Otoprotective effects of mouse nerve growth factor in DBA/2J mice with early‐onset progressive hearing loss

Abstract

DBA/2J is an inbred mouse strain widely used in hearing research, as it displays progressive hair cell loss and degeneration of spiral ganglion neurons (SGNs) characterized by early-onset progressive hearing loss (ePHL). Mouse nerve growth factor (mNGF), as a common exogenous nerve growth factor (NGF), has been studied extensively for its ability to promote neuronal survival and growth. To determine whether mNGF can ameliorate progressive hearing loss (PHL) in DBA/2J mice, saline or mNGF was given to DBA/2J mice of either sex by daily intramuscular injection from the 1st to the 9th week after birth. At 5, 7, and 9 weeks of age, in comparison with vehicle groups, mNGF groups experienced decreased auditory-evoked brainstem response (ABR) thresholds and increased distortion product otoacoustic emission (DPOAE) amplitudes, the prevention of hair cell loss, and the inhibition of apoptosis of SGNs. Downregulation of Bak/Bax and Caspase genes and proteins in cochleae of mice receiving the mNGF treatment was detected by Real-time PCR, Western Blot and Immunohistochemistry. This suggests that the Bak-dependent mitochondrial apoptosis pathway may be involved in the otoprotective mechanism of mNGF in progressive hearing loss of DBA/2J mice. Our results demonstrate that mNGF can act as an otoprotectant in the DBA/2J mice for the early intervention of PHL and, thus, could become of great value in clinical applications.

An Age-Related Hearing Protection Locus on Chromosome 16 of BXD Strain Mice

“…As demonstrated in previous studies and our current investigation, hearing loss in B6 and D2 mice are accompanied by degeneration of the organ of Corti and spiral ganglia (see Figure 1(b)) [19,45]. This degeneration is caused mainly by Cdh23 [17,18,46].…”

“…The features of deafness in D2 mice segregate among BXD family members. The B6 mice share the Cdh23 c.753A mutation with D2 [11,19], having mid-aged hearing loss. The features of hearing protection also segregate among BXD family members.…”

“…Both C57BL/6J (B6) and DBA/2J (D2) strains of mice are homozygous for the Cdh23 c.753A allele and have progressive hearing loss [10]. However, the D2 strain exhibits a much earlyonset of hearing loss, starting from 3 weeks old, and most animals are deaf by 3 months [8,19,20]. In contrast, B6 mice only develop high-frequency hearing loss starting at 3 months old, and the loss progresses to low-frequencies and worsen to a profound level only by 12 months [8,10,11,21].…”

Chronic Oral Selegiline Treatment Mitigates Age-Related Hearing Loss in BALB/c Mice

“…In contrast, the protective effect of selegiline cannot be observed in DBA/2J mice. BALB/c strain is homozygous for the Ahl1 allele, while the larger susceptibility of DBA/2J strain for ARHL is due to the presence of Ahl1, Ahl8, and Ahl9 genes [ 40 , 41 , 42 ]. Differences in the efficacy of selegiline would presumably be due to the presence of more ARHL predisposing genes in DBA/2J strain, which might cause the higher progression rate, severity, and probably a more complex pathology leading to ARHL.…”

Growth factor and receptor malfunctions associated with human genetic deafness

“…Genetic studies of hundreds of genes necessary for audition have uncovered several pathways important for normal hearing. Based initially upon studies of animal model, growth factors are now being explored for treatment of noise and ototoxic induced deafness and age-related hearing loss, [100][101][102][103][104][105][106][107][108][109] and some of these are currently in clinical trials. 110,111 For example, topical application of IGF1 to the middle ear was used to treat sudden sensorineural hearing loss in humans, and some treated individuals showed improvements of 10 to 30 dB for tested frequencies as compared to controls.…”