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5: Valnoctamide rescues CMV-induced deafness in a murine model

      Objective

      Congenital cytomegalovirus (CMV) is the leading infectious cause of non-hereditary sensorineural hearing loss in newborns and children. No treatments are currently recommended for infected fetuses and postnatal therapy is only available for the most severe cases of infection due to substantial safety concerns. We showed that valnoctamide (VCD), a mood stabilizer, effectively blocks CMV. Here we investigate CMV infection in the developing auditory system of newborn mice and the potential benefits of VCD on long-term hearing outcomes.

      Study Design

      Pups inoculated i.p. with CMV (750 PFU) on the day of birth received VCD (n=8) or vehicle (VEH, n=8) daily (1.4mg/mL) from p1 to p21. Brain development of newborn mice parallels that of an early 2nd trimester human fetus. Uninfected animals served as controls (n=8). CMV load and distribution in the cochlea and central auditory regions were assessed by qPCR and histochemistry at multiple time-points post-infection. Hearing was investigated blindly with respect to the experimental group using Auditory Brainstem Responses in 7 week-old mice. Statistical significance was determined by mixed-model ANOVA with repeated measures.

      Results

      CMV was detected in the cochlea as early as 2 dpi, with viral load peaking at p16-21 and viral particles still measurable at p50. CMV-infected cells were identified in several areas of the inner ear, including the stria vascularis, the temporal bone, and the cochlea, where selective loss of outer hair cells was evident by p12. CMV+ cells were also recognized in central components of the auditory system, such as cochlear nuclei, inferior colliculus, and auditory cortex. Infected mice showed increased hearing thresholds at multiple frequency tone stimuli. VCD substantially reduced CMV load in the cochlea (Fig. 1) and the brain, and ameliorated hearing development with restoration of normal auditory responses (Fig. 2).

      Conclusion

      VCD effectively blocks CMV infection in the developing auditory system and rescues virally induced hearing impairment. VCD is approved for treatment of neuropsychiatric disorders and lacks teratogenic activity. Thus, it may merit consideration as a novel approach in treating CMV-mediated deafness during development.
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