Connexin 30 deletion exacerbates cochlear senescence and age-related hearing loss

Paciello, Fabiola; Zorzi, Veronica; Raspa, Marcello; Scavizzi, Ferdinando; Grassi, Claudio; Mammano, Fabio; Fetoni, Anna Rita

doi:10.3389/fcell.2022.950837

Cited by 6 publications

(4 citation statements)

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“…Indeed, it has been shown that homozygous offspring with targeted deletion of Cx26 in the epithelial gap junction network of the cochlea (Gjb2−/− mice) failed to acquire hearing function [79], whereas the heterozygous (Gjb2+/−) mice show an accelerated presbycusis phenotype that appears at 6 months of age [80]. Moreover, we found that in Cx30 knock-out (KO) mice (Cx30 ∆∆ mice), ARHL and cochlear dysfunctions were exacerbated, and hearing thresholds were significantly higher at 12 months of age in KO mice with respect to age-matched wild-type animals [81]. Namely, these data show that both Gjb2 and Gjb6 mutations are candidate genetic risk factors for ARHL.…”

Section: Age-induced Hearing Lossmentioning

confidence: 75%

Redox Imbalance as a Common Pathogenic Factor Linking Hearing Loss and Cognitive Decline

et al. 2023

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Experimental and clinical data suggest a tight link between hearing and cognitive functions under both physiological and pathological conditions. Indeed, hearing perception requires high-level cognitive processes, and its alterations have been considered a risk factor for cognitive decline. Thus, identifying common pathogenic determinants of hearing loss and neurodegenerative disease is challenging. Here, we focused on redox status imbalance as a possible common pathological mechanism linking hearing and cognitive dysfunctions. Oxidative stress plays a critical role in cochlear damage occurring during aging, as well as in that induced by exogenous factors, including noise. At the same time, increased oxidative stress in medio-temporal brain regions, including the hippocampus, is a hallmark of neurodegenerative disorders like Alzheimer’s disease. As such, antioxidant therapy seems to be a promising approach to prevent and/or counteract both sensory and cognitive neurodegeneration. Here, we review experimental evidence suggesting that redox imbalance is a key pathogenetic factor underlying the association between sensorineural hearing loss and neurodegenerative diseases. A greater understanding of the pathophysiological mechanisms shared by these two diseased conditions will hopefully provide relevant information to develop innovative and effective therapeutic strategies.

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Section: Age-induced Hearing Lossmentioning

confidence: 75%

Redox Imbalance as a Common Pathogenic Factor Linking Hearing Loss and Cognitive Decline

et al. 2023

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“…9 A, B, Cx43 n = 3 animals/group; Student’s t test, p = 0.03; Panx1 n = 3 animals/group; Student’s t test, p = 0.0001). In the cochlea, we focused on Cx30 and Cx26, that are known to play a crucial role in cochlear physiology [ 91 , 92 ]. Differently from what observed in the brain, we found a strong reduction of Cx30 and Cx26 in the cochlea of styrene-treated animals, compared with control specimens (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, in animal models of age-related hearing loss it has been demonstrated that oxidative stress can downregulate cochlear Cx26 and Cx30 expression [ 138 , 139 ]. On the other hand, decreased Cx26 and Cx30 levels can exacerbate redox imbalance, impairing the endogenous antioxidant enzyme efflux in the cochlear sensory epithelium [ 92 , 140 ]. Thus, our data seem to be consistent with the increased oxidative stress observed in styrene-treated samples.…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress and inflammation cause auditory system damage via glial cell activation and dysregulated expression of gap junction proteins in an experimental model of styrene-induced oto/neurotoxicity

