<i>G6PD</i>overexpression protects from oxidative stress and age‐related hearing loss

Bermúdez-Muñoz, Jose Ma; Celaya, Adelaida M.; Hijazo-Pechero, Sara; Wang, Jing; Serrano, Manuel; Varela-Nieto, Isabel

doi:10.1111/acel.13275

Cited by 38 publications

(34 citation statements)

References 49 publications

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“…As individuals age, there is a gradual decrease in IGF-1 and an increase in the generation of pro-oxidative and proinflammatory products that have an impact on tissue homeostasis and longevity [ 39 , 45 , 46 ]. In the mouse hearing organ, IGF-1 is essential for the final differentiation of the spiral ganglion and organ of Corti [ 38 , 43 ], and with aging, it maintains the stria vascularis physiology and auditory neuron survival.…”

Section: Discussionmentioning

confidence: 99%

IGF-1 Haploinsufficiency Causes Age-Related Chronic Cochlear Inflammation and Increases Noise-Induced Hearing Loss

Celaya

Rosa

Bermúdez-Muñoz

et al. 2021

Cells

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Insulin-like growth factor 1 (IGF-1) deficiency is an ultrarare syndromic human sensorineural deafness. Accordingly, IGF-1 is essential for the postnatal maturation of the cochlea and the correct wiring of hearing in mice. Less severe decreases in human IGF-1 levels have been associated with other hearing loss rare genetic syndromes, as well as with age-related hearing loss (ARHL). However, the underlying mechanisms linking IGF-1 haploinsufficiency with auditory pathology and ARHL have not been studied. Igf1-heterozygous mice express less Igf1 transcription and have 40% lower IGF-1 serum levels than wild-type mice. Along with ageing, IGF-1 levels decreased concomitantly with the increased expression of inflammatory cytokines, Tgfb1 and Il1b, but there was no associated hearing loss. However, noise exposure of these mice caused increased injury to sensory hair cells and irreversible hearing loss. Concomitantly, there was a significant alteration in the expression ratio of pro- and anti-inflammatory cytokines in Igf1+/− mice. Unbalanced inflammation led to the activation of the stress kinase JNK and the failure to activate AKT. Our data show that IGF-1 haploinsufficiency causes a chronic subclinical proinflammatory age-associated state and, consequently, greater susceptibility to stressors. This work provides the molecular bases to further understand hearing disorders linked to IGF-1 deficiency.

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Section: Discussionmentioning

confidence: 99%

IGF-1 Haploinsufficiency Causes Age-Related Chronic Cochlear Inflammation and Increases Noise-Induced Hearing Loss

Celaya

Rosa

Bermúdez-Muñoz

et al. 2021

Cells

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“…Inner ear dissection was performed as described [ 25 ] and samples were frozen in RNAlater ® solution (Ambion, Foster City, CA, USA). Cochlear RNA was extracted using the RNeasy Plus Mini kit (Qiagen, Hilden, Germany) automated on the Qiacube (Qiagen, Hilden, Germany).…”

Section: Methodsmentioning

confidence: 99%

“…Quality determination and cDNA generation from pooled cochlear RNA extracts (3 cochlea from different animals per group) were performed as reported [ 35 ]. Quantitative amplification was performed in triplicate on a Quant Studio 7 Flex PCR System (Applied Biosystems, Foster City, CA, USA) using either commercial TaqMan probes or gene specific primers ( Table S2 and [ 25 ]). Data were collected after each amplification step and analyzed with QuantStudio™ Real-Time PCR software 1.3 (Applied Biosystems).…”

