Hearing impairment in MELAS: new prospective in clinical use of microRNA, a systematic review

Aim To evaluate the feasibility of microRNAs (miR) in clinical use to fill in the gap of current methodology commonly used to test hearing impairment in MELAS patients. Material and method A literature review was performed using the following keywords, i.e., MELAS, Hearing Loss, Hearing Impairment, Temporal Bone, Otoacustic Emission (OTOAE), Auditory Brain Response (ABR), and microRNA. We reviewed the literature and focused on the aspect of the temporal bone, the results of electrophysiological tests in human clinical studies, and the use of miR for detecting lesions in the cochlea in patients with MELAS. Results In patients with MELAS, Spiral Ganglions (SG), stria vascularis (SV), and hair cells are damaged, and these damages affect in different ways various structures of the temporal bone. The function of these cells is typically investigated using OTOAE and ABR, but in patients with MELAS these tests provide inconsistent results, since OTOAE response is absent and ABR is normal. The normal ABR responses are unexpected given the SG loss in the temporal bone. Recent studies in humans and animals have shown that miRs, and in particular miRs 34a, 29b, 76, 96, and 431, can detect damage in the cells of the cochlea with high sensitivity. Studies that focus on the temporal bone aspects have reported that miRs increase is correlated with the death of specific cells of the inner ear. MiR − 9/9* was identified as a biomarker of human brain damage, miRs levels increase might be related to damage in the central auditory pathways and these increased levels could identify the damage with higher sensitivity and several months before than electrophysiological testing. Conclusion We suggest that due to their accuracy and sensitivity, miRs might help monitor the progression of SNHL in patients with MELAS

The Pathogenesis of Noise-Induced Hearing Loss is Mediated by the Activation of AMPK via LKB1 and CaMKKβ

Noise-induced hearing loss (NIHL) is a major public health issue and an unresolved clinical problem. Here we investigate pathomechanisms of auditory sensory cell death and suggest a novel target pathway for intervention. Cellular survival from stress depends upon maintenance of energy homeostasis, largely by the adenosine monophosphate-activated protein kinase (AMPK) which coordinates metabolic pathways with the energy demands of the cell. In response to traumatic noise exposure which resulted in hair cell death, levels of p-AMPKα increased in hair cells in a noise intensity-dependent manner. Inhibition of AMPK via administration of siRNA or a pharmacological inhibitor attenuated noise-induced losses of hair cells and synaptic ribbons, and preserved auditory sensitivity. The phosphorylation of liver kinase B1 (p-LKB1), an AMPK kinase, was increased by noise exposure in cochlear tissues. Additionally, the phosphorylation of calcium-calmodulin kinases I and IV (p-CaMKI/IV), the targets of calcium-calmodulin kinase kinase beta (CaMKKβ), an alternative AMPK kinase that is mediated by calcium, was increased in outer hair cells (OHCs) after the exposure. Inhibition of LKB1 or CaMKKβ by siRNA or knockout mice reduced OHC loss and NIHL. Finally, the increased p-AMPKα in OHCs after noise exposure was attenuated by silencing LKB1 or using CaMKKβ knockout mice. These results indicate that noise exposure leads to hair cell death by activating AMPK via LKB1- and CaMKKβ-mediated pathways, facilitating the pathogenesis of NIHL

Mechanisms of Aminoglycoside Ototoxicity and Targets of Hair Cell Protection

Aminoglycosides are commonly prescribed antibiotics with deleterious side effects to the inner ear. Due to their popular application as a result of their potent antimicrobial activities, many efforts have been undertaken to prevent aminoglycoside ototoxicity. Over the years, understanding of the antimicrobial as well as ototoxic mechanisms of aminoglycosides has increased. These mechanisms are reviewed in regard to established and potential future targets of hair cell protection

Molecular and Pathological Analyses of Three New Mouse Mutations That Affect Ear Development and Function

This dissertation presents three new mouse models that help to study the functions of Enpp1, Atp6v1b1, and Tbx1 for ear development and function. asj (aging with stiffened joints) carries a missense mutation in the mouse Enpp1 gene. Enpp1 encodes the enzyme ENPP1 that regulate soft-tissue calcification and bone mineralization, and is associated with generalized arterial calcification of infancy and hypophosphatemic rickets in human patients. asj mutant mice show severe middle ear infection and tissue calcification, which provide a new mouse model to study otitis media and tympanoscleorosis. Atp6v1b1 encode a protein that is a subunit of the V-ATPase pump, which is the key regulator of pH homeostasis. Atp6v1b1 mutation is associated with human distal renal tubular acidosis (dRTA) with hearing loss; however, Atp6v1b1 knockout mice have mild kidney phenotype and normal hearing. vtx (vortex) mice carry a missense mutation in the mouse Atp6v1b1 gene on a MRL.Mpj background, that shows severe hearing loss and vestibular dysfunction. Transfer the vtx mutation to a B6 background did not cause hearing loss, indicating genetic background effects underlie this variation. We performed linkage backcross to map the genetic loci that modify the degree of hearing loss on the two different background strains and found statistically significant linkage with a region on Chr13. Because MRL-vtx mice exhibit enlargements of the endolymphatic sac and duct in the inner ear but do not exhibit the overt metabolic acidosis characteristic of dRTA, they provide a new genetic model for nonsyndromic deafness with enlarged vestibular aqueducts. TBX1 haploinsufficieny is associated with human DiGeorge syndrome. Tbx1 knockout mice are embryonic lethal and ear morphogenesis stops around E10 in the mutant mice. Study showed expression of TBX1 in the stria vascularis and vestibular dark cells, but because Tbx1 KO mice don’t have fully developed inner ear, new model is required to study Tbx1 function at later development stage. Tbx1wdml (windmill) mice carry a missense mutation in the mouse Tbx1 gene and have fully developed inner ear. Hearing loss and vestibular dysfunction correlate well with TBX1 expression in the stria vascularis and dark cells. This new Tbx1 mouse model provides a valuable tool to study Tbx1 function in the development of stria vascularis and semicircular canal