Paciello,

Pisani,

Rolesi

et al. 2024

J Neuroinflammation

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Background Redox imbalance and inflammation have been proposed as the principal mechanisms of damage in the auditory system, resulting in functional alterations and hearing loss. Microglia and astrocytes play a crucial role in mediating oxidative/inflammatory injury in the central nervous system; however, the role of glial cells in the auditory damage is still elusive. Objectives Here we investigated glial-mediated responses to toxic injury in peripheral and central structures of the auditory pathway, i.e., the cochlea and the auditory cortex (ACx), in rats exposed to styrene, a volatile compound with well-known oto/neurotoxic properties. Methods Male adult Wistar rats were treated with styrene (400 mg/kg daily for 3 weeks, 5/days a week). Electrophysiological, morphological, immunofluorescence and molecular analyses were performed in both the cochlea and the ACx to evaluate the mechanisms underlying styrene-induced oto/neurotoxicity in the auditory system. Results We showed that the oto/neurotoxic insult induced by styrene increases oxidative stress in both cochlea and ACx. This was associated with macrophages and glial cell activation, increased expression of inflammatory markers (i.e., pro-inflammatory cytokines and chemokine receptors) and alterations in connexin (Cxs) and pannexin (Panx) expression, likely responsible for dysregulation of the microglia/astrocyte network. Specifically, we found downregulation of Cx26 and Cx30 in the cochlea, and high level of Cx43 and Panx1 in the ACx. Conclusions Collectively, our results provide novel evidence on the role of immune and glial cell activation in the oxidative/inflammatory damage induced by styrene in the auditory system at both peripheral and central levels, also involving alterations of gap junction networks. Our data suggest that targeting glial cells and connexin/pannexin expression might be useful to attenuate oxidative/inflammatory damage in the auditory system.

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“…Consequently, the early detection of HL could promote its intervention and encourage the evaluation of other risk factors. Increasing experimental findings provide evidence for a common pathology linking the accelerated ARHL and memory defects and, subsequently, dementia [ 4 , 5 , 7 , 20 , 21 ]. According to the evidence that depression and anxiety are common in MCI [ 22 ], and are often diagnosed in the early stage of dementia, they typically manifest in patients with presbycusis and contribute to the progression of frailty [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

Vascular Factors in Patients with Midlife Sensorineural Hearing Loss and the Progression to Mild Cognitive Impairment

et al. 2023

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Background and Objectives: Midlife hearing loss (HL) has been considered as a major modifiable risk factor for a later-life progression to dementia. Our aim was to detect a link between precocious sensorineural hearing loss (SNHL) and mild cognitive impairment (MCI) and their association to putative risk factors for a common pathology. Materials and methods: In this study, a retrospective case-control study was carried out. A total of 112 patients were enrolled as following: 81 patients with bilateral SNHL and 31 subjects with normal hearing, whose ages ranged from 50 to 65 years. Both groups performed pure tone audiometry, a tinnitus handicap inventory (THI), Mini-Mental State examination (MMSE), and the Montreal Cognitive Assessment (MoCA), Hospital Anxiety and Depression Scale (HADS-A and HADS-D). Results: The mean age was 58 ± 5.2 in SNHL patients and 53.2 ± 4.8 in the control group. The mean pure tone average in the SNHL group was 40.2 ± 18.7 dB HL on the right side and 41.2 ± 17.2 dB HL on the left side, while in the control group it was 12.5 ± 2.8 dB HL on right side and 12.4 ± 3.1 dB HL on left side. About 64% of patients with SNHL exhibited comorbidities, and the most common condition was hypertension. Altered MoCA test scores were significantly related to the pure tone averages in patients with SNHL compared to the control group (p = 0.0004), while the differences in the HADS-A and HADS-D were not significant. Furthermore, a significant correlation was observed in SNHL patients between an altered MoCA test and hypercholesterolemia (p = 0.043). Conclusions: Hearing impairment and screening tests to detect MCI should be considered in the midlife in order to carry out strategies to prevent the progression to dementia. Hypertension and hypercholesterolemia are two risk factors in the development of endothelial dysfunction, oxidative stress, and vascular inflammation, and may represent the common pathology linking the inner ear and brain damage.

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Connexin 30 deletion exacerbates cochlear senescence and age-related hearing loss

Cited by 6 publications

References 58 publications

Redox Imbalance as a Common Pathogenic Factor Linking Hearing Loss and Cognitive Decline

Redox Imbalance as a Common Pathogenic Factor Linking Hearing Loss and Cognitive Decline

Oxidative stress and inflammation cause auditory system damage via glial cell activation and dysregulated expression of gap junction proteins in an experimental model of styrene-induced oto/neurotoxicity

Vascular Factors in Patients with Midlife Sensorineural Hearing Loss and the Progression to Mild Cognitive Impairment

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