Section: Methodsmentioning

confidence: 99%

Dual-Specificity Phosphatase 1 (DUSP1) Has a Central Role in Redox Homeostasis and Inflammation in the Mouse Cochlea

et al. 2021

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Stress-activated protein kinases (SAPK) are associated with sensorineural hearing loss (SNHL) of multiple etiologies. Their activity is tightly regulated by dual-specificity phosphatase 1 (DUSP1), whose loss of function leads to sustained SAPK activation. Dusp1 gene knockout in mice accelerates SNHL progression and triggers inflammation, redox imbalance and hair cell (HC) death. To better understand the link between inflammation and redox imbalance, we analyzed the cochlear transcriptome in Dusp1−/− mice. RNA sequencing analysis (GSE176114) indicated that Dusp1−/− cochleae can be defined by a distinct profile of key cellular expression programs, including genes of the inflammatory response and glutathione (GSH) metabolism. To dissociate the two components, we treated Dusp1−/− mice with N-acetylcysteine, and hearing was followed-up longitudinally by auditory brainstem response recordings. A combination of immunofluorescence, Western blotting, enzymatic activity, GSH levels measurements and RT-qPCR techniques were used. N-acetylcysteine treatment delayed the onset of SNHL and mitigated cochlear damage, with fewer TUNEL+ HC and lower numbers of spiral ganglion neurons with p-H2AX foci. N-acetylcysteine not only improved the redox balance in Dusp1−/− mice but also inhibited cytokine production and reduced macrophage recruitment. Our data point to a critical role for DUSP1 in controlling the cross-talk between oxidative stress and inflammation.

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“…The pathophysiological response to oxidative stress has been a widely studied and is a well-established cochlear mechanism of injury leading to hearing loss ( Choi and Choi, 2015 ; Wang and Puel, 2018 ; Bermúdez-Muñoz et al, 2020 , 2021 ; Varela-Nieto et al, 2020 ). Oxidative stress occurs when cochlear cells show excessive amounts of oxidants or decreased levels of antioxidants and causes formation of free radicals.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

“…Nitrone derivatives have been extensively used in both preclinical models and clinical assays as therapeutics to reduce oxidative stress in several pathologies, mainly stroke ( Marco-Contelles, 2020 ), neurodegenerative disorders ( Cancela et al, 2020 ) and cancer ( Thomas et al, 2020 ). Oxidative stress is also considered a major pathological mechanism in several auditory pathologies, including ototoxicity, noise-induced hearing loss (NIHL) and presbycusis ( Bermúdez-Muñoz et al, 2020 , 2021 ; Varela-Nieto et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Use of Radical Oxygen Species Scavenger Nitrones to Treat Oxidative Stress-Mediated Hearing Loss: State of the Art and Challenges

Varela‐Nieto

Murillo-Cuesta²,

Rosa³

et al. 2021

Front. Cell. Neurosci.

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Nitrones are potent antioxidant molecules able to reduce oxidative stress by trapping reactive oxygen and nitrogen species. The antioxidant potential of nitrones has been extensively tested in multiple models of human diseases. Sensorineural hearing loss has a heterogeneous etiology, genetic alterations, aging, toxins or exposure to noise can cause damage to hair cells at the organ of Corti, the hearing receptor. Noxious stimuli share a battery of common mechanisms by which they cause hair cell injury, including oxidative stress, the generation of free radicals and redox imbalance. Therefore, targeting oxidative stress-mediated hearing loss has been the subject of much attention. Here we review the chemistry of nitrones, the existing literature on their use as antioxidants and the general state of the art of antioxidant treatments for hearing loss.

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G6PDoverexpression protects from oxidative stress and age‐related hearing loss

Cited by 38 publications

References 49 publications

IGF-1 Haploinsufficiency Causes Age-Related Chronic Cochlear Inflammation and Increases Noise-Induced Hearing Loss

IGF-1 Haploinsufficiency Causes Age-Related Chronic Cochlear Inflammation and Increases Noise-Induced Hearing Loss

Dual-Specificity Phosphatase 1 (DUSP1) Has a Central Role in Redox Homeostasis and Inflammation in the Mouse Cochlea

Use of Radical Oxygen Species Scavenger Nitrones to Treat Oxidative Stress-Mediated Hearing Loss: State of the Art and Challenges

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