Cellular glutathione content in the organ of Corti and its role during ototoxicity.

Glutathione (GSH) is the major scavenger of reactive oxygen species (ROS) inside cells. We used live confocal imaging in order to clarify the role of GSH in the biology of the organ of Corti, the sensory epithelium of the cochlea, before, during and after the onset of hearing and in ~1 year old mice. GSH content was measured using monochlorobimane (MCB), a non-fluorescent cell permeant bimane that reacts with GSH, forming a fluorescent adduct through a reaction catalyzed by glutathione-S-transferase. GSH content increased significantly in inner hair cells during maturation in young adult animals, whereas there was no significant change in the outer hair cells. However, the GSH content in inner hair cells was significantly reduced in ~1 year old mice. The GSH content of supporting cells was comparatively stable over these ages. To test whether the GSH content played a significant protective role during ototoxicity, GSH synthesis was inhibited by buthionine sulfoximine (BSO) in organotypic cochlear explant cultures from immature mice. BSO treatment alone, which reduced GSH by 65 and 85% in inner hair cells and outer hair cells respectively, did not cause any significant cell death. Surprisingly, GSH depletion had no significant effect on hair cell survival even during exposure to the ototoxic aminoglycoside neomycin. These data suggest that the involvement of ROS during aminoglycoside-induced hair cell death is less clear than previously thought and requires further investigation

Oxidative stress and inflammation induced by environmental and psychological stressors: a biomarker perspective

Significance. The environment can elicit biological responses such as oxidative stress (OS) and inflammation as consequence of chemical, physical or psychological changes. As population studies are essential for establishing these environment-organism interactions, biomarkers of oxidative stress or inflammation are critical in formulating mechanistic hypotheses. Recent advances. By using examples of stress induced by various mechanisms, we focus on the biomarkers that have been used to assess oxidative stress and inflammation in these conditions. We discuss the difference between biomarkers that are the result of a chemical reaction (such as lipid peroxides or oxidized proteins that are a result of the reaction of molecules with reactive oxygen species, ROS) and those that represent the biological response to stress, such as the transcription factor NRF2 or inflammation and inflammatory cytokines. Critical issues. The high-throughput and holistic approaches to biomarker discovery used extensively in large-scale molecular epidemiological exposome are also discussed in the context of human exposure to environmental stressors. Future directions. We propose to consider the role of biomarkers as signs and distinguish between signs that are just indicators of biological processes and proxies that one can interact with and modify the disease process

PROTECTION OF THE HAIR CELLS FROM THE OTOTOXIC EFFECT OF STREPTOMYCIN

Ototoxicity is the property of being toxic to the ear (oto), specifically the cochlea or auditory nerve and sometimes the vestibular system; it is commonly medication-induced. It has long been known that the major irreversible toxicity of aminoglycosides is ototoxicity. In many developing countries, where drugs such as the aminoglycosides are frequently prescribed to treat pneumonia, diarrhoea, and tuberculosis, the incidence of ototoxicity is high. Physicians in practice need to recognize that ototoxic drugs can cause significant auditory and in many instances, poorly recognized, vestibular toxicity. Aminoglycosides can cause eighth cranial nerve damage, resulting in vestibular and/or auditory toxicities. Aminoglycosides appear to generate free radicals within the inner ear, with subsequent permanent damage to sensory cells and neurons, resulting in permanent hearing loss. Two mutations in the mitochondrial 12S ribosomal RNA gene have been previously reported to predispose carriers to aminoglycoside-induced ototoxicity. As aminoglycosides are indispensable agents both in the treatment of infections and Menieres disease, a great effort has been made to develop strategies to prevent aminoglycoside ototoxicity. Efforts have been made against streptomycin toxicity using corticosteroid and Caffeic acid phenethyl ester. Chemicals are being evaluated for their ability to prevent ototoxicity and that might be prescribed in tandem with ototoxic drugs in the future. Investigators are also studying methods of hair-cell and nerve-cell regeneration