An acute experimental model of hearing loss using noise in combination with hypoxia and its use in the investigation of a putative cochleoprotectant

The aim of this study was to develop a model of acute noise induced hearing loss that focused on excitotoxic damage, in the albino guinea pig. The model used moderate 12% hypoxia in combination with 100 dB SPL bandpass 5-20 kHz noise. The model employed gross electrophysiological measures as auditory endpoints, comprising the brainstem auditory evoked response (BAER) the cochlear compound action potential (CAP), and the ensemble spontaneous or driven cochlear nerve activity (ESAC/EDAC) derived from the Fast Fourier Transform of gross cochlear nerve (CN) activity. Preliminary model development was carried out using BAER. These experiments established an optimal sedation and hypoxia regimen, demonstrating that systemic physiological stability was maintained with this regime. Significant changes in the BAER were seen within the first 15 minutes of exposure with noise and noise/hypoxia. There was significant synergy between noise and hypoxia, but hypoxia alone did not result in any significant changes in BAER. More detailed development of the model utilised frequency specific CAP threshold, amplitude and latency measurements at 8, 16, 24 and 30 kHz. Significant frequency dependent changes were seen in all these parameters that again revealed synergy between acute noise and hypoxia. These results inferred excitotoxic damage at the afferent nerve synapse, and damage due to metabolic overload further downstream in the afferent nerve fibre. The ESAC/EDAC results also supported this. The above model was then used to show that a single oral dose (20mg/kg) of lamotrigine (LTG) provided cochleoprotection against acute noise. LTG rapidly penetrated the inner ear and there was marginal evidence of a tonotopic effect on CAP threshold and amplitude, but no effect on ESAC. LTG also ameliorated noise induced threshold shifts at 8 and 16 kHz by approximately 10 dB. The ED AC signal during noise exposure was also significantly reduced. These results suggest that LTG acts by reducing driven activity of the CN and thus reduces metabolic overload on the nerve through its voltage dependent action on the Na+ channel.