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Hypothesis: Interruption of the excitotoxic and inflammatory pathways implicated in endolymphatic hydrops (ELH)-associated hearing loss (HL) should afford hearing protection at the neuronal level., Background: Previous work in our laboratory in the mouse model of ELH shows that dimethyl sulfoxide (DMSO), an anti-inflammatory solvent, can slow the progression of HL before neuronal degeneration occurs. Riluzole, a glutamate release inhibitor, may provide synergistic benefit. This study was designed to quantify the effects of DMSO and riluzole in a long-term model., Methods: Guinea pigs with surgically induced ELH were sorted into 3 groups: riluzole+DMSO (Group 1), DMSO alone (Group 2), and untreated controls (Group 3). Animals in Groups 1 and 2 received daily injections of the study drug(s). All animals underwent auditory-evoked brainstem response evaluation every 4 weeks until 24 weeks, when they were sacrificed. Cochleae were preserved; spiral ganglion density was quantified. Animals without hydrops were excluded from the study as surgical failures., Results: Animals from all groups developed unilateral HL. At the end of the experiment, HL was significantly lower in Group 1 relative to Group 3 (p = 0.049) and trended toward lower in Group 2 relative to Group 3 (p = 0.097). Groups 1 and 2 were not different (p = 0.311). At the cellular level, there is no evidence of neuronal degeneration in either treated group, whereas there is a significant neuronal degeneration in the untreated group., Conclusion: These results confirm the hearing protection observed with DMSO in short-term studies. However, unlike the previous study, which showed no additive benefit to riluzole, the combined treatment group in this study showed a hearing-protective effect at 24 weeks. This indicates a potential additive benefit conferred by riluzole toward long-term hearing protection. The study also finds evidence of statistically significant neuronal protection with both treatment groups. Overall, study provides additional evidence that DMSO and riluzole may preserve or slow the long-term progression of ELH-associated HL.