a trauma-induced decline of LFP in response to amplitude-modulated tones >80Hz, a subcortical origin of the drug was suggested. DX243 showed no effect on hearing sensitivity and did not affect subcortical processing of sound features that depend on phase locking at the stimulus onset (e.g. near-threshold ASSR responses, close-to-threshold ABR growth functions or spontaneous cortical LFP responses). However, with the same dose-response dependency as shown for cortical LFP effects, DX243 significantly protected from AT-induced decreases in ABR growth functions for loud sound stimuli and in background noise, protected from AT-induced loss of inner hair-cell (IHC) ribbons and AT-induced decline of fast ABRs with decreasing time intervals. Conclusion: These findings suggest DX243 as a novel neuroprotective drug, that specifically protects auditory fibers contributing to the coding of the temporal envelope and detection of tones in masking noise, tasks of our auditory senses, both of which, if they fail, lead to age-related speech-in-noise comprehension deficits.