Age-related hearing loss in CD/1 mice is associated to ROS formation and HIF target proteins up-regulation in the cochlea (original) (raw)
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Ageing Research, 2012
Molecular mechanisms underlining hypoxia-induced aged-hearing loss were studied. 3months C57BL/6 mice were subjected to four weeks of hypoxia (10% 0 2 ), whereas, controls were kept under normoxic condition for up to six months. Auditory function was explored by CAP and Preyer's reflex measurements and correlated with histological analysis of the cochlea. The presence of oxidative damage, HIF-1 responsive target genes regulation involved in cell death, inflammation and neovascularization were assessed by immunofluorescence analysis. Hypoxia was associated to severe hearing loss at 4-8 and 16 KHz and degeneration of the cochlea, with significant cell loss (30%) in the spiral ganglion, the lateral wall, and the hair cells with a basal-apical alteration gradient. This was correlated with ROS formation and HIF-1a overexpression. Cochlear degeneration was due to apoptosis via activated caspase-3, P53, Bax and Bcl-2 protein differential expression in spiral ganglion, modiolus and spiral ligament. On the other hand, Hsp70, NF-kB transcription factor pathway and inflammatory mediators (caspase-1 and TNF-a) were induced in the stria vascularis. Furthermore, a phenomenon of neovascularization was observed with significant thickening of stria vascularis and increased expression of VEGF. In total, we demonstrated that the tandem-HIF-ROS is responsible for the caspase-3 and Bax-mediated apoptosis via P53 protein accumulation in the cochlear neurons, while inflammatory response mediated by Hsp70 stress protein and NF-kB transcription factor generating a neovascularization phenomenon occurred in stria vascularis.
Oxidative stress-induced apoptosis of cochlear sensory cells: otoprotective strategies
International Journal of Developmental Neuroscience, 2000
Apoptosis is an important process, both for normal development of the inner ear and for removal of oxidative-stress damaged sensory cells from the cochlea. Oxidative-stressors of auditory sensory cells include: loss of trophic factor support, ischemiareperfusion, and ototoxins. Loss of trophic factor support and cisplatin ototoxicity, both initiate the intracellular production of reactive oxygen species and free radicals. The interaction of reactive oxygen species and free radicals with membrane phospholipids of auditory sensory cells creates aldehydic lipid peroxidation products. One of these aldehydes, 4-hydroxynonenal, functions as a mediator of apoptosis for both auditory neurons and hair cells. We present several approaches for the prevention of auditory sensory loss from reactive oxygen species-induced apoptosis: 1) preventing the formation of reactive oxygen species;
Central Asian Scientific Press (CAS-Press), 2022
• ARHL is characterized by increasing age and hearing loss from low to high frequencies. • Factors involved in ARHL are divided into two genetic and nongenetic categories. • Inflammation, apoptosis, and oxidative stress are three main mechanisms of ARHL. Age-related hearing loss (ARHL) is a type of bilateral hearing loss that progresses from low frequencies to high frequencies with age. This disorder is classified as a multifactorial disease. Factors involved in ARHL pathology are divided into two categories of genetic and non-genetic factors. The genes involved in this disorder include three categories of genes involved in cochlear structure and function, genes correlated with oxidative stress, and mitochondrial-dependent genes. Oxidative stress, apoptosis, and inflammation are the three main causes of ARHL. Damage to hair cells induces intrinsic and extrinsic apoptosis and can therefore accelerate ARHL. Some process in cells leads to the production of high amounts of reactive oxygen species including hydrogen peroxide (H 2 O 2), anion superoxide (O 2-), and hydroxyl radical (OH). Reactive oxygen species or ROS can generally have several sources including nitric oxide synthase, NADPH oxidase, microsomal, mitochondrial, and proxisomal pathways. In typical conditions, ROS is produced and neutralized by antioxidant enzymes such as superoxide dismutase, catalase, and glutathione, balancing cell homeostasis. Though, the process of aging, drug treatment, and some other factors upset this homeostasis, and this causes oxidative stress and induction of ARHL in the cells of the auditory system. The aim of this study was to describe the cellular and molecular mechanisms involved in ARHL with a focus on oxidative stress.
PLoS ONE, 2014
Age-related hearing loss -presbycusis -is the number one neurodegenerative disorder and top communication deficit of our aged population. Like many aging disorders of the nervous system, damage from free radicals linked to production of reactive oxygen and/or nitrogen species (ROS and RNS, respectively) may play key roles in disease progression. The efficacy of the antioxidant systems, e.g., glutathione and thioredoxin, is an important factor in pathophysiology of the aging nervous system. In this investigation, relations between the expression of antioxidant-related genes in the auditory portion of the inner ear -cochlea, and age-related hearing loss was explored for CBA/CaJ mice. Forty mice were classified into four groups according to age and degree of hearing loss. Cochlear mRNA samples were collected and cDNA generated. Using AffymetrixH GeneChip, the expressions of 56 antioxidant-related gene probes were analyzed to estimate the differences in gene expression between the four subject groups. The expression of Glutathione peroxidase 6, Gpx6; Thioredoxin reductase 1, Txnrd1; Isocitrate dehydrogenase 1, Idh1; and Heat shock protein 1, Hspb1; were significantly different, or showed large fold-change differences between subject groups. The Gpx6, Txnrd1 and Hspb1 gene expression changes were validated using qPCR. The Gpx6 gene was upregulated while the Txnrd1 gene was downregulated with age/hearing loss. The Hspb1 gene was found to be downregulated in middle-aged animals as well as those with mild presbycusis, whereas it was upregulated in those with severe presbycusis. These results facilitate development of future interventions to predict, prevent or slow down the progression of presbycusis.
