An efficient strategy for establishing a model of sensorineural deafness in rats

Ototoxic drugs can be used to produce a loss of cochlear hair cells to create animal models of deafness. However, to the best of our knowledge, there is no report on the establishment of a rat deafness model through the combined application of aminoglycosides and loop diuretics. The aim of this study was to use single or combined administration of furosemide and kanamycin sulfate to establish rat models of deafness. The rats received intravenous injections of different doses of furosemide and/or intramuscular injections of kanamycin sulfate. The auditory brainstem response was measured to determine the hearing threshold after drug application. Immunocytochemistry and confocal microscopy were performed to evaluate inner ear morphology. In the group receiving combined administration of furosemide and kanamycin, the auditory brainstem response threshold showed significant elevation 3 days after administration, higher than that produced by furosemide or kanamycin alone. The hair cells showed varying degrees of injury, from the apical turn to the basal turn of the cochlea and from the outer hair cells to the inner hair cells. The spiral ganglion cells maintained a normal morphology during the first week after the hair cells completely disappeared, and then gradually degenerated. After 2 months, the majority of spiral ganglion cells disappeared, but a few remained. These findings demonstrate that the combined administration of furosemide and kanamycin has a synergistic ototoxic effect, and that these drugs can produce hair cell loss and hearing loss in rats. These findings suggest that even in patients with severe deafness, electronic cochlear implants may partially restore hearing.

Effect of auditory stress agents on heterozygous German waltzing guinea pigs

The German waltzing guinea pig is a strain of animals expressing deafness and severe balance disorders at birth.The mutation arose spontaneously in a breeding facility in Germany and as the affected animals show a characteristic waltzing behavior,the strain is named the German waltzing guinea pig.The strain is presently bred only at Karolinska Institutet.The hereditary inner ear impairment has a recessive mode of inheritance and the strain thus produces not only affected homozygotes but also symptom-free heterozygotes and fully normal offspring.The outcome depends solely on the genotype of the parents.The heterozygotes,which have obtained the 'waltzing' gene from one parent only,have normal hearing and no balance dysfunction.The heterozygous animals appear normal but will,in turn,carry the genetic defect to the next generation.The present thesis is focused on these animals.Noise and ototoxic drugs are well known stress factors that interfere negatively with the hearing organ in both humans and animals,causing hearing impairment.However,the inter-individual variability in susceptibility to auditory stress factors is surprisingly large,most likely due to different genetic predisposition.In this study,heterozygous animals of the German waltzing guinea pig,animals carrying a genetic defect known to cause severe hearing impairment,were used to study how an unexplored gene for deafness interacts with auditory stress agents,i.e.noise exposure and the ototoxic drugs gentamicin and cisplatin.Animals were exposed to both narrowband as well as broadband noise at different ages and hearing thresholds were measured using ABRs.Heterozygotes of the German waltzing guinea pig showed less threshold shifts compared to control strains.Older animals were less affected by the noise trauma than younger animals.To test the hypothesis that the efferent system contributes to protection of the inner ear against noise trauma,measurements using a new method of post onset adaptation of DPOAEs and maximum adaptation magnitude were conducted.The post onset adaptation of DPOAEs detected a strain difference at the higher frequency region while in the maximum adaptation magnitude method showed no difference between the strains.The heterozygous German waltzing guinea pigs displayed a distinctly increased resistance to noise exposures,manifested as reduced threshold shifts and faster recovery following acoustic overstimulation.However,when exposed to ototoxic drugs,the heterozygous carriers suffered from a more pronounced hearing loss.It is concluded that endogenous resistance to noise in the heterozygotes does not offer any protection against ototoxic drugs.The detailed mechanisms remain to be explored.

Injury and protection of spiral ganglion neurons

Cochlear spiral ganglion neurons(SGNs)are bipolar ganglion cells and are the first neurons in the auditory transduction pathway.They transmit complex acoustic information from hair cells to second-order sensory neurons in the cochlear nucleus for sound processing.Injury to SGNs causes largely irreversible hearing impairment because these neurons are highly differentiated cells and cannot regenerate,making treatment of sensorineural hearing loss(SNHL)arising from SGN injury difficult.When exposed to ototoxic drugs or damaging levels of noise or when there is loss of neurotrophic factors(NTFs),aging,and presence of other factors,SGNs can be irreversibly damaged,resulting in SNHL.It has been found that NTFs and stem cells can induce regeneration among dead spiral ganglion cells.In this paper,we summarized the present knowledge regarding injury,protection,and regeneration of SGNs.

Development of Chinese herbal medicine for sensorineural hearing loss

According to the World Health Organization’s world report on hearing,nearly 2.5 billion people worldwide will suffer from hearing loss by 2050,which may contribute to a severe impact on individual life quality and national economies.Sensorineural hearing loss(SNHL)occurs commonly as a result of noise exposure,aging,and ototoxic drugs,and is pathologically characterized by the impairment of mechanosensory hair cells of the inner ear,which is mainly triggered by reactive oxygen species accumulation,inflammation,and mitochondrial dysfunction.Though recent advances have been made in understanding the ability of cochlear repair and regeneration,there are still no effective therapeutic drugs for SNHL.Chinese herbal medicine which is widely distributed and easily accessible in China has demonstrated a unique curative effect against SNHL with higher safety and lower cost compared with Western medicine.Herein we present trends in research for Chinese herbal medicine for the treatment of SNHL,and elucidate their molecular mechanisms of action,to pave the way for further research and development of novel effective drugs in this field.