Reactive Oxygen Species, Apoptosis, and Mitochondrial Dysfunction in Hearing Loss
BioMed research international, 2015
Reactive oxygen species (ROS) production is involved in several apoptotic and necrotic cell death pathways in auditory tissues. These pathways are the major causes of most types of sensorineural hearing loss, including age-related hearing loss, hereditary hearing loss, ototoxic drug-induced hearing loss, and noise-induced hearing loss. ROS production can be triggered by dysfunctional mitochondrial oxidative phosphorylation and increases or decreases in ROS-related enzymes. Although apoptotic cell death pathways are mostly activated by ROS production, there are other pathways involved in hearing loss that do not depend on ROS production. Further studies of other pathways, such as endoplasmic reticulum stress and necrotic cell death, are required.
Oxidative stresses and mitochondrial dysfunction in age-related hearing loss
Oxidative medicine and cellular longevity, 2014
Age-related hearing loss (ARHL), the progressive loss of hearing associated with aging, is the most common sensory disorder in the elderly population. The pathology of ARHL includes the hair cells of the organ of Corti, stria vascularis, and afferent spiral ganglion neurons as well as the central auditory pathways. Many studies have suggested that the accumulation of mitochondrial DNA damage, the production of reactive oxygen species, and decreased antioxidant function are associated with subsequent cochlear senescence in response to aging stress. Mitochondria play a crucial role in the induction of intrinsic apoptosis in cochlear cells. ARHL can be prevented in laboratory animals by certain interventions, such as caloric restriction and supplementation with antioxidants. In this review, we will focus on previous research concerning the role of the oxidative stress and mitochondrial dysfunction in the pathology of ARHL in both animal models and humans and introduce concepts that hav...
Neurobiology of Aging, 2012
The biological mechanisms that give rise to age-related hearing loss (ARHL) are still poorly understood. However, there is growing recognition that oxidative stress may be an important factor. To address this issue, we measured the changes in the expression of cochlear oxidative stress and antioxidant defense-related genes in young (2 months old), middle-aged (12 months old), and old (21-25 months old) Fischer 344/NHsd (F344/NHsd) rats and compared gene expression changes with ARHL. A quantitative real-time reverse transcription polymerase chain reaction array revealed a significant age-related downregulation of only 1 gene, stearoyl-coenzyme A desaturase 1, and upregulation of 12 genes: 24-dehydrocholesterol reductase; aminoadipatesemialdehyde synthase; cytoglobin; dual oxidase 2; glutathione peroxidase 3; glutathione peroxidase 6; glutathione S-transferase, kappa 1; glutathione reductase; nicotinamide adenine dinucleotide phosphate (NAD(P)H) dehydrogenase, quinone 1; solute carrier Family 38, Member 5; thioredoxin interacting protein; and vimentin. Statistical analyses revealed significant correlations between gene expression and auditory function in 8 genes. Our results identified specific subsets of oxidative stress genes that appear to play an important role in ARHL in the Fischer 344/NHsd rat.
Antioxidants & Redox Signaling, 2012
Aims: In our aging society, age-related hearing loss (ARHL) or presbycusis is increasingly important. Here, we study the mechanism of ARHL using the senescence-accelerated mouse prone 8 (SAMP8) which is a useful model to probe the effects of aging on biological processes. Results: We found that the SAMP8 strain displays premature hearing loss and cochlear degeneration recapitulating the processes observed in human presbycusis (i.e., strial, sensory, and neural degeneration). The molecular mechanisms associated with premature ARHL in SAMP8 mice involve oxidative stress, altered levels of antioxidant enzymes, and decreased activity of Complexes I, II, and IV, which in turn lead to chronic inflammation and triggering of apoptotic cell death pathways. In addition, spiral ganglion neurons (SGNs) also undergo autophagic stress and accumulated lipofuscin. Innovation and Conclusion: Our results provide evidence that targeting oxidative stress, chronic inflammation, or apoptotic pathways may have therapeutic potential. Modulation of autophagy may be another strategy. The fact that autophagic stress and protein aggregation occurred specifically in SGNs also offers promising perspectives for the prevention of neural presbycusis. Antioxid. Redox Signal. 16, 263-274.
Apoptosis-related genes change their expression with age and hearing loss in the mouse cochlea
Apoptosis, 2008
To understand possible causative roles of apoptosis gene regulation in age-related hearing loss (presbycusis), apoptotic gene expression patterns in the CBA mouse cochlea of four different age and hearing loss groups were compared, using GeneChip and real-time (qPCR) microarrays. GeneChip transcriptional expression patterns of 318 apoptosis-related genes were analyzed. Thirty eight probes (35 genes) showed significant differences in expression. The significant gene families include Caspases, B-cell leukemia/lymphoma2 family, P53, Cal-pains, Mitogen activated protein kinase family, Jun oncogene, Nuclear factor of kappa light chain gene enhancer in B-cells inhibitorrelated and tumor necrosis factor-related genes. The GeneChip results of 31 genes were validated using the new TaqMan ® Low Density Array (TLDA). Eight genes showed highly correlated results with the GeneChip data. These genes are: activating transcription factor3, B-cell leukemia/ lymphoma2, Bcl2-like1, caspase4 apoptosis-related cysteine protease 4, Calpain2, dual specificity phosphatase9, tumor necrosis factor receptor superfamily member12a, and Tumor necrosis factor superfamily member13b, suggesting they may play critical roles in inner ear